CN109988124B - 一种含氧族元素二唑或四氮唑结构的肾型谷氨酰胺酶变构位点的抑制剂 - Google Patents
一种含氧族元素二唑或四氮唑结构的肾型谷氨酰胺酶变构位点的抑制剂 Download PDFInfo
- Publication number
- CN109988124B CN109988124B CN201811629951.XA CN201811629951A CN109988124B CN 109988124 B CN109988124 B CN 109988124B CN 201811629951 A CN201811629951 A CN 201811629951A CN 109988124 B CN109988124 B CN 109988124B
- Authority
- CN
- China
- Prior art keywords
- diazole
- selenadiazole
- tumor
- inhibitor
- glutaminase
- 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.)
- Active
Links
- 102000009127 Glutaminase Human genes 0.000 title claims abstract description 18
- 108010073324 Glutaminase Proteins 0.000 title claims abstract description 18
- 230000003281 allosteric effect Effects 0.000 title claims abstract description 17
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 239000003112 inhibitor Substances 0.000 title claims abstract description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 125000003831 tetrazolyl group Chemical group 0.000 title abstract 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 10
- 201000011510 cancer Diseases 0.000 claims abstract description 7
- 201000007270 liver cancer Diseases 0.000 claims abstract description 6
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims abstract description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 claims description 9
- 230000004060 metabolic process Effects 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
- 229930195712 glutamate Natural products 0.000 claims description 3
- 208000012902 Nervous system disease Diseases 0.000 claims description 2
- 208000025966 Neurological disease Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- -1 thiadiazole compound Chemical class 0.000 abstract description 45
- BUOKUWQCVSZNCF-UHFFFAOYSA-N selenadiazole Chemical compound C1=C[se]N=N1 BUOKUWQCVSZNCF-UHFFFAOYSA-N 0.000 abstract description 14
- 230000005764 inhibitory process Effects 0.000 abstract description 12
- 239000002246 antineoplastic agent Substances 0.000 abstract description 8
- 230000000259 anti-tumor effect Effects 0.000 abstract description 7
- PPHPRJQYDNAYPQ-UHFFFAOYSA-N N1N=CC=C1.[Se] Chemical compound N1N=CC=C1.[Se] PPHPRJQYDNAYPQ-UHFFFAOYSA-N 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 5
- 231100000053 low toxicity Toxicity 0.000 abstract description 5
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 4
- 229910052714 tellurium Inorganic materials 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000037149 energy metabolism Effects 0.000 abstract description 3
- 229940121727 Glutaminase inhibitor Drugs 0.000 abstract description 2
- 230000004898 mitochondrial function Effects 0.000 abstract description 2
- 230000002195 synergetic effect Effects 0.000 abstract description 2
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- 239000000243 solution Substances 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 230000002146 bilateral effect Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 150000003536 tetrazoles Chemical group 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- MDJIPXYRSZHCFS-UHFFFAOYSA-N 2-phenyl-n-[5-[2-[2-[5-[(2-phenylacetyl)amino]-1,3,4-thiadiazol-2-yl]ethylsulfanyl]ethyl]-1,3,4-thiadiazol-2-yl]acetamide Chemical compound N=1N=C(CCSCCC=2SC(NC(=O)CC=3C=CC=CC=3)=NN=2)SC=1NC(=O)CC1=CC=CC=C1 MDJIPXYRSZHCFS-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 102100025960 Glutaminase kidney isoform, mitochondrial Human genes 0.000 description 4
- 101000856990 Homo sapiens Glutaminase kidney isoform, mitochondrial Proteins 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 210000003470 mitochondria Anatomy 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LSBDFXRDZJMBSC-UHFFFAOYSA-N Amide-Phenylacetic acid Natural products NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 3
- 101000856993 Homo sapiens Glutaminase liver isoform, mitochondrial Proteins 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 150000004867 thiadiazoles Chemical class 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- LOZWAPSEEHRYPG-UHFFFAOYSA-N 1,4-dithiane Chemical compound C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- MVXVYAKCVDQRLW-UHFFFAOYSA-N 1h-pyrrolo[2,3-b]pyridine Chemical compound C1=CN=C2NC=CC2=C1 MVXVYAKCVDQRLW-UHFFFAOYSA-N 0.000 description 2
- QSLLFYVBWXWUQT-UHFFFAOYSA-N 7-Azaindolizine Chemical compound C1=NC=CN2C=CC=C21 QSLLFYVBWXWUQT-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 102100025961 Glutaminase liver isoform, mitochondrial Human genes 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- TXCDCPKCNAJMEE-UHFFFAOYSA-N dibenzofuran Chemical compound C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 description 2
- IYYZUPMFVPLQIF-UHFFFAOYSA-N dibenzothiophene Chemical compound C1=CC=C2C3=CC=CC=C3SC2=C1 IYYZUPMFVPLQIF-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- IYKVLICPFCEZOF-UHFFFAOYSA-N selenourea Chemical compound NC(N)=[Se] IYKVLICPFCEZOF-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 230000004102 tricarboxylic acid cycle Effects 0.000 description 2
- 230000004565 tumor cell growth Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- CZICLKKAVOBWSW-UHFFFAOYSA-N 1,2-selenazole Chemical compound C=1C=N[se]C=1 CZICLKKAVOBWSW-UHFFFAOYSA-N 0.000 description 1
- FKASFBLJDCHBNZ-UHFFFAOYSA-N 1,3,4-oxadiazole Chemical compound C1=NN=CO1 FKASFBLJDCHBNZ-UHFFFAOYSA-N 0.000 description 1
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- ODIRBFFBCSTPTO-UHFFFAOYSA-N 1,3-selenazole Chemical compound C1=C[se]C=N1 ODIRBFFBCSTPTO-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VSOSXKMEQPYESP-UHFFFAOYSA-N 1,6-naphthyridine Chemical compound C1=CN=CC2=CC=CN=C21 VSOSXKMEQPYESP-UHFFFAOYSA-N 0.000 description 1
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- XLKDJOPOOHHZAN-UHFFFAOYSA-N 1h-pyrrolo[2,3-c]pyridine Chemical compound C1=NC=C2NC=CC2=C1 XLKDJOPOOHHZAN-UHFFFAOYSA-N 0.000 description 1
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- SRSKXJVMVSSSHB-UHFFFAOYSA-N 1h-pyrrolo[3,2-c]pyridine Chemical compound N1=CC=C2NC=CC2=C1 SRSKXJVMVSSSHB-UHFFFAOYSA-N 0.000 description 1
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 1
- VFLHWTMBJAFPEC-UHFFFAOYSA-N 2-(1-methylindol-3-yl)-N-[5-[2-[2-[5-[[2-(1-methylindol-3-yl)acetyl]amino]-1,3,4-selenadiazol-2-yl]ethylsulfanyl]ethyl]-1,3,4-selenadiazol-2-yl]acetamide Chemical compound S(CCC1=NN=C([Se]1)NC(CC1=CN(C2=CC=CC=C12)C)=O)CCC1=NN=C([Se]1)NC(CC1=CN(C2=CC=CC=C12)C)=O VFLHWTMBJAFPEC-UHFFFAOYSA-N 0.000 description 1
- NFZQVADYFXRRPM-UHFFFAOYSA-N 2-[3-(trifluoromethoxy)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC(OC(F)(F)F)=C1 NFZQVADYFXRRPM-UHFFFAOYSA-N 0.000 description 1
- RHOPUUFLVKWWFP-UHFFFAOYSA-N 2-phenylacetic acid;hydrochloride Chemical compound Cl.OC(=O)CC1=CC=CC=C1 RHOPUUFLVKWWFP-UHFFFAOYSA-N 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- QMDFJHAAWUGVKQ-UHFFFAOYSA-N 2h-thiopyran Chemical compound C1SC=CC=C1 QMDFJHAAWUGVKQ-UHFFFAOYSA-N 0.000 description 1
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 description 1
- JVQIKJMSUIMUDI-UHFFFAOYSA-N 3-pyrroline Chemical compound C1NCC=C1 JVQIKJMSUIMUDI-UHFFFAOYSA-N 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- PTULSAGNGYNIHN-UHFFFAOYSA-N 5-[2-[2-(5-amino-1,3,4-selenadiazol-2-yl)ethylsulfanyl]ethyl]-1,3,4-selenadiazol-2-amine Chemical compound S(CCC1=NN=C([Se]1)N)CCC1=NN=C([Se]1)N PTULSAGNGYNIHN-UHFFFAOYSA-N 0.000 description 1
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- QHEUBRHRIJMZOR-UHFFFAOYSA-N 6-iodopyridazin-3-amine Chemical compound NC1=CC=C(I)N=N1 QHEUBRHRIJMZOR-UHFFFAOYSA-N 0.000 description 1
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 1
- 101150037468 CPD1 gene Proteins 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KWZUDGWKTNIKJY-UHFFFAOYSA-N FC(F)(F)Oc1cccc(CC(=O)Nc2ccc(CCCCc3nnc(NC(=O)Cc4ccccn4)[se]3)nn2)c1 Chemical compound FC(F)(F)Oc1cccc(CC(=O)Nc2ccc(CCCCc3nnc(NC(=O)Cc4ccccn4)[se]3)nn2)c1 KWZUDGWKTNIKJY-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 101100108853 Mus musculus Anp32e gene Proteins 0.000 description 1
- KHBFOXPPERCDLP-UHFFFAOYSA-N N-[5-[2-[2-(5-amino-1,3,4-selenadiazol-2-yl)ethylsulfanyl]ethyl]-1,3,4-selenadiazol-2-yl]-2-(1-methylindol-3-yl)acetamide Chemical compound NC1=NN=C([Se]1)CCSCCC1=NN=C([Se]1)NC(CC1=CN(C2=CC=CC=C12)C)=O KHBFOXPPERCDLP-UHFFFAOYSA-N 0.000 description 1
- 101100221809 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cpd-7 gene Proteins 0.000 description 1
- 101100165815 Oryza sativa subsp. japonica CYP90A3 gene Proteins 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 101100490727 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) AIF1 gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 230000006682 Warburg effect Effects 0.000 description 1
- AYSYSOQSKKDJJY-UHFFFAOYSA-N [1,2,4]triazolo[4,3-a]pyridine Chemical compound C1=CC=CN2C=NN=C21 AYSYSOQSKKDJJY-UHFFFAOYSA-N 0.000 description 1
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GNVMUORYQLCPJZ-UHFFFAOYSA-N carbamothioic s-acid Chemical group NC(S)=O GNVMUORYQLCPJZ-UHFFFAOYSA-N 0.000 description 1
- 125000005521 carbonamide group Chemical group 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- GPTXWRGISTZRIO-UHFFFAOYSA-N chlorquinaldol Chemical compound ClC1=CC(Cl)=C(O)C2=NC(C)=CC=C21 GPTXWRGISTZRIO-UHFFFAOYSA-N 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 101150025236 dmaW gene Proteins 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 101150084310 gls-1 gene Proteins 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- MBVAHHOKMIRXLP-UHFFFAOYSA-N imidazo[1,2-a]pyrazine Chemical compound C1=CN=CC2=NC=CN21 MBVAHHOKMIRXLP-UHFFFAOYSA-N 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- INSWZAQOISIYDT-UHFFFAOYSA-N imidazo[1,2-a]pyrimidine Chemical compound C1=CC=NC2=NC=CN21 INSWZAQOISIYDT-UHFFFAOYSA-N 0.000 description 1
- VTVRXITWWZGKHV-UHFFFAOYSA-N imidazo[1,2-b]pyridazine Chemical compound N1=CC=CC2=NC=CN21 VTVRXITWWZGKHV-UHFFFAOYSA-N 0.000 description 1
- PQWQQQGKMHENOC-UHFFFAOYSA-N imidazo[1,2-c]pyrimidine Chemical compound C1=NC=CC2=NC=CN21 PQWQQQGKMHENOC-UHFFFAOYSA-N 0.000 description 1
- AKJQYWFGJWOGKD-UHFFFAOYSA-N imidazo[1,5-b]pyridazine Chemical compound N1=CC=CC2=CN=CN21 AKJQYWFGJWOGKD-UHFFFAOYSA-N 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- VMUWIDHKAIGONP-UHFFFAOYSA-N pent-4-ynenitrile Chemical compound C#CCCC#N VMUWIDHKAIGONP-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DVUBDHRTVYLIPA-UHFFFAOYSA-N pyrazolo[1,5-a]pyridine Chemical compound C1=CC=CN2N=CC=C21 DVUBDHRTVYLIPA-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IHYJXEQIZYROGA-UHFFFAOYSA-N pyrido[3,4-d]pyridazine Chemical compound N1=NC=C2C=NC=CC2=C1 IHYJXEQIZYROGA-UHFFFAOYSA-N 0.000 description 1
- JBDKAABFESSFMV-UHFFFAOYSA-N pyrrolo[1,2-a]pyrimidine Chemical compound N1=CC=CN2C=CC=C21 JBDKAABFESSFMV-UHFFFAOYSA-N 0.000 description 1
- NISJKLIMPQPAQS-UHFFFAOYSA-N pyrrolo[1,2-b]pyridazine Chemical compound C1=CC=NN2C=CC=C21 NISJKLIMPQPAQS-UHFFFAOYSA-N 0.000 description 1
- RIEKLTCRUGDAPM-UHFFFAOYSA-N pyrrolo[1,2-c]pyrimidine Chemical compound C1=CN=CN2C=CC=C21 RIEKLTCRUGDAPM-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 210000004767 rumen Anatomy 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- MABNMNVCOAICNO-UHFFFAOYSA-N selenophene Chemical compound C=1C=C[se]C=1 MABNMNVCOAICNO-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000004756 silanes Chemical class 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- YGNGABUJMXJPIJ-UHFFFAOYSA-N thiatriazole Chemical compound C1=NN=NS1 YGNGABUJMXJPIJ-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- AQWOIRBQLOOZGX-UHFFFAOYSA-N triazolo[1,5-a]pyridine Chemical compound C1=CC=CC2=CN=NN21 AQWOIRBQLOOZGX-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
- C07D293/02—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms not condensed with other rings
- C07D293/04—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
本发明属于生物医药领域，具体涉及到一种含氧族元素二唑或四氮唑结构的肾型谷氨酰胺酶变构位点的抑制剂，包括该新型具有硒二唑或碲二唑结构特征的谷氨酰酶抑制剂对肿瘤，特别是肝癌和胰腺癌等多种恶性肿瘤的高抑制活性用途；具有硒二唑和碲二唑结构特征的比相应的噻二唑化合物有更好的抗肿瘤活性；药代动力学研究发现硒二唑化合物在肿瘤中更易富集；同时，这些新结构硒二唑和碲二唑化合物靶向肾型谷氨酰胺酶(KGA)变构位点，对KGA有更好的抑制；同时有效抑制线粒体功能，阻断肿瘤能量代谢，是一种广谱低毒的抗肿瘤抑制剂，与现有抗肿瘤药物具有协同效应，联合用药具有很好的治疗效果。
Description
技术领域
本发明属于生物医药领域，具体涉及到一种含氧族元素二唑或四氮唑结构的肾型谷氨酰胺酶变构位点的抑制剂，包括该新型具有硒二唑结构特征的谷氨酰酶抑制剂对肿瘤(特别是肝癌和胰腺癌等多种恶性肿瘤)的高抑制活性用途。
背景技术
肿瘤细胞基因突变，可造成葡萄糖有氧糖代谢途径的明显改变，即Warburg效应：葡萄糖代谢增加200倍，但产物乳酸被排出体外，不能进入线粒体三羧酸循环，则谷氨酰胺成为肿瘤细胞线粒体产生能量所依赖的原料，而谷氨酰胺酶是谷氨酰胺进入线粒体三羧酸循环必不可少的酶。谷氨酰胺缺乏或谷氨酰胺酶的抑制均能抑制肿瘤细胞的生长。
谷氨酰胺酶在细胞代谢中十分重要，尤其是在癌细胞中。哺乳动物体内含有两个不同的基因编码谷氨酰胺酶：GLS1和GLS2。二者的蛋白结构、动力学特征以及涉及的调节机制均不相同。GLS1基因位于2号染色体，编码的是肾型同工酶。GLS2基因位于12号染色体，编码的是肝型同工酶。现已发现3种GLS1变异体：典型的的剪接变异体1(KGA)；被截去顶端、无催化作用的剪接变异体2；一个引申的剪接变异体3(GAC)。GAC与KGA具有相同的N端，不同的C末端。GLS1的变异体GAC在许多原发性肿瘤和肿瘤细胞系中都有强烈的表达，而GLS2在肿瘤细胞中的表达则是相对有限的。
GLS1的相应蛋白(KGA和GAC)的变构位点是由残基276-420组成的7个α螺旋结构延伸为α螺旋结构域，从而形成α/β结构域。该结构域包含构成谷氨酸结合袋的大部分残基，包括最为有序的螺旋(α-13，残基386-399)短二聚体-二聚体界面和其抑制剂BPTES最佳作用位置的环(残基309-334)。界面螺旋α-13以头尾方式与相邻亚基的螺旋α-13相互作用，例如来自一个亚基的Tyr393与另一个亚基的Phe389形成π-堆积相互作用，反之亦然。通过在界面两端的Asp386和Lys396之间的相互作用使得盐桥更加稳定。延伸的α螺旋结构域包含分子的催化核心部位以及潜在连接GAC寡聚体的构象部位。
发明内容
GAC四聚体和BPTES结合图见附图1.计算机模拟显示，中间的脂肪链将直接影响化合物与KGA变构位点的关键残基的相互作用。因此我们设计合成一些具有硒二唑和碲二唑结构特征的，不同链接，对称和不对称五元杂环或六元杂环结构，及不同的官能团的组合；同时芳香环进行了修饰，增加或减少化合物的取代基团、优化化合物的药学性质、谷氨酰胺酶变构位点的结合力、及化合物的抗肿瘤活性。
本发明发现了具有靶向性的高效低毒抗肿瘤新药化合物，许多肿瘤细胞的生长依赖于谷氨酰胺在线粒体中的代谢。具有硒二唑结构特征的比相应的噻二唑化合物有更好的抗肿瘤活性；药代动力学研究发现硒二唑化合物在肿瘤中更易富集；同时，这些新结构硒二唑和碲二唑化合物靶向肾型谷氨酰胺酶(KGA)变构位点，对KGA有更好的抑制；同时有效抑制线粒体功能，阻断肿瘤能量代谢，不但对谷氨酰胺依赖的肿瘤抑制能力非常强，而且对恶性程度高的肝癌和胰腺癌的抑制能力比噻二唑化合物强，是一种广谱低毒的抗肿瘤抑制剂，与现有抗肿瘤药物具有协同效应，联合用药具有很好的治疗效果。
本发明包括如下内容：一种含氧族元素二唑结构肾型谷氨酰胺酶变构位点的抑制剂，该化合物的结构通式为
或者
其中Z:氧族元素的原子Se.当Z＝Se和X&Y＝C时，A不为硒二唑
X，Y:选自氧族元素的原子S、Se、C、N原子取代的；
A：代表1-2个芳香环，芳香杂环；
n和m:分别为1,2,3；
R1、R2：分别代表一个或多个独立的取代基包含通过烷基，芳环基，酰胺，氨基甲酸酯基，碳酰胺基，氨基硫代甲酸酯基，醚，酯基，卤素，硅烷类，硫醚，胺类，磷酸基团，亚砜类，磺酰基连接的芳香类杂环，取代烷，或有生物活性的天然化合物的衍生物。
优选地，所述的含氧族元素二唑或四氮唑结构的肾型谷氨酰胺酶变构位点的抑制剂，其特征在于：所述的A为任选的以下有取代或没有取代的芳香杂环结构式：包括五元环：四氢吡咯，吡咯，2,5-二氢-1H-吡咯，咪唑，2-咪唑啉，咪唑啉，吡唑，吡唑啶，三氮唑，1,2,4-三氮唑，四氮唑，四氢呋喃，呋喃，恶唑，异恶唑，1,2,3-噁二唑，1,3,4-噁二唑，1,2,4-噁二唑，1,2,3,4-噁二唑，四氢噻吩，噻吩，噻唑，异噻唑，1,2,3-噻二唑，1,2,3,4-噻***,硒吩，硒唑，异硒唑，1,2,3-硒二唑，碲二唑；
六元环：六氢吡啶，哌嗪，吡啶，吡嗪，嘧啶，哒嗪，1,3,5-三嗪，2H-吡喃，3,4-二氢-2H-吡喃，四氢吡喃，1,4-二氧六环，吗啉，硫化环戊烷，1,4-二噻烷，2H-噻喃；
稠环化合物：吲哚，苯并咪唑，吲唑，苯并三氮唑，4-氮杂吲哚，5-氮杂吲哚，6-氮杂吲哚，7-氮杂吲哚，1H-1,2,3-***[4,5-b]吡啶，7H-吡咯并[2,3-d]嘧啶，5H-吡咯并[3,2-d]嘧啶，嘌呤，吲嗪，吡咯并[1,2-a]嘧啶，吡咯并[1,2-a]吡嗪，吡咯并[1,2-c]嘧啶，吡咯并[1,2-b]哒嗪，1H-咪唑并[4,5-b]吡啶，吡唑并[1,5-a]吡啶，咪唑并[1,5-a]吡啶，咪唑并[1,5-b]哒嗪，咪唑并[1,2-a]吡啶，咪唑并[1,2-b]哒嗪，咪唑并[1,2-c]嘧啶，咪唑并[1,2-a]吡嗪，咪唑并[1,2-a]嘧啶，[1,2,4]***并[4,3-a]吡啶，[1,2,3]***并[1,5-a]吡啶，喹啉，异喹啉，1,2-二氮萘，喹唑啉，喹喔啉，2,3-二氮杂萘，2,3-二吡啶吡嗪，喋啶，吡啶并[3,4-d]哒嗪，1,6-萘啶，1,8-萘啶，咔唑，苯并恶唑，二苯并呋喃，苯并噻吩，二苯并噻吩；
优选地，所述的含氧族元素二唑或四氮唑结构的肾型谷氨酰胺酶变构位点的抑制剂，R1、R2：分别代表一个或多个链状或环状的包含1～20个选自C、H、N、O、S、Se、Te、P、Si和卤素原子的原子或者基团。
优选地，所述的含氧族元素二唑或四氮唑结构的肾型谷氨酰胺酶变构位点的抑制剂，其特征在于所述的化合物包括：
优选地，一种药物组合物，包括所述的化合物及其药物活性上可接受的盐的化合物的药物组合物。
优选地，一种包括所述的化合物的药物组合物及其药物活性上可接受的盐的化合物的药物组合物在对谷氨酰胺代谢有依赖性的癌症治疗中的用途。
优选地，一种包括所述的药物组合物在对肝癌和胰腺癌的治疗过程中的用途。
优选地，一种包括所述的化合物的药物组合物及其药物活性上可接受的盐的化合物的药物组合物在对谷氨酸代谢有关的神经方面疾病的治疗用途
优选地，一种包括所述的药物组合物在对癫痫和脑中风的治疗过程中的用途。
本发明提供了一类具有靶向性的广谱高效低毒治疗癌症新药药物，设计合成的化合物具有靶向性，抑制线粒体功能，阻断肿瘤能量代谢，对谷氨酰胺依赖的肿瘤抑制能力非常强，可用于多种癌症的治疗或手术后的预防；本发明提供的具有靶向性的高效低毒抗肿瘤新药化合物，通过抑制许多肿瘤细胞的生长依赖于谷氨酰胺在线粒体中的代谢；具有硒二唑和碲二唑结构特征的比相应的噻二唑化合物有更好的抗肿瘤活性。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，还可以根据这些附图获得其他的附图。
图1为GAC四聚体和BPTES结合图。
1、底物结合的活性位点；2、BPTES结合的变构位点。
图2为(CPD1-CPD39)对KGA的抑制效果示意图。
具体实施方式
下面结合实施例对本发明做进一步的详细说明，以下实施例是对本发明的解释而本发明并不局限于以下实施例。
实施例
本发明中硒二唑结构肾型谷氨酰胺酶变构位点的抑制剂的合成方式：
1.硒二唑乙基硫醚
取氰基化合物(1eq)，硒脲(2eq)，TFA 5ml，于85℃下反应4小时，TLC监控反应完全，将反应液倒入50ml冰水混合物中，用NaOH固体调至PH＝14，提取过柱纯化，得粉红色固体胺基化合物硒二唑乙基硫醚(M/Z＝385(M++1))。
5,5'-(thiobis(ethane-2,1-diyl))bis(1,3,4-selenadiazol-2-amine)
1H NMR(500MHz,DMSO)δ7.17(s,2H),3.06(t,J＝7.1Hz,2H),2.83(t,J＝13.2,6.0Hz,2H).
LRMs:m/z＝384[M+H]+,406[M+Na]+
所得胺基化合物(4eq)，与各类酸(1eq)混合，加HBTU 0.478g，DIPEA 0.233g，DCM7ml于室温下反应过夜，将反应液倒入水中，加入DCM萃取，提取过柱纯化，获单边和双边酰胺化的化合物。
2、单边N-甲基吲哚乙酰胺基-硫醚硒二唑
N-(5-(2-((2-(5-amino-1,3,4-selenadiazol-2-yl)ethyl)thio)ethyl)-1,3,4-selenadiazol-2-yl)-2-(1-methyl-1H-indol-3-yl)acetamide
1H NMR(500MHz,DMSO)δ12.73(s,1H),7.57(d,J＝8.0Hz,1H),7.40(d,J＝8.2Hz,1H),7.27(s,1H),7.21(s,2H),7.14(t,J＝7.3Hz,1H),7.03(t,J＝7.4Hz,1H),3.92(s,2H),3.76(s,3H),3.23(t,J＝15.2,8.2Hz,2H),3.06(t,J＝7.1Hz,2H),2.90(t,J＝7.0Hz,2H),2.85(t,J＝7.1Hz,2H).
3、双边N-甲基吲哚乙酰胺基-硫醚硒二唑
N,N'-((thiobis(ethane-2,1-diyl))bis(1,3,4-selenadiazole-5,2-diyl))bis(2-(1-methyl-1H-indol-3-yl)acetamide)
1H NMR(500MHz,DMSO)δ12.73(s,1H),7.57(d,J＝7.9Hz,1H),7.39(d,J＝8.2Hz,1H),7.26(s,1H),7.14(t,J＝7.3Hz,1H),7.02(t,J＝7.4Hz,1H),3.89(s,2H),3.75(s,3H),3.24(t,J＝7.1Hz,2H),2.91(t,J＝7.1Hz,2H).
LRMs:m/z＝727[M+H]+
4、单边N-甲基甲氧基吲哚乙酰胺基-硫醚硒二唑
5、双边N-甲基吲哚乙酰胺基-硫醚硒二唑
6、单边N-甲基吡咯乙酰胺基-硫醚硒二唑
N-(5-(2-((2-(5-amino-1,3,4-selenadiazol-2-yl)ethyl)thio)ethyl)-1,3,4-selenadiazol-2-yl)-2-(1-methyl-1H-pyrrol-2-yl)acetamide
1H NMR(500MHz,DMSO)δ12.69(s,1H),7.18(s,1H),6.67(s,1H),5.89(d,J＝8.8,4.4Hz,2H),3.83(s,2H),3.53(s,3H),3.25(t,2H),3.07(t,J＝7.1Hz,1H),2.92(t,J＝7.0Hz,1H),2.86(t,J＝7.1,3.9Hz,2H),2.73(t,J＝7.3Hz,1H),2.34(t,J＝7.3Hz,1H).
7、双边N-甲基吡咯乙酰胺基-硫醚硒二唑
N,N'-((thiobis(ethane-2,1-diyl))bis(1,3,4-selenadiazole-5,2-diyl))bis(2-(1-methyl-1H-pyrrol-2-yl)acetamide)
1H NMR(500MHz,DMSO)δ12.69(s,1H),6.66(t,1H),5.91–5.89(m,1H),5.89–5.87(m,1H),3.82(s,2H),3.53(s,3H),3.27(t,J＝7.1Hz,2H),2.93(t,J＝7.1Hz,2H).
8、单边苯乙酰胺基-硫醚硒二唑
9、双边苯乙酰胺基-硫醚硒二唑
10、单边甲氧基苯乙酰胺基-硫醚硒二唑
11、双边甲氧基苯乙酰胺基-硫醚硒二唑
12、单边金刚烷酰胺基-硫醚硒二唑
2-((3r,5r,7r)-adamantan-1-yl)-N-(5-(2-((2-(5-amino-1,3,4-selenadiazol-2-yl)ethyl)thio)ethyl)-1,3,4-selenadiazol-2-yl)acetamide
1H NMR(500MHz,DMSO)δ12.40(s,1H),7.17(s,2H),3.26(t,J＝7.1Hz,2H),3.08(t,J＝7.2Hz,2H),2.92(t,J＝7.1Hz,2H),2.87(t,J＝7.2Hz,2H),2.24(s,2H),1.96–1.88(m,2H),1.70–1.61(m,2H),1.60–1.54(m,11H).
13、双边金刚烷酰胺基-硫醚硒二唑
14、单边N-甲基吡咯乙酰胺基-己烷硒二唑
15、双边N-甲基吡咯乙酰胺基-己烷硒二唑
16、单边N-甲基吲哚乙酰胺基-二硫乙基硒二唑
17、双边N-甲基吲哚乙酰胺基-二硫乙基硒二唑
18、苯乙酰胺-硒二唑-哒嗪-三氟甲氧基苯基乙酰胺的合成
步骤1的合成：将3-氨基-6-碘代哒嗪(50g，0.388mol)和3-(三氟甲氧基)苯基乙酸(59.7g，0.271mol)以及2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU：220g，0.581mol)置于2L的单口瓶内，加入1500mL的二氯甲烷溶液，室温下滴加78.5mL的N,N-二异丙基乙胺(DIEA：74.95g，0.581mol)，室温下搅拌过12h后，用饱和碳酸氢钠溶液洗涤多次，然后用二氯甲烷萃取两遍，柱层析纯化得到77.6g米黄色固体，产率为76.0％。(1HNMR(500MHz,Chloroform-d)δ10.94(s,1H),8.37(d,J＝9.4Hz,1H),7.87(d,J＝9.3Hz,1H),7.38(t,J＝7.8Hz,1H),7.35(s,1H),7.30-7.28(m,1H),7.16(ddt,J＝7.8,2.4,1.2Hz,1H),3.99(s,2H)；MS(ESI)424[M+1]+)
步骤2的合成：将原料CPD1(20.0g，0.0615mol)和碘化亚铜(820mg，3.69mmol)以及双苯基膦二氯化钯(1.73g，1.85mmol)置于1L的两颈瓶内，***温度计，加入260mL的干燥后的四氢呋喃溶液，滴入38mL三乙胺溶液(24.9g，0.246mol)，最后滴入4-戊炔腈(5.38g，0.068mol)，氩气置换空气后，在氩气保护下，升温至78℃，回流搅拌12h。待点板(石油醚/丙酮2/1)反应完成后，用饱和食盐水洗涤两次，再用乙酸乙酯萃取两遍，合并有机相，用无水硫酸钠干燥后，通过柱层析纯化得到16.2g白色化合物，产率为70.2％。(1H-NMR(500MHz,DMSO-d6)δ11.62(s,1H),8.30(d,J＝9.2Hz,1H),7.75(d,J＝9.2Hz,1H),7.48(t,J＝8.0Hz,1H),7.38(dd,J＝7.5,1.4Hz,2H),7.27(dd,J＝8.5,2.1Hz,1H),3.89(d,J＝1.6Hz,2H)2.88(qt,J＝9.2,4.6Hz,4H)；MS(ESI)373.3[M-1]-)
步骤3：将纯化过的CPD2(1.00g，2.67mmol)置于100mL的单口瓶内，加入25mL的乙酸乙酯溶液和13mL甲醇溶液以及13mL的四氢呋喃溶液，加入200mg的氢氧化钯，氢气置换瓶内空气后，连通氢气袋反应24h，原料基本反应完全，用硅藻土挡住钯碳过滤，选干滤液，得到1.00g黄白色固体，产率为99.0％。(1H NMR(500MHz,DMSO-d6)δ11.34(s,1H),8.21(d,J＝9.2Hz,1H),7.58(d,J＝9.1Hz,1H),7.48(t,J＝8.0Hz,1H),7.43–7.34(m,2H),7.32–7.23(m,1H),3.86(s,2H),2.89(t,J＝7.6Hz,2H),2.54(t,J＝7.1Hz,2H),1.78(tt,J＝9.0,6.8Hz,2H),1.67–1.56(m,2H)；MS(ESI)379.1[M+1]+)
步骤4：CPD3(1.5g，4.0mmol)置于10mL的单口瓶内，加入氨基硒脲(722mg，5.2mmol)，再加入23.0mL的三氟乙酸，加热至80℃，回流搅拌4h，待点板(二氯甲烷/甲醇10/1)反应完全后，将反应液冷却至室温后，滴加至冰水中，溶液变浑浊，有黄白色固体析出，过滤，将滤渣收集过柱得950mg白色化合物，产率为51.6％。(1H NMR(500MHz,DMSO-d6)δ11.33(s,1H),8.20(d,J＝9.1Hz,1H),7.57(d,J＝9.2Hz,1H),7.47(t,J＝7.9Hz,1H),7.38(dt,J＝9.9,1.7Hz,2H),7.31–7.24(m,1H),7.18(s,2H),3.86(s,2H),2.88(t,J＝7.5Hz,2H),2.84(t,J＝7.3Hz,2H),1.77–1.69(m,2H),1.69–1.61(m,2H)；MS(ESI)501[M+1]+)
步骤5：将SN1(950mg，2.1mmol)置于10mL的单口烧瓶内，加入苯乙酸盐酸盐(440mg,2.5mmol)，加入2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.35g，3.57mmol)，滴加10mLDMF将其溶解，滴加1.0mLN,N-二异丙基乙胺(0.46g，3.57mmol)，室温下搅拌12h。将反应液滴入冰水溶液中，有大量灰白色固体析出，过滤，用水冲洗滤渣，将滤渣收集，柱层析纯化得到600mg的黄白色固体，产率为50.4％。1H NMR(500MHz,DMSO-d6)δ7.25-8.49(芳环，11H),4.00(s,2H),3.86(s,2H),3.34(s,4H),3.02(t,2H),2.92–2.86(m,2H).MS(ESI)641[M+23]+)
19、吡啶乙酰胺-硒二唑-哒嗪-三氟甲氧基苯基乙酰胺
2-(pyridin-2-yl)-N-(5-(4-(6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1,3,4-selenadiazol-2-yl)acetamide
1H NMR(500MHz,DMSO)δ12.75(s,1H),11.31(s,1H),8.49(dd,J＝4.8,1.7,0.8Hz,1H),8.18(d,J＝9.1Hz,1H),7.77(td,J＝7.7,1.8Hz,1H),7.55(d,J＝9.2Hz,1H),7.46(t,J＝7.9Hz,1H),7.41–7.34(m,3H),7.31–7.22(m,2H),4.01(s,2H),3.85(s,2H),3.02(t,J＝6.7Hz,2H),2.88(t,J＝7.1Hz,2H),1.82–1.68(m,4H).
质谱LRMs:(M/Z＝620(M++1))
20、甲基吡咯-硒二唑-哒嗪-三氟甲氧基苯基乙酰胺
21、N-甲基吲哚-硒二唑-哒嗪-三氟甲氧基苯基乙酰胺
22、N-甲基甲氧基吲哚-硒二唑-哒嗪-三氟甲氧基苯基乙酰胺
23、N-甲基-二甲基胺基乙基醚吲哚-硒二唑-哒嗪-三氟甲氧基苯基乙酰胺
24、甲氧基-N-二甲基胺基乙氧基吲哚-硒二唑-哒嗪-三氟甲氧基苯基乙酰胺
25、5氟尿嘧啶-硒二唑-哒嗪-三氟甲氧基苯基乙酰胺
29、生物素-硒二唑-哒嗪-三氟甲氧基苯基乙酰胺
26、甲基吡咯-硒二唑-哒嗪-羟基苯基乙酰胺
27、甲基吡咯-硒二唑-哒嗪-二甲胺基乙氧基苯基乙酰胺
28、甲基吡咯-硒二唑-哒嗪-叠氮醚苯基乙酰胺
29、甲基吡咯-噻二唑-哒嗪-三氟甲氧基苯基乙酰胺
30、甲基吡咯-四氮唑-哒嗪-三氟甲氧基苯基乙酰胺
31、硫醚硒二唑-雷帕霉素衍生物
32，吡啶碳酰胺-硒二唑-哒嗪-三氟甲氧基苯基乙酰胺
质谱LRMs:(M/Z＝621(M++1))
33、甲基吡咯-硒二唑-三氮唑-三氟甲氧基苯基乙酰胺
34、甲基吡咯-硒二唑-四氮唑-三氟甲氧基苯基乙酰胺
35、甲基吡咯-硒二唑-二氮唑-三氟甲氧基苯基乙酰胺
二、含硒二唑或碲二唑结构肾型谷氨酰胺酶变构位点的抑制剂化合物的效果：
1、(CPD1-CPD39)对KGA有较强的抑制
96孔板中将1μl3倍稀释的待测化合物系列，与初始浓度为8nM的KGA于70μl缓冲液A中混合，室温下低速振荡反应2h；加入等体积含20mM Gln的缓冲液B，室温下反应2h；最后加入20μl缓冲液C的混合试剂(4nM GDH，200μM NADP+，EZMTT检测试剂)，4h后测定450nm下吸光度(参比波长620nm)，详见图2。
2、.硒二唑和碲二唑对恶性高的肿瘤细胞的抑制能力高于噻二唑
完全培养基100μL/孔接种细胞于96孔板，细胞1000个/孔。4h贴壁后将化合物溶于新鲜完全培养基，每组设置最高给药终浓度为10μM，3倍稀释，共9个浓度，最低浓度为1.5nM，0.05％DMSO设置为空白对照0nM，每个浓度设置3个复孔。溶解混匀后转移入细胞培养液中。培养箱孵育3-5天后吸尽培养液，加入新鲜EZMTT工作液检测2-4h后读数。
表1：比较噻二唑与硒二唑对肿瘤细胞生长的抑制
三、动物模型中硒二唑化合物比噻二唑化合物有更好的抗肿瘤活性
将80只小鼠随机分成4个组A、B、C、D组，每组10只。在腋下接种H22肝癌肿瘤，2天后，皮下注射配好的药物A、B、C、D。每天给药一次(10mg/kg)，连续给药10天。10天后将小鼠用10％的水合氯醛麻醉(0.16ml)，腹主动脉取血，并将血液2000×g离心20min，将收集的血清于-40℃保存。小鼠死后剥离皮下瘤子称重并拍照，再放在4％的多聚甲醛溶液中固定保存，以后用作HE染色。
表2：比较噻二唑与硒二唑对肿瘤生长的抑制
10mg/kg CB839和10mg/kg CPD22给药组体重没有减少，10天没有死亡。
表3：比较噻二唑与硒二唑在肿瘤中的富集
| 化合物 | Compound in tumor(mg)/Tumor weight(g) |
| 10mg/Kg CB839 treated | 3.4 |
| 10mg/Kg CPD22 treated | 9.8 |
此外，需要说明的是，本说明书中所描述的具体实施例，其相关化合物的名称等可以不同，凡依本发明专利构思所述的原理所做的等效或简单变化，均包括于本发明专利的保护范围内。本发明所属技术领域的技术人员可以对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代，只要不偏离本发明的结构或者超越本权利要求书所定义的范围，均应属于本发明的保护范围。
Claims (6)
1.一种含氧族元素二唑结构的肾型谷氨酰胺酶变构位点的抑制剂化合物，其特征在于：该化合物的结构式为：
2.一种药物组合物，包括如权利要求1中任一所述的化合物及其药物活性上可接受的盐。
3.权利要求2所述的药物组合物在制备对谷氨酰胺代谢有依赖性的癌症治疗药物中的用途。
4.权利要求2所述的药物组合物在制备肝癌和胰腺癌的治疗药物中的用途。
5.权利要求2所述的药物组合物在制备与谷氨酸代谢有关的神经方面疾病的治疗药物中的用途。
6.权利要求2所述的药物组合物在制备癫痫和脑中风的治疗药物中的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2017114818391 | 2017-12-29 | ||
| CN201711481839 | 2017-12-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109988124A CN109988124A (zh) | 2019-07-09 |
| CN109988124B true CN109988124B (zh) | 2024-01-09 |
Family
ID=67129776
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811629951.XA Active CN109988124B (zh) | 2017-12-29 | 2018-12-29 | 一种含氧族元素二唑或四氮唑结构的肾型谷氨酰胺酶变构位点的抑制剂 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109988124B (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114681446A (zh) * | 2020-12-30 | 2022-07-01 | 南京盛德生物科技研究院有限公司 | 一种乙酰胺类化合物作为谷氨酸脱氢酶抑制剂的应用 |
| CN114805346A (zh) * | 2021-07-08 | 2022-07-29 | 成都硕德药业有限公司 | 杂环类衍生物、其制备方法及用途 |
| CN115286625A (zh) * | 2022-06-23 | 2022-11-04 | 浙江工业大学 | 谷氨酰胺酶别构位点共价抑制剂及其制备方法与应用 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106699687A (zh) * | 2015-11-17 | 2017-05-24 | 杭州伽玛生物科技有限公司 | 一种含硒的kga/gac和/或gdh抑制剂化合物 |
| CN106866581A (zh) * | 2015-12-14 | 2017-06-20 | 杭州健昵福生物科技有限公司 | 一种具有药物活性的1，3，4-硒二唑类化合物 |
| CN106905261A (zh) * | 2015-12-14 | 2017-06-30 | 杭州健昵福生物科技有限公司 | 1，3，4‑硒二唑衍生物的合成方法 |
| CN107074805A (zh) * | 2014-07-03 | 2017-08-18 | 德州大学***董事会 | 用于治疗疾病的gls1抑制剂 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10660861B2 (en) * | 2014-07-09 | 2020-05-26 | The Johns Hopkins University | Glutaminase inhibitor discovery and nanoparticle-enhanced delivery for cancer therapy |
-
2018
- 2018-12-29 CN CN201811629951.XA patent/CN109988124B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107074805A (zh) * | 2014-07-03 | 2017-08-18 | 德州大学***董事会 | 用于治疗疾病的gls1抑制剂 |
| CN106699687A (zh) * | 2015-11-17 | 2017-05-24 | 杭州伽玛生物科技有限公司 | 一种含硒的kga/gac和/或gdh抑制剂化合物 |
| CN106866581A (zh) * | 2015-12-14 | 2017-06-20 | 杭州健昵福生物科技有限公司 | 一种具有药物活性的1，3，4-硒二唑类化合物 |
| CN106905261A (zh) * | 2015-12-14 | 2017-06-30 | 杭州健昵福生物科技有限公司 | 1，3，4‑硒二唑衍生物的合成方法 |
Non-Patent Citations (3)
| Title |
|---|
| Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer;Matt I. Gross et al.;《Molecular Cancer Therapeutics》;20140212;第13卷(第4期);第890-901页 * |
| Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES);Mary M. ROBINSON et al.;《The Biochemical journal》;20070621;第406卷(第3期);第407-414页 * |
| Novel mechanism of inhibition of rat kidney-type glutaminase by bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES);Mary M. ROBINSON et al.;Biochem. J.;第406卷;第407-414页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109988124A (zh) | 2019-07-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9951062B2 (en) | Substituted 1 H-pyrrolo [2, 3-b] pyridine and 1 H-pyrazolo [3, 4-b] pyridine derivatives as salt inducible kinase 2 (SIK2) inhibitors | |
| CN109988124B (zh) | 一种含氧族元素二唑或四氮唑结构的肾型谷氨酰胺酶变构位点的抑制剂 | |
| US20180370966A1 (en) | Methods of treatment using pyridinonyl pdk1 inhibitors | |
| ES2835553T3 (es) | Inhibidores de indazol de la vía de señalización de Wnt y sus usos terapéuticos | |
| ES2652287T3 (es) | 1H-pirazol [3,4-b] piridinas y usos terapéuticos de las mismas | |
| Vats et al. | Continued exploration and tail approach synthesis of benzenesulfonamides containing triazole and dual triazole moieties as carbonic anhydrase I, II, IV and IX inhibitors | |
| FR2970967A1 (fr) | Derives de type azaindazole ou diazaindazole comme medicament | |
| CA2784393A1 (en) | Compounds and methods for kinase modulation, and indications therefor | |
| JP7131837B2 (ja) | Ｃｓｆ－１ｒ阻害活性を有するアザアリール誘導体、その製造方法および応用 | |
| Hofny et al. | Design, synthesis, and antibacterial evaluation of new quinoline-1, 3, 4-oxadiazole and quinoline-1, 2, 4-triazole hybrids as potential inhibitors of DNA gyrase and topoisomerase IV | |
| CA2896822A1 (en) | Azaindole derivatives as inhibitors of protein kinases | |
| CN102399233A (zh) | PI3K和mTOR双重抑制剂类化合物 | |
| CN113166156B (zh) | 酪氨酸激酶抑制剂、组成及其方法 | |
| AU2010212560B2 (en) | Derivatives of azaindoles as inhibitors of protein kinases Abl and Src | |
| CN105732614A (zh) | 磺酰胺基芳基炔类化合物及其用途 | |
| EP1919910A1 (en) | Azabenzimidazole derivatives, their manufacture and use as anti-cancer agents | |
| US20140315909A1 (en) | 3,5-(Un)substituted-1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine and 5H- pyrrolo[2,3-b]pyrazine dual ITK and JAK3 Kinase Inhibitors | |
| WO2014100540A1 (en) | Pyrazole substituted imidazopyrazines as casein kinase 1 d/e inhibitors | |
| EP3856186A1 (en) | Small molecule inhibitors of dyrk1/clk and uses thereof | |
| EP4019521A1 (en) | Azaheteroaryl compound and application thereof | |
| CN117355532A (zh) | 三并环类usp1抑制剂及其用途 | |
| EP4089089A1 (en) | Polycyclic compounds for inhibiting rna helicase dhx33 and use thereof | |
| JP2019001715A (ja) | 三環性化合物 | |
| CA2908824A1 (en) | Five-member-heterocycle fused pyridine compounds, method of producing the same, and use thereof | |
| WO2023130539A1 (zh) | 一种***并嘧啶醇类化合物及其制备方法和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |