CN117820236A - Histone acetyltransferase small molecule inhibitor and preparation method and application thereof - Google Patents
Histone acetyltransferase small molecule inhibitor and preparation method and application thereof Download PDFInfo
- Publication number
- CN117820236A CN117820236A CN202310740267.3A CN202310740267A CN117820236A CN 117820236 A CN117820236 A CN 117820236A CN 202310740267 A CN202310740267 A CN 202310740267A CN 117820236 A CN117820236 A CN 117820236A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- compound
- branched
- linear
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 102000003893 Histone acetyltransferases Human genes 0.000 title abstract description 12
- 108090000246 Histone acetyltransferases Proteins 0.000 title abstract description 12
- 150000003384 small molecules Chemical class 0.000 title description 7
- -1 aryl carboxylic acid compounds Chemical class 0.000 claims abstract description 82
- 239000000203 mixture Substances 0.000 claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 239000000651 prodrug Substances 0.000 claims abstract description 11
- 229940002612 prodrug Drugs 0.000 claims abstract description 11
- 230000006195 histone acetylation Effects 0.000 claims abstract description 6
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 57
- 230000005764 inhibitory process Effects 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000004434 sulfur atom Chemical group 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 4
- 125000003435 aroyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 230000028709 inflammatory response Effects 0.000 claims description 3
- 229940124597 therapeutic agent Drugs 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000006319 alkynyl amino group Chemical group 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 230000003474 anti-emetic effect Effects 0.000 claims description 2
- 239000000043 antiallergic agent Substances 0.000 claims description 2
- 239000002111 antiemetic agent Substances 0.000 claims description 2
- 229940125683 antiemetic agent Drugs 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 230000001120 cytoprotective effect Effects 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000003205 fragrance Substances 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 239000002955 immunomodulating agent Substances 0.000 claims description 2
- 229940121354 immunomodulator Drugs 0.000 claims description 2
- 229940127084 other anti-cancer agent Drugs 0.000 claims description 2
- 229910052701 rubidium Inorganic materials 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
- 235000019634 flavors Nutrition 0.000 claims 1
- 229940124641 pain reliever Drugs 0.000 claims 1
- 230000021736 acetylation Effects 0.000 abstract description 13
- 238000006640 acetylation reaction Methods 0.000 abstract description 13
- 206010061218 Inflammation Diseases 0.000 abstract description 3
- 230000004054 inflammatory process Effects 0.000 abstract description 3
- 230000002018 overexpression Effects 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 32
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 26
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 20
- 239000000047 product Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 230000000694 effects Effects 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 101000978776 Mus musculus Neurogenic locus notch homolog protein 1 Proteins 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 108010040163 CREB-Binding Protein Proteins 0.000 description 11
- 102100021975 CREB-binding protein Human genes 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- SEDFZSHSBUXKAC-NIYFSFCBSA-N (2R)-2-[[(2S)-2-(4-cyanophenyl)propyl]amino]-N-[5-(1-methylpyrazol-4-yl)pyridin-2-yl]-2-phenylacetamide Chemical compound C(#N)C1=CC=C(C=C1)[C@@H](CN[C@@H](C(=O)NC1=NC=C(C=C1)C=1C=NN(C=1)C)C1=CC=CC=C1)C SEDFZSHSBUXKAC-NIYFSFCBSA-N 0.000 description 10
- 229940125508 CPI-1612 Drugs 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 108010033040 Histones Proteins 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000006947 Histones Human genes 0.000 description 6
- WZELXJBMMZFDDU-UHFFFAOYSA-N Imidazol-2-one Chemical compound O=C1N=CC=N1 WZELXJBMMZFDDU-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 150000002431 hydrogen Chemical class 0.000 description 6
- 239000011325 microbead Substances 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- ZSLZBFCDCINBPY-ZSJPKINUSA-N acetyl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 ZSLZBFCDCINBPY-ZSJPKINUSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 230000001973 epigenetic effect Effects 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- 101710155878 Histone acetyltransferase p300 Proteins 0.000 description 4
- 108010047956 Nucleosomes Proteins 0.000 description 4
- 206010060862 Prostate cancer Diseases 0.000 description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000002391 heterocyclic compounds Chemical class 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 150000002828 nitro derivatives Chemical class 0.000 description 4
- 210000001623 nucleosome Anatomy 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 208000034578 Multiple myelomas Diseases 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- 108010087230 Sincalide Proteins 0.000 description 3
- 108010090804 Streptavidin Proteins 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 238000010609 cell counting kit-8 assay Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- XYVMOLOUBJBNBF-UHFFFAOYSA-N 3h-1,3-oxazol-2-one Chemical compound OC1=NC=CO1 XYVMOLOUBJBNBF-UHFFFAOYSA-N 0.000 description 2
- NVKJOXRVEKMMHS-UHFFFAOYSA-N 5-nitro-1,2,4-triazol-3-one Chemical compound [O-][N+](=O)C1=NC(=O)N=N1 NVKJOXRVEKMMHS-UHFFFAOYSA-N 0.000 description 2
- 238000012815 AlphaLISA Methods 0.000 description 2
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 2
- 108010077544 Chromatin Proteins 0.000 description 2
- 102000003964 Histone deacetylase Human genes 0.000 description 2
- 108090000353 Histone deacetylase Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 102000005421 acetyltransferase Human genes 0.000 description 2
- 108020002494 acetyltransferase Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 210000003483 chromatin Anatomy 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 239000012160 loading buffer Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000000527 sonication Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- AXORVIZLPOGIRG-MRVPVSSYSA-N (2s)-2-phenylpropan-1-amine Chemical compound NC[C@@H](C)C1=CC=CC=C1 AXORVIZLPOGIRG-MRVPVSSYSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 1
- MNIKERWISBANET-UHFFFAOYSA-N 1-n-methyl-4-nitrobenzene-1,2-diamine Chemical compound CNC1=CC=C([N+]([O-])=O)C=C1N MNIKERWISBANET-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- HBVYOCJBEXSCQE-UHFFFAOYSA-N 2-phenylpropan-1-amine;hydrochloride Chemical compound Cl.NCC(C)C1=CC=CC=C1 HBVYOCJBEXSCQE-UHFFFAOYSA-N 0.000 description 1
- ZUJWUWOIJQZIKK-MRVPVSSYSA-N 4-[(2S)-1-aminopropan-2-yl]benzonitrile Chemical compound NC[C@@H](C)C1=CC=C(C#N)C=C1 ZUJWUWOIJQZIKK-MRVPVSSYSA-N 0.000 description 1
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 1
- TXAMXRHQYUGXOV-UHFFFAOYSA-N 5-nitro-1,3-dihydroimidazo[4,5-b]pyridin-2-one Chemical compound [O-][N+](=O)C1=CC=C2NC(=O)NC2=N1 TXAMXRHQYUGXOV-UHFFFAOYSA-N 0.000 description 1
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 102100025339 ATP-dependent DNA helicase DDX11 Human genes 0.000 description 1
- 238000011729 BALB/c nude mouse Methods 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- 102100039869 Histone H2B type F-S Human genes 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000722210 Homo sapiens ATP-dependent DNA helicase DDX11 Proteins 0.000 description 1
- 101001035372 Homo sapiens Histone H2B type F-S Proteins 0.000 description 1
- 101001112222 Homo sapiens Neural cell adhesion molecule L1-like protein Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000006180 TBST buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229940100228 acetyl coenzyme a Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- KAOMOVYHGLSFHQ-UTOQUPLUSA-N anacardic acid Chemical compound CCC\C=C/C\C=C/CCCCCCCC1=CC=CC(O)=C1C(O)=O KAOMOVYHGLSFHQ-UTOQUPLUSA-N 0.000 description 1
- 235000014398 anacardic acid Nutrition 0.000 description 1
- ADFWQBGTDJIESE-UHFFFAOYSA-N anacardic acid 15:0 Natural products CCCCCCCCCCCCCCCC1=CC=CC(O)=C1C(O)=O ADFWQBGTDJIESE-UHFFFAOYSA-N 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000007541 cellular toxicity Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 238000005370 electroosmosis Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 231100001129 embryonic lethality Toxicity 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- BKTKLDMYHTUESO-UHFFFAOYSA-N ethyl 2-bromo-2-phenylacetate Chemical compound CCOC(=O)C(Br)C1=CC=CC=C1 BKTKLDMYHTUESO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 210000003194 forelimb Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- RIVIDPPYRINTTH-UHFFFAOYSA-N n-ethylpropan-2-amine Chemical compound CCNC(C)C RIVIDPPYRINTTH-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 230000001124 posttranscriptional effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 description 1
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DWVQIDLQGUKRLS-SNVBAGLBSA-N tert-butyl n-[(2s)-2-(4-bromophenyl)propyl]carbamate Chemical compound CC(C)(C)OC(=O)NC[C@@H](C)C1=CC=C(Br)C=C1 DWVQIDLQGUKRLS-SNVBAGLBSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000006694 transcriptional co-activation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- 229910000166 zirconium phosphate Inorganic materials 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and relates to a Histone Acetyl Transferase (HAT) inhibitor, a preparation method and application thereof. In particular to aryl carboxylic acid compounds with a general formula (I), pharmaceutically acceptable salts, stereoisomers, prodrug molecules or a mixture thereof, a preparation method thereof and application of the aryl carboxylic acid compounds as histone acetylation inhibitors. Can be used for treating various diseases related to acetylation over-expression, mainly including tumor, inflammatory reaction, neurodegenerative diseases and the like.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a Histone Acetyl Transferase (HAT) inhibitor, a preparation method and application thereof.
Background
The prior art discloses that in the nucleus of eukaryotic cells, nucleosomes are the main structural elements of chromatin. The nucleosome is mainly composed of four histones (H2A, H2B, H3 and H4), which together with DNA entangled in histones constitute the nucleosome. Each histone protein has an evolutionarily conserved N-terminal tail extending outside the nucleosome. These tails are the target sites for many signaling pathways, resulting in post-transcriptional modifications. Acetylation is among the most common post-translational modifications in epigenetic science, and the level of acetylation is regulated by a dynamic balance of acetylation of Histone Acetyltransferases (HATs) and deacetylation of Histone Deacetylases (HDACs). Acetyl transferase transfers acetyl to amino group at tail of amino acid residue, neutralizes positive charge of lysine side chain, and reduces ability of forming salt bridge or electroosmosis, thereby loosening combination of chromatin and DNA, and promoting DNA transcription and combination.
Studies have disclosed that p300 (E1A-binding protein) and CBP (CREB-binding protein) are important macromolecular proteins in the family of acetyltransferases. p300 and CBP have a high degree of sequence homology and functional similarity and play a key transcriptional co-activation in many important cellular processes. Studies have shown that early embryonic lethality in p300/CBP knockout mice suggests that this gene plays an important role in normal development. Studies have shown that abnormal expression of p300/CBP is associated with a variety of human diseases such as inflammation, diabetes, heart disease and Huntington's chorea. It should be mentioned in particular that in many malignant tumors mutations of varying degrees of p300/CBP are observed. Abnormal acetylation of histone H3 results in prostate cancer, hepatocellular carcinoma, and lung cancer. The relationship between acetylation and autoimmune, metabolic, cardiovascular, neurological diseases and inflammatory responses is also widely reported. Therefore, the p300/CBP becomes an important potential medicinal target, and a plurality of pharmaceutical companies at home and abroad are actively laying out new drug development pipelines related to the targeted p300/CBP acetylation inhibitor. However, until now, there have been no reports of small molecule inhibitors entering clinical studies, and the reasons for these are probably related to poor physicochemical properties of the compounds, off-target effects in vivo, and poor pharmacokinetic properties. Therefore, researchers in the industry consider that there is an urgent need to develop p300/CBP acetylation inhibitors with high selectivity, excellent physicochemical properties, and high activity intensity.
Based on the current state of the art, the inventors of the present application have sought to provide small molecule inhibitors of histone acetyltransferase, methods of making and uses thereof.
Disclosure of Invention
The invention aims at providing a histone acetyltransferase small molecule inhibitor, a preparation method and application thereof based on the current state of the art.
In particular, the method comprises the steps of,
it is an object of the present invention to provide a Histone Acetyltransferase (HAT) inhibitor compound, a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate or isotopically-labeled compound (including tritium substitution).
It is a further object of the present invention to provide a process for preparing said inhibitor compounds.
It is a further object of the present invention to provide pharmaceutical compositions comprising said inhibitor compounds.
It is a further object of the present invention to provide the use of said inhibitor compounds in the manufacture of a medicament. According to one embodiment of the present invention, there is provided a compound represented by the general formula (I), a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, polytype, solvate or isotopically labeled compound thereof:
in the tool;
r1 is a benzene ring or a 5-7 membered aromatic heterocyclic ring, each ring having 1 to 3 substituents selected from Rb, the heteroatoms in the aromatic heterocyclic group being selected from the group consisting of oxygen, nitrogen and sulfur atoms;
ra and Rb are each independently of the other hydrogen, halogen, hydroxy, hydroxymethyl, mercapto, amino, cyano, nitro, carboxyl, ester, trifluoromethyl, trifluoromethoxy, C1-C6 linear alkyl or C3-C6 branched alkyl, C1-C6 linear haloalkyl or C3-C6 branched haloalkyl, C1-C6 linear alkoxy or C3-C6 branched alkoxy, C1-C6 linear haloalkoxy or C3-C6 branched haloalkoxy, C1-C6 linear alkylcarbonyloxy or C3-C6 branched alkylcarbonyloxy, C1-C6 linear hydroxyalkyl or C3-C6 branched hydroxyalkyl, and mercapto;
r2, R3 are the same or different and are each independently selected from the group consisting of hydrogen, fluorine, trifluoromethyl, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 branched alkyl, C3-C8 cycloalkyl, C3-C8 alkanoyl, C7-C8 aroyl, and 4-7 membered heterocyclyl containing oxygen, nitrogen, and/or sulfur atoms; wherein R2 and R3 may or may not together form a ring;
x, Y, Z are each independently CH or N;
w, Q are each independently CH, CRc, NH, NRc, O, S;
rc is selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, -ch=noh, haloalkyl, alkoxyalkoxy, formaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl.
The invention is defined as follows:
in the present invention, the halogen is selected from the group consisting of F, C, br and I.
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
In the present invention, the C1-C6 straight-chain alkyl group means a straight-chain alkyl group having 1 to 6 carbon atoms, and the C3-C6 branched-chain alkyl group means a branched-chain alkyl group having 3 to 6 carbon atoms, and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.
In the present invention, the straight-chain alkoxy group of Cl-C6 means a straight-chain alkoxy group having 1 to 6 carbon atoms, and the branched-chain alkoxy group of C3-C6 means a branched-chain alkoxy group having 3 to 6 carbon atoms, and includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.
In the present invention, the C1-C6 linear hydroxyalkyl group means a linear hydroxyalkyl group having 1 to 6 carbon atoms, and the C3-C6 branched hydroxyalkyl group means a linear hydroxyalkyl group having 3 to 6 carbon atoms, and includes, but is not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, and the like.
In the present invention, the C3-C8 cycloalkyl group means a cycloalkyl group having 3 to 8 carbon atoms in the ring, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the present invention, the C3-C8 alkanoyl group means an alkanoyl group having 3-8 carbon atoms, including, but not limited to, formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl and the like.
In the present invention, the C7-C8 aroyl refers to aroyl having 7 to 8 carbon atoms, including but not limited to benzoyl, phenylacetyl.
In the present invention, the 4-7 membered heterocyclic group containing oxygen, nitrogen and/or sulfur atom means a non-aromatic cyclic group containing 4-7 atoms in the ring and containing at least one hetero atom selected from the group consisting of O, N and S, and includes, but is not limited to, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl, piperidinyl and the like.
In the present invention, the 5-6 membered aromatic hetero group means an aromatic ring group having 5 to 6 atoms in the ring and at least one hetero atom selected from the group consisting of O, N and S, and includes, without limitation, thienyl, thiazolyl, pyridyl, furyl, pyranyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl, triazinyl and the like.
In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The substituent is the substituent correspondingly described in the previous description or the substituent appearing in each embodiment; thus, a substituted substituent means a group that, when referred to as substituted, replaces one or more hydrogen atoms on a particular group. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any of the substituent positions of the group, and the substituents may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
In a more preferred embodiment of the present invention, the compounds of the general formula (I) according to the invention are preferably from the group consisting of the following specific compounds:
the present invention provides a process for preparing a compound of the present invention, wherein the process is as shown in scheme one below:
scheme one:
in scheme one, a process for preparing compounds of formula (I) is provided. That is, an amino compound (formula G-1) and an ester-based compound (formula G-2) are reacted in an organic solvent under basic conditions. Examples of such bases include, but are not limited to, cesium carbonate, sodium hydroxide, potassium tert-butoxide, sodium hydrogen, n-butyllithium, diisopropylethylamine, lithium bis trimethylsilylamide, preferably lithium bis trimethylsilylamide; such as, but not limited to, N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, dichloromethane, dichloroethane, chloroform, preferably tetrahydrofuran.
Wherein R1, R2, R3, X, Y, Z, W, Q are as defined above.
Preparation of the intermediate:
a process for preparing an amino compound (formula G-1) from a heterocyclic compound of H-1 is provided in the above reaction scheme. That is, the heterocyclic compound of H-1 is reacted with concentrated nitric acid under acidic conditions, such as, but not limited to, sulfuric acid, hydrochloric acid, acetic acid, trifluoroacetic acid, preferably sulfuric acid. The above reaction scheme also gives a method for preparing an amino compound of H-2 from a nitro compound of H-1. That is, the nitro compound of H-1 is reacted under catalytic conditions with a source of hydrogen, such as, but not limited to, an ammonium chloride solution, a hydrochloric acid solution, hydrogen, including, but not limited to, iron powder, zinc chloride, tin chloride, metallic palladium.
Wherein, the definitions of X, Y, Z, W and Q are the same as the above.
Scheme II:
in scheme II, another method for preparing compounds of formula (I) is provided. That is, an amino compound (formula G-1) and a carboxyl compound (formula G-3) are reacted in an organic solvent under basic conditions. Examples of such bases include, but are not limited to, triethylamine, N, N-isopropylethylamine, potassium carbonate, sodium hydroxide, potassium oxy-hydroxide, potassium t-butoxide, sodium oxy-hydroxide, preferably N, N-diisopropylethylamine; such as, but not limited to, N-methylformamide, tetrahydrofuran, acetonitrile, dioxane, dichloromethane, dichloroethane, chloroform, preferably N, N-dimethylformamide.
Wherein R1, R2, R3, X, Y, Z, W, Q are as defined above.
Preparation of the intermediate:
another method for preparing an amino compound (formula G-1) from a heterocyclic compound of H-3 is provided in the above reaction scheme. That is, the heterocyclic compound of H-3 is reacted with N, N-carbodiimidazole in an organic solvent such as, but not limited to, N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, dichloromethane, dichloroethane, chloroform, preferably tetrahydrofuran. The above reaction scheme also provides a method for preparing an amino compound of H-2 from a nitro compound of H-1. That is, the nitro compound of H-1 is reacted under catalytic conditions with a source of hydrogen, such as, but not limited to, an ammonium chloride solution, a hydrochloric acid solution, hydrogen, including, but not limited to, iron powder, zinc chloride, tin chloride, metallic palladium.
Wherein, the definitions of X, Y, Z, W and Q are the same as the above.
In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of compounds of the above general formula (I), pharmaceutically acceptable salts, prodrug molecules, stereoisomers, enantiomers, diastereomers, atropisomers, racemates, polymorphs, solvates or isotopically labeled compounds thereof, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents. The auxiliary material may be, for example, an odorant, a flavoring agent, a sweetener, or the like.
The pharmaceutical compositions provided by the invention preferably contain 1-99% (e.g. 1,2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 or 99%) by weight of active ingredient, preferably in a proportion of 65-99% (e.g. 65, 70, 75, 80, 85, 90, 95 or 99%) by weight of the compound of formula (I) as active ingredient, the remainder being pharmaceutically acceptable carriers, excipients, adjuvants, diluents and/or saline solutions, based on the total weight of the pharmaceutical composition.
The compounds and pharmaceutical compositions provided herein may be in a variety of forms, such as tablets, capsules, powders, syrups, solutions, suspensions or aerosols, and the like, and may be presented as a suitable solid or liquid carrier or diluent and/or may be presented as a suitable sterile device for injection or infusion.
The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dose of the formulation comprises from 0.05 to 200mg (e.g. 0.05, 0.1, 0.2, 0.5, 1,2, 5, 10, 20, 50, 100, 150 or 200 mg) of a compound of formula (I), preferably from 0.1mg to 100mg (e.g. 0.1, 0.2, 05, 1,2, 5, 10, 20, 50 or 100 mg) of a compound of formula (I).
The compounds and pharmaceutical compositions of the present invention may be used clinically in mammals, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes of administration. Most preferably orally, most preferably at a daily dose of 0.01-200mg/kg body weight, for example 0.01, 0.05, 0.1, 02, 0.5, 1,2, 5, 10, 20, 50, 100, 150 or 200mg/kg body weight. Typically, the dosage may be gradually increased from a small dose until the most appropriate dosage is found at the time of use.
The present invention provides a histone acetylation inhibitor comprising one or more of the compounds selected from the above general formula (I), pharmaceutically acceptable salts, prodrug molecules, stereoisomers, diastereomers, or mixtures thereof, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents. The compounds and compositions of the present invention are useful for the treatment and prevention of diseases associated with histone acetylation, including tumors, inflammatory responses, neurodegenerative diseases, and the like.
The invention provides application of a compound shown in the general formula (I), pharmaceutically acceptable salt, stereoisomer or a composition thereof in preparing medicines for treating diseases related to histone acetylation inhibitors, such as tumors, inflammatory reactions, neurodegenerative diseases and the like. The use is carried out by using the compound of the general formula (I), pharmaceutically acceptable salt, prodrug molecule, stereoisomer or mixture thereof or the inhibitor.
The pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of any one of the general formula (I), a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate or isotopically labeled compound thereof, and a pharmaceutically acceptable carrier, diluent or excipient. Preferably, the pharmaceutical composition further comprises at least one other therapeutic agent, preferably the at least one other therapeutic agent comprised in the pharmaceutical composition is selected from the group consisting of other anticancer agents, immunomodulators, antiallergic agents, anti-emetics, pain relieving agents, cytoprotective agents and combinations thereof.
Drawings
FIG. 1 shows the inhibitory activity of different compounds on prostate cancer cell lines 22Rv1 and OPM-2 cells at test concentrations of 0.1. Mu.M to 10. Mu.M.
FIG. 2 shows the cytostatic activity exhibited by various compounds against acute myeloid leukemia and multiple myeloma cells; wherein "pro state" means prostate cancer; AMl represents acute myeloid leukemia; MM represents multiple myeloma; CAL-51 in other represents human breast cancer cells, JHH-7 represents human liver cancer cell line, and CHL1 represents human melanoma cells.
Figure 3 shows the change in tumor volume (left panel) and body weight (right panel) with time (days) after treatment.
FIG. 4 shows the target effect exhibited by the different compounds CPI-1612 and A11 in 22RV1 and OPM-2 cell lines, where "compound" represents compound and T (hr) represents time (hours).
Detailed Description
The invention will be further illustrated with reference to specific examples. The examples are not intended to limit the scope of the invention. The experimental methods described in the following examples, unless otherwise specified, are all conventional reagents: the reagents and materials, unless otherwise specified, are commercially available.
Example 1:
synthesis of chiral fragment N-1:
step one:
2-phenyl-1-propylamine hydrochloric acid quail (1-1, 10 g) was dissolved in absolute ethanol (50 mL), and sodium hydroxide (2.3)6g) Stirred for 60 minutes to form a milky suspension. And (5) filtering. The filtrate was warmed to 75℃and D-malic acid (1.9 g) was dissolved in absolute ethanol, and the mixture was stirred and then added dropwise, followed by heating and reaction for 30 minutes. Slowly cooling, standing for crystallization, and filtering. Dispersing the filter cake with 20mL of absolute ethyl alcohol, heating to 90 ℃, dropwise adding 90% ethanol water solution until the system is clear, and closing heating to slowly separate out white crystals. The crystallization process was repeated once more and the filter cake was added to dichloromethane (20 mL) and 1.0N sodium hydroxide solution was added dropwise until the solid was completely dissolved. The organic phase was separated, washed with saturated brine (2X 25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-2 (29 g) as a colorless transparent oil, LC-MS:136.1[ M+H ]] + ,[α] 25 D-43 ° (c, 4; water).
Step two:
(S) -2-phenyl-1-propylamine (2.5 g) was dissolved in 5mL of acetonitrile, 60mL of water was added, 9mL of trifluoroacetic acid and 3.7mL of concentrated sulfuric acid were slowly added dropwise under ice-bath conditions, and stirring was continued until clarification. The argon was replaced for protection, NBS (3.5 g) was added and the reaction was carried out overnight. Removing trifluoroacetic acid by distillation under reduced pressure, adjusting pH to 8 with sodium carbonate under ice bath, adding Boc 2 O (di-tert-butyl dicarbonate), after the reaction is finished, the mixture is extracted by ethyl acetate (3X 50 mL), dried by anhydrous sodium sulfate, filtered and dried by spin to obtain a crude product, and the crude product is separated and purified by column chromatography to obtain a pale yellow oily product (1-3, 5.1 g), LC-MS:214.1[ M+H ]] + , 1 H NMR(400MHz,Chloroform-d)7.32-7.37(m,2H),7.10-7.20(m,2H),2.63-2.88(m,3H),1.24(d,J=6.9Hz,3H)。
Step three:
tert-butyl (S) - (2- (4-bromophenyl) propyl) carbamate (1-3, 5 g) was dissolved in anhydrous DMF (30 mL), zinc cyanide (3 g), tetrakis (triphenylphosphine) palladium (350 mg) was added and the mixture was protected by replacing argon and reacted for 8 hours in an oil bath at 120 ℃. After completion of the reaction, TLC showed that ethyl acetate (200 mL) was added thereto for dilution, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried to give a crude product, which was separated and purified by column chromatography to give a pale yellow oily product. The resulting product was dissolved in 20mL of methylene chloride, 4mL of trifluoroacetic acid was added, the reaction was carried out for 2 hours, the mixture was dried by spinning, and the free trifluoroacetic acid was removed by adding methylene chloride. Column chromatography separation and purification gave pale yellow crystalline solid (1-4, 13 g), LC-MS:1601[ M+H ]] + 。
Step four:
(S) -4- (1-aminopropane-2-yl) benzonitrile (1-4, 1.3 g) was dissolved in anhydrous DMF (20 mL), and ethyl alpha-bromophenylacetate (2 g), which was protected by substituting argon, was added to triethylamine (1.2 mL), and the mixture was heated at 60℃in an oil bath to react overnight. After TLC showed completion of the reaction, ethyl acetate (200 mL) was added thereto for dilution, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give a crude product, which was isolated and purified by column chromatography to give a pale yellow oily product, 1 H NMR(400MHz,DMSO-d 6 ):1.08(t,J=6.8Hz,3H),1.16(d,J=6.8Hz,3H),2.35-2.44(m,1H),2.49-2.66(m,1H),2.96(q,J=6.8Hz,1H),3.96-4.06(m,2H),4.32(s,1H),7.26-7.42(m,7H),7.74(t,J=7.6Hz,2H).LC-MS:323.2[M+H] + 。
synthesis of chiral fragment N-2:
ethyl 2- (((S) -2- (4-cyanophenyl) propyl) amino) -2-phenylacetate (N-1, 966 mg) was dissolved in ethanol (10 mL), stirred at room temperature, 1M sodium hydroxide solution (5 mL) and tetrahydrofuran (5 mL) were added dropwise to the reaction system until the solution was clear, and stirring was continued for 20 minutes. The mixture was neutralized with 1M hydrochloric acid solution (pH 7), concentrated under reduced pressure, and filtered with ethanol to give 661mg of a white solid, LC-MS:295.2[ M+H ]] + 。
(R) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (A-1) [ (R) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide ]
(S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (A-2) [ (S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide ]
The synthetic route is as follows:
step one:
5-nitro-1, 3-dihydro-2H-benzo [ d ]]Imidazol-2-one (1 a,360 mg) was dissolved in methanol, palladium on carbon (36 mg) was added to replace hydrogen for reaction, and stirred at room temperature for 2 hours. The reaction was filtered through celite, and the filtrate was purified by spin-dry column chromatography to give the product (1 b,190 mg) as a colourless oil, LC-MS:150.2[ M+H ]] + 。
Step two:
2- (((S) -2- (4-cyanophenyl) propyl) amino) -2-phenylacetic acid (N-2, 294 mg) was dissolved in anhydrous DMF (5 mL), 570mg of HATU (2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate) and 270. Mu.L of DIPEA (N, N-diisopropylethylamine) were added, the mixture was protected with argon substitution, stirred at room temperature for 30 minutes, and 5-amino-1, 3-dihydro-2H-benzo [ d ] was added thereto]Imidazol-2-one (2 a,150 mg) was reacted for 4 hours. After completion of the reaction by TLC, ethyl acetate (100 mL) was added thereto for dilution, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and dried by spin-drying to give a crude product, which was purified by column chromatography to give a pale yellow oily product (1 c,85 mg), 1 H NMR(600MHz,Chloroform-d)δ9.38(s,1H),9.04(s,1H),8.83(s,1H),7.61(d,J=7.0Hz,2H),7.57(s,1H),7.48(s,1H),7.33(dd,J=13.0,7.9Hz,8H),6.89(d,J=8.5Hz,1H),4.24(s,1H),3.05(dd,J=11.7,4.3Hz,1H),2.96(q,J=6.1Hz,1H),2.85-2.77(m,1H),1.29(d,J=7.0Hz,3H),LC-MS:426.2[M+H] + 。
step three:
the product from the previous step, 2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (30 mg), was isolated by chiral preparative column to give (R) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (A-1, 12 mg) and (S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (A-2, 12 mg).
Example 2
2- (((R) -2- (4-cyanophenyl) propyl) amino) -N- (2-carbonyl-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2-phenylacetamide (A-3) [2- (((R) -2- (4-cyanophenyl) propyl) amino) -N- (2-oxo-2, 3-dihydropiezo [ d ] oxazol-6-yl) -2-phenylacetamide ]
2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-carbonyl-2, 3-dihydrobenzo [ d ] oxazol-6-yl) -2-phenylacetamide (A-4) [2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-oxo-2, 3-dihydropiezo [ d ] oxazol-6-yl) -2-phenylacetamide ]
The synthetic route is as follows:
step one:
5-Nitropheno [ d ]]Oxazol-2 (3H) -one (2 a,360 mg) was dissolved in methanol (5 mL), palladium on carbon (36 mg) was added to replace hydrogen for reaction, and stirred at air temperature for 2 hours. The reaction was filtered through celite, and the filtrate was purified by spin-dry column chromatography to give the product (1 b,207 mg) as a colourless oil, LC-MS:151.1[ M+H ]] + 。
Step two:
2- (((S) -2- (4-cyanophenyl) propyl) amino) -2-phenylacetic acid (N-2, 294 mg) was dissolved in anhydrous DMF (5 mL), 570mg HATU and 270. Mu.L DIPEA were added, protection was provided by argon substitution, stirring at room temperature for 30 min, and 5-aminobenzo [ d ] was added]Oxazol-2 (3H) -one (2 a,150 mg) was reacted for 4 hours. TLC showed completion of the reaction, diluted with ethyl acetate (100 mL) and taken on saturated foodWashing with brine, drying over anhydrous sodium sulfate, filtering, spin-drying to obtain crude product, separating and purifying by column chromatography to obtain pale yellow oily product (1 c,85 mg), 1 H NMR(600MHz,Chloroform-d)δ9.14(s,1H),8.89(s,1H),7.65(d,J=7.0Hz,2H),7.55(s,1H),7.49(s,1H),7.43(dd,J=13.0,7.9Hz,8H),6.91(d,J=8.5Hz,1H),4.25(s,1H),3.05(dd,J=11.7,4.3Hz,1H),2.97(q,J=6.1Hz,1H),2.85-2.77(m,1H),1.29(d,J=7.0Hz,3H),LC-MS:427.2[M+H] + 。
step three:
the product from the previous step, 2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (30 mg), was isolated by chiral preparative column to give (S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-carbonyl-2, 3-dihydrobenzo [ d ] oxazol-5-yl) -2-phenylacetamide (a-3, 11 mg) and (S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (2-carbonyl-2, 3-dihydrobenzo [ d ] oxazol-5-yl) -2-phenylacetamide (a-4, 10.6 mg).
Example 3
(R) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide [ (R) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (1, 3-dimethyl-2-oxo-2, 3-dihydro-1H-benzod ] imidozol-5-yl) -2-phenacetamide ]
(S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide [ (S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (1, 3-dimethyl-2-oxo-2, 3-dihydro-1H-benzod ] imidozol-5-yl) -2-phenacetamide ]
The synthetic route is as follows:
step one:
5-nitro-1, 3-dihydro-2H-benzo [ d ]]Imidazole-2-one (1 a,360 mg) was dissolved in anhydrous DMSO (5 mL), the protection was performed by replacing argon gas, sodium hydroxide solid (200 mg) was added, and methyl iodide (273. Mu.L) was added dropwise after stirring and reaction was continued for 4 hours. After TLC showed completion of the reaction, ethyl acetate (100 mL) was added thereto for dilution, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give a crude product, which was separated and purified by column chromatography to give a bright yellow solid (3 b,332 mg), 1 H NMR(Chloroform-d)δ8.72(s,1H),8.05(s,J=8.2Hz,1H),8.05(s,J=8.2Hz,1H),3.81(s,3H),3.80(s,3H)。
step two:
1, 3-dimethyl-5-nitro-1, 3-dihydro-2H-benzo [ d ]]Imidazol-2-one (1 a,330 mg) was dissolved in methanol (5 mL), palladium on carbon (33 mg) was added to replace hydrogen for reaction, and stirred at room temperature for 2 hours. The reaction was completed with celite filtration, and the filtrate was purified by spin-dry column chromatography to give a colorless oily product (3 b,167 mg), 1 H NMR(Chloroform-d)δ7.72(s,1H),7.05(s,J=8.2Hz,1H),6.16(s,1H),3.87(s,3H),3.88(s,3H),LC-MS:178.1[M+H] + 。
step three:
2- (((S) -2- (4-cyanophenyl) propyl) amino) -2-phenylacetic acid (N-2, 294 mg) was dissolved in 5mL of anhydrous DMF, 570mg of HATU and 270. Mu.L of DIPEA were added, the mixture was protected by replacing argon, stirred at room temperature for 30 minutes, and 1, 3-dimethyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] was added]Imidazol-2-one (3 c,150 mg) was reacted for 4 hours. After completion of the reaction by TLC, ethyl acetate (100 mL) was added thereto for dilution, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and dried by spin-drying to give a crude product, which was isolated and purified by column chromatography to give a pale yellow oily product (1 c,95 mg), 1 H NMR(600MHz,Chloroform-d)δ9.38(s,1H),7.61(d,J=7.0Hz,2H),7.57(s,1H),7.48(s,1H),7.33(dd,J=13.0,7.9Hz,8H),6.89(d,J=8.5Hz,1H),4.24(s,1H),3.89(s,3H),3.90(s,3H),3.05(dd,J=11.7,4.3Hz,1H),2.96(q.J=6.1Hz,1H),2.85-2.77(m,1H),1.29(d,J=7.0Hz,3H),LC-MS:454.2[M+H] + 。
step four:
the product obtained in the previous step, namely 2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (30 mg), was separated by chiral preparative column to give (R) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (A-5, 11.3 mg) and (S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (A-6, 10.6 mg).
Example 4
(R) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (3-methyl-2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide [ (R) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide ]
(S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (3-methyl-2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide [ (S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (3-methyl-2-oxo-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide ]
/>
Step one:
n1-methyl-4-nitrobenzene-1, 2-diamine (4 a,836 mg) was dissolved in anhydrous tetrahydrofuran (10 mL), the protection was performed by replacing argon, CDI (N, N' -carbonyldiimidazole, 852 mg) was added, the mixture was reacted under heating at 65℃for 2 hours, the solvent was removed under reduced pressure, and the pale yellow solid (4 b, 292 mg) was obtained by column chromatography separation and purification.
Step two:
1-methyl-5-nitro group-1, 3-dihydro-2H-benzo [ d ]]Imidazole-2-one (1 a,330 mg) was dissolved in 5mL of methanol, palladium on carbon (33 mg) was added thereto, and hydrogen was exchanged for reaction, and the mixture was stirred at room temperature for 2 hours. The reaction was completed with celite filtration, the filtrate was dried by spin-drying, and the product (3 b,167 mg) was isolated and purified by column chromatography as a colorless oil, 1 H NMR(Chloroform-d)δ8.71(s,1H),8.01(s,J=8.2Hz,1H),8.01(s,J=8.2Hz,1H),3.80(s,3H),LC-MS:194.2[M+H] + 。
step three:
2- (((S) -2- (4-cyanophenyl) propyl) amino) -2-phenylacetic acid (N-2, 294 mg) was dissolved in anhydrous DMF (5 mL), HATU (570 mg) and DIPEA (270. Mu.L) were added, argon was replaced for protection, stirring was performed at room temperature for 30 minutes, and 1, 3-dimethyl-5-nitro-1, 3-dihydro-2H-benzo [ d ] was added]Imidazol-2-one (3 c,150 mg) was reacted for 4 hours. After completion of the reaction by TLC, ethyl acetate (100 mL) was added thereto for dilution, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and dried by spin-drying to give a crude product, which was isolated and purified by column chromatography to give a pale yellow oily product (1 c,95 mg), 1 H NMR(600MHz,Chloroform-d)δ9.21(s,1H),7.85(d,J=7.0Hz,2H),7.51(s,1H),7.48(s,1H),7.33(dd,J=13.0,7.9Hz,8H),7.29(d,J=8.5Hz,1H),5.04(s,1H),3.89(s,3H),3.05(dd,J=11.7,4.3Hz,1H),2.94(q,J=6.1Hz,1H),2.75-2.67(m,1H),1.27(d,J=7.0Hz,3H),LC-MS:440.2[M+H] + 。
step four:
the product obtained in the previous step, namely 2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (30 mg), was separated by chiral preparative column to give (R) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (A-7, 10.1 mg) and (S) -2- (((S) -2- (4-cyanophenyl) propyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-benzo [ d ] imidazol-5-yl) -2-phenylacetamide (A-8, 9.4 mg).
Corresponding haloalkanes and starting materials are selected through similar synthetic routes to prepare A-9 to A18.
Example 5
(R) -2- (((1- (4-cyanophenyl) cyclopropyl) methyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-imidazo [4, 5-b)]Pyridin-5-yl) -2-phenylacetamide [ (R) -2- (((1- (4-cyanophenyl) cyclopyl) methyl) amino) -N- (1, 3-dimethyl-2-oxo-2, 3-dihydro-1H-imidozo [4, 5-b)]pyridin-5-y l )-2-phenylacetamide]
(S) -2- (((1- (4-cyanophenyl) cyclopropyl) methyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-5-yl) -2-phenylacetamide [
(S)-2-(((1-(4-cyanophenyl)cyclopropyl)methyl)amino)-N-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl)-2-phenylacetamide]
Step one:
5-nitro-1, 3-dihydro-2H-imidazo [4,5-b]Pyridine-2-one (1 a,360 mg) was dissolved in anhydrous DMSO (5 mL), replaced with argon for protection, sodium hydroxide solid (200 mg) was added, and methyl iodide (273. Mu.L) was added dropwise after stirring for 10 minutes for reaction, and the reaction was continued for 4 hours. After TLC showed completion of the reaction, ethyl acetate (100 mL) was added thereto for dilution, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by spin-drying to give a crude product, which was separated and purified by column chromatography to give a bright yellow solid (3 b,332 mg), 1 H NMR(400MHz,Chloroform-d)δ8.15(d,J=8 . 2Hz,1H),7.32(d,J=8.0Hz,1H),3.58(s,2H),3.52(s,1H)。
step two:
1, 3-dimethyl-5-nitro-1, 3-dihydro-2H-benzo [ d ]]Imidazol-2-one (1 a,330 mg) was dissolved in methanol (5 mL), palladium on carbon (33 mg) was added to replace hydrogen for reaction, and stirred at room temperature for 2 hours. The reaction was completed with celite filtration, and the filtrate was purified by spin-dry column chromatography to give a colorless oily product (3 b,167 mg), 1 H NMR(400MHz,Chloroform-d)δ7.00(d,J=8.0Hz,1H),6.21(d,J=8.4Hz,1H),3.41(s,3H),3.37(s,3H),LC-MS:179.1[M+H] + 。
step three:
ethyl 2- (((1- (4-cyanophenyl) cyclopropyl) methyl) amino) -2-phenylacetate (N-3, 334 mg) was dissolved in anhydrous tetrahydrofuran (10 mL), and 5-amino-1, 3-dimethyl-1, 3-dihydro-2H-imidazo [4, 5-b) was added]Pyridine-2-one (180 mg), protected with argon, was cooled in an ice bath for 10 minutes, liHMDS (1M, 1.5 mL) was added thereto, and the reaction was continued for 4 hours. After TLC showed completion of the reaction, ethyl acetate (100 mL) was added thereto for dilution, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spun-dried to give the crude product as a pale yellow oily product (5 d,80 mg), which was isolated and purified by column chromatography, LC-MS:467.2[ M+H ]] + 。
Step four:
the product obtained in the previous step, namely 2- (((1- (4-cyanophenyl) cyclopropyl) methyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-5-yl) -2-phenylacetamide (30 mg) was isolated by chiral preparative column to give ((R) -2- (((1- (4-cyanophenyl) cyclopropyl) methyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-5-yl) -2-phenylacetamide (a-19, 8.9 mg) and (S) -2- (((1- (4-cyanophenyl) cyclopropyl) methyl) amino) -N- (1, 3-dimethyl-2-carbonyl-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-5-yl) -2-phenylacetamide (a-20, 9.6 mg).
Fifth embodiment: biological Activity test
Inhibition assay of histone acetyltransferase p300 Activity at molecular level
Test purpose:
determination of the molecular inhibitory Activity of the Compounds of the invention against the p300 protein
Test principle:
an Aphalisa method is adopted to establish an enzyme activity test method. In this experiment, histone acetyltransferase p300 transfers acetyl on acetyl-coa to histone H3K9, which is acetylated, and inhibition of p300 by the compound can be achieved by detecting the degree of acetylation of the H3K9 site. The H3 biotinylated substrate was bound to donor microbeads. The receptor microbeads coupled with the specific anti-H3K 9 acetylation antibody are also combined with the site of acetylation, if the degree of acetylation is high, the receptor microbeads combined with the substrate are more, and the donor microbeads and the receptor microbeads can interact, so that 615nm optical signals are generated. The intensity of the optical signal is related to the acetylation degree of the H3K9 locus, so that the inhibition effect of the compound on p300 can be reflected.
The test method comprises the following steps:
1. p300 enzyme (EP 300 enzyme), acetyl CoA (acetyl coenzyme A, COA)), inhibitor and Histone H3 peptide (Histone H3 (1-21) peptide) were diluted with Assay buffer (Assay buffer).
2. The following reagents were added sequentially to 384 microplate whites:
---5μL of inhibitor(2X)or Assay Buffer
---2.5μL of enzyme(4X)
---2.5μL of Histone H3(1-21)peptide/acetyl COA mix(4X)
3. the microwell plates were blocked with Topseal, mixed well with shaker and incubated for 90 min at room temperature.
4. 1X epigenetic analysis buffer (Epigenetic Buffer 1) was prepared.
5. A mixture of Anti-acetyl-Histone H3 Lysine 9 (H3K 9 Ac) AlphaLISA Acceptor Beads (100. Mu.g/mL) and anacardic acid (250. Mu.M) was prepared by 1X Epigenetic Buffer1 at a final concentration of 20 ng/. Mu.L, 50. Mu.M, respectively.
6. Add 5. Mu.L of diluted Anti-acetate-Histone H3 Lysine 9 (H3K 9 Ac) AlphaLISA Acceptor Beads mix, seal, shake mix and incubate for 60 minutes.
7. Streptavidin-coupled microbeads (Streptavidin Donor beads) (50. Mu.g/mL) were configured with 1X Epigenetic Buffer1 at a final concentration of 20 ng/. Mu.L.
8. 10. Mu.L of Streptavidin Donor beads was added and incubated for 30 minutes under sealed light protection.
8. EnVision multifunctional microplate reader was used.
Two pairs of holes are arranged in each group of experiments, and a blank control group is arranged
The inhibition (%) of the enzyme activity by the compound was calculated using the following formula:
inhibition (%) = (Fluor control well-Fluor dosing well)/Fluor control well x 100%
Calculating corresponding IC according to each concentration inhibition rate 50 。
The test results are as follows:
numbering of compounds | IC 50 (μM) | Compounds of formula (I) | IC 50 (μM) |
A1 | 0.296 | A14 | 2.948 |
A2 | >3 | A15 | 1.620 |
A3 | >3 | A16 | >3 |
A4 | >3 | A17 | 3.620 |
A5 | 2.132 | A18 | >3 |
A6 | >3 | A19 | 2.118 |
In 7 | 1.271 | A20 | >3 |
A8 | >3 | A21 | |
A9 | >3 | A22 | |
A10 | >3 | A23 | |
A11 | 0.007 | A24 | |
A12 | 1.066 | A-485 | 0.145 |
A13 | 0.151 | CPI-1612 | 0.004 |
The A-485 is a p300/CBP small molecule inhibitor reported by AbbVie in 2017, and is a common positive control drug for the target. CPI-1612 is a p300/CBP small molecule inhibitor reported in Constellation Pharmaceuticals 2020, and its structural type is very different from that of A-485. The structural formulas of CPI-1612 and A-485 are shown below:
the results showed that A13 was comparable to A-485 activity, while A11 was significantly better than A-485 and comparable to CPI-1612 activity.
Example six: biological Activity test
Cell level histone acetyltransferase p300 Activity inhibition assay
Test purpose: evaluation of Compounds' influence on cell proliferation Effect
Test principle:
the growth of cells can be represented by an increase in the number of cells and an increase in the volume of cells, which is usually within a certain range, whereas cells can increase the number of cells by being continuously divided, so that the number of cells is an index reflecting the state and degree of cell growth. The CCK-8 chromogenic agent can reduce tetrazolium salt WST-8[2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disufo-phenyl) -2H-tetrazolium by utilizing dehydrogenase possessed by cells per se to generate a water-soluble yellow product formazan, and the number of living cells is proportional to the amount of formazan dye generated, so that the method can be used for detecting the number of the living cells in cell proliferation and toxicity analysis experiments.
The test method comprises the following steps:
proliferation inhibition of different cell lines by the compounds was tested using the CCK-8 cell counting kit (Dojindo). The specific steps for detecting the inhibition of the proliferation of the tumor cells by the compound are as follows: cells in the logarithmic growth phase were seeded at the appropriate density (22 RV 1:2K/well, OPM-2:5K/well) in 96-well plates at 200. Mu.L per well, incubated overnight, and a gradient diluted compound stock solution at an initial concentration of 10mM was added for 6 days and a blank group was set. After 6 days of compound action on the cells, 10. Mu.L of CCK-8 reagent was added to each well, and after incubation in an incubator at 37℃for 3 hours, OD at 450nm was measured with a full-wave microplate reader SpectraMax 190. The inhibition (%) of the compound on tumor cell growth was calculated using the following formula:
inhibition (%) = (OD control well-OD dosing well)/OD control well x 100%
Calculating corresponding IC according to each concentration inhibition rate 50 。
Experimental results:
the inhibitory activity of the compounds at concentrations of 0.1. Mu.M to 10. Mu.M on the prostate cancer cell line 22Rv1 and OPM-2 cells is shown in FIG. 1, and it can be seen that our compound A11 has an equivalent activity on OPM-2 to CPI-1612, and shows a more pronounced inhibitory activity on 22Rv1 at 0.1. Mu.M. Also showed significantly better cytostatic activity against both acute myeloid leukemia and multiple myeloma cells than positive compound a-485 (figure 2).
Example seven biological Activity test
Inhibition assay of in vivo levels of histone acetyltransferase p300 activity
Test purpose: test of the anti-tumor efficacy of Compounds on the OPM-2 nude mice subcutaneous transplantation tumor model
The test method comprises the following steps:
animals were housed adaptively for one week prior to the experiment using Balb/C nude mice (6 weeks, female, available from Shanghai Ling Biotechnology Co., ltd.). In vitro expansion of OPM-2 cells, suspension of cells in log phase in serum-free RPMI1640 medium, injection of 100 μl (5.0X10) of cell suspension into the armpit of right forelimb 6 And (c) a). Dynamic movementThe experimental procedure was performed strictly according to the ethical guidelines of animal experiments. Average tumor volume of tumor-bearing mice reaches 50-100mm 3 At this time, the mice were divided into two groups by random differentiation: the solvent control group and the compound group were dosed daily, and tumor volumes were tested three times every three days and weighed. Tumor Volume (TV) calculation formula: tv=1/2×a×b 2 Wherein a and b represent length and width, respectively. The tumor inhibition ratio (tumor growth inhibition, TGI) is calculated according to the measurement result, and the calculation formula is as follows: TGI= [1-RTV (experimental group)/RTV (control group)]*100%。
Experimental results:
a11 and CPI-1612 were dosed at 5mg/kg on an OPM-2 nude mice subcutaneous graft model, and group A11 was set with a halved dose of 2.5 mg/kg. From the tumor volumes of fig. 3, it can be seen that our compounds significantly inhibited tumor growth, still significantly effective at halved doses, and had less side effects relative to CPI-1612.
Western blot (Western blot)
Tumor tissue pieces (about 20 mg) were isolated subcutaneously from mice, 200 μl of RIPA lysate (containing protease inhibitor and phosphatase inhibitor) was added, the tissue pieces were cut into small pieces on ice, the pieces were thoroughly lysed by sonication (Apml 45%), and the sonication was stopped when no macroscopic pieces were visible. Centrifuging at 15000rpm in a pre-cooled centrifuge at 4deg.C for 15-20min, collecting supernatant, and quantifying by BCAF method. According to the quantitative result, 4 Xprotein Loading buffer (Loading buffer) (200 mM Tris-HCl pH 6.8, 100mM DTT,2%SDS,20% glycerol, 1mM sodium vanadate, 0.1% bromophenol blue) was added to dilute to 1X, and the excess was made up with 2% SDS, and the metal bath was continued at 100℃for 10min. SDS-PAGE was performed on 7. Mu.L samples per well. After electrophoresis, the protein is transferred to a nitrocellulose membrane by a full-automatic rapid wet transfer instrument, the approximate position of the target protein is determined according to the size of a Marker, and the target protein is cut into strips with proper size. The cellulose membrane strips were blocked 1h in 3% BSA and incubated overnight at 4 ℃ in primary antibody buffer. The next day the strip is washed with TBST, and finally the cellulose membrane printed with protein is incubated with the prepared secondary antibody solution for 1h at room temperature; after washing the strips three times, chromogenic imaging was performed with Millipore (Millipore, USA) reagents in an imagequat imaging system.
On 22RV1 and OPM-2 cell lines, CPI-1612 and A11 start to act after 7 hours of administration, can still keep the inhibition effect for 72 hours, presents a stronger target effect, and has no obvious difference between different time points; at the same time point, compounds CPI-1612 and a11 both exhibited stronger target effect than positive compound a485 (see fig. 4).
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or equivalent substitutions can be made to some technical features; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. An aryl carboxylic acid compound represented by the general formula (I), a pharmaceutically acceptable salt, stereoisomer, prodrug molecule or a mixture thereof:
in the tool;
r1 is phenyl or a 5-6 membered aromatic heterocyclic ring, each of said aromatic heterocyclic rings having 1 to 3 substituents selected from Rb, the heteroatoms in said aromatic heterocyclic ring being selected from the group consisting of oxygen, nitrogen and sulfur atoms;
ra and Rb are each independently of the other hydrogen, halogen, hydroxy, hydroxymethyl, mercapto, amino, cyano, nitro, carboxyl, ester, trifluoromethyl, trifluoromethoxy, C1-C6 linear alkyl or C3-C6 branched alkyl, C1-C6 linear haloalkyl or C3-C6 branched haloalkyl, C1-C6 linear alkoxy or C3-C6 branched alkoxy, C1-C6 linear haloalkoxy or C3-C6 branched haloalkoxy, C1-C6 linear alkylcarbonyloxy or C3-C6 branched alkylcarbonyloxy, C1-C6 linear hydroxyalkyl or C3-C6 branched hydroxyalkyl, and mercapto;
r2, R3 are each independently selected from the group consisting of hydrogen, fluorine, trifluoromethyl, C1-C6 linear or C3-C6 branched alkyl, C3-C8 cycloalkyl, C3-C8 alkanoyl, C7-C8 aroyl, and 4-7 membered heterocyclyl containing oxygen, nitrogen, and/or sulfur atoms; wherein R2 and R3 together form a ring or do not form a ring;
x, Y, Z are each independently CH or N;
w, Q are each independently CH, CRc, NH, NRc, O, S;
rc is selected from alkyl, alkenyl, alkynyl, hydroxyalkyl, aliphatic acyl, alkynylamino, alkoxycarbonyl, heterocyclic acyl, -ch=noh, haloalkyl, alkoxyalkoxy, formaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl.
2. The aryl carboxylic acid compound of the general formula (I), pharmaceutically acceptable salts, stereoisomers, prodrug molecules or mixtures thereof according to claim 1, wherein:
r1 is phenyl, each phenyl has 1 to 3 substituents selected from Rb;
ra, rb are each independently selected from halogen, cyano, hydroxy, hydroxymethyl, trifluoromethyl;
r2, R3 are each independently selected from hydrogen, halogen, hydroxy, hydroxymethyl, ester, trifluoromethyl, trifluoromethoxy, C1-C6 straight chain alkyl or C3-C6 branched alkyl,
x, Y, Z are each independently CH or N;
w, Q are each independently CH, CRc, NH, NRc, O, S.
3. The aryl carboxylic acid compound of general formula (I), pharmaceutically acceptable salts, stereoisomers, prodrug molecules or mixtures thereof according to claim 1, wherein said compound is selected from the group consisting of compounds A1 to a 24:
4. use of a compound according to claim 1, a pharmaceutically acceptable salt or stereoisomer thereof or a prodrug molecule thereof or a mixture thereof for the preparation of a histone acetylation inhibitor.
5. The use of a compound of claim 1, a pharmaceutically acceptable salt, stereoisomer, prodrug molecule thereof, or a mixture thereof, for the manufacture of a medicament for the treatment of a disease associated with histone acetylation inhibition.
6. The use according to claim 5, wherein the disease is selected from one or more of a tumor, an inflammatory response and a neurodegenerative disease.
7. A pharmaceutical composition comprising a therapeutically effective amount of the aryl carboxylic acid compound of any one of claim 1, a pharmaceutically acceptable salt, stereoisomer, prodrug molecule, or a mixture thereof, and a pharmaceutically acceptable carrier, diluent, and/or excipient.
8. The composition of claim 7, wherein the pharmaceutical composition comprises at least one additional therapeutic agent; selected from other anticancer agents, immunomodulators, antiallergic agents, antiemetics, pain reliever, cytoprotective agents and combinations thereof.
9. The pharmaceutical composition according to claim 7 or 8, wherein the compound, a pharmaceutically acceptable salt or stereoisomer thereof or a prodrug molecule thereof or a mixture thereof comprises 20% to 99% of the total weight of the pharmaceutical composition.
10. The pharmaceutical composition of any one of claims 7 to 9, wherein the composition comprises one or more pharmaceutically acceptable carriers, odorants, flavours, excipients and/or diluents.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2022106998425 | 2022-06-20 | ||
CN202210699842 | 2022-06-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117820236A true CN117820236A (en) | 2024-04-05 |
Family
ID=90506533
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310740267.3A Pending CN117820236A (en) | 2022-06-20 | 2023-06-20 | Histone acetyltransferase small molecule inhibitor and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117820236A (en) |
-
2023
- 2023-06-20 CN CN202310740267.3A patent/CN117820236A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2672530T3 (en) | Heterocyclic amides as kinase inhibitors | |
EP1845978B1 (en) | Substituted pyrazolo-pyridines, compositions containing them, method for the production thereof, and their use | |
KR101486026B1 (en) | Derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine and uses thereof | |
JP7320263B2 (en) | EZH2 inhibitors and uses thereof | |
KR101118807B1 (en) | ?-substituted hydroxyaryl derivatives | |
EP3068785A1 (en) | Substituted 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine derivatives as casein kinase 1 d/e inhibitors | |
EP2949647B1 (en) | Deuterated phenyl amino pyrimidine compound and pharmaceutical composition containing same | |
JPH11302173A (en) | Histone deacetylase inhibitor | |
CA2965512C (en) | Trifluoromethyl alcohols as modulators of ror.gamma.t | |
KR20160094980A (en) | (6s,9as)-n-benzyl-6-[(4-hydroxyphenyl)methyl]-4,7-dioxo-8-({6-[3-(piperazine-1-yl)azetidine-1-yl]pyridine-2-yl}methyl)-2-(prop-2-en-1-yl)-octahydro-1h-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide compound | |
MX2014014622A (en) | Pyrrolo[2,1-f][1,2,4]triazine compound, and preparation method and application thereof. | |
EP3590920A1 (en) | 2-(substituted benzene matrix) aromatic formate fto inhibitor, preparation method therefor, and applications thereof | |
US11780841B2 (en) | 3,6-methano-1H-pyrrolo[3,2-b]pyridine and 3,6-methano-1H-pyrrolo[3,2-c]pyridine compounds and medicaments using same | |
KR100696139B1 (en) | Alkylcarbamoyl naphthalenyloxyoctenoylhydroxyamide derivatives having inhibitory activity against histone deacetylase and preparation thereof | |
HUE024989T2 (en) | Derivatives of azaindoles as inhibitors of protein kinases abl and src | |
WO2019120237A1 (en) | Indoleamine-2,3-dioxygenase inhibitor, preparation method therefor, and application thereof | |
Biasotti et al. | Synthesis of photoactivable inhibitors of osteoclast vacuolar ATPase | |
EP3083624B1 (en) | Tetrahydro-tetrazolo[1,5-a]pyrazines as ror-gamma inhibitors | |
CN114437113B (en) | Thiazolopyridine cyclotriazole compound, and preparation method and application thereof | |
CN110028508A (en) | A kind of antitumor diazo bicyclic class apoptosis protein inhibitor | |
CN117820236A (en) | Histone acetyltransferase small molecule inhibitor and preparation method and application thereof | |
JP7110335B2 (en) | Pyridoquinazoline derivatives useful as protein kinase inhibitors | |
CN110407770B (en) | 3-substituted-1, 5-benzazepine compound and pharmaceutical use thereof | |
CN116390923A (en) | Heterocyclic derivative and preparation method and application thereof | |
WO2021082181A1 (en) | Set8 lysine methyltransferase inhibitor, preparation method therefor, and use thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication |