CN114685504A - Fascaplysin derivative and preparation method and application thereof - Google Patents
Fascaplysin derivative and preparation method and application thereof Download PDFInfo
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- CN114685504A CN114685504A CN202210145336.1A CN202210145336A CN114685504A CN 114685504 A CN114685504 A CN 114685504A CN 202210145336 A CN202210145336 A CN 202210145336A CN 114685504 A CN114685504 A CN 114685504A
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- acceptable salt
- iron
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- PWUOOJVYZQILBG-UHFFFAOYSA-N fascaplysine Chemical class [Cl-].C1=CC=C2C3=CC=[N+]4C5=CC=CC=C5C(=O)C4=C3NC2=C1 PWUOOJVYZQILBG-UHFFFAOYSA-N 0.000 title abstract description 20
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 78
- 229910052742 iron Inorganic materials 0.000 claims abstract description 41
- 102100020760 Ferritin heavy chain Human genes 0.000 claims abstract description 20
- 101001002987 Homo sapiens Ferritin heavy chain Proteins 0.000 claims abstract description 20
- 101000829725 Homo sapiens Phospholipid hydroperoxide glutathione peroxidase Proteins 0.000 claims abstract description 18
- 102100023410 Phospholipid hydroperoxide glutathione peroxidase Human genes 0.000 claims abstract description 18
- 238000009825 accumulation Methods 0.000 claims abstract description 15
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000000411 inducer Substances 0.000 claims abstract description 12
- 239000001301 oxygen Substances 0.000 claims abstract description 12
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 230000006698 induction Effects 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 30
- 239000003642 reactive oxygen metabolite Substances 0.000 claims description 18
- 239000003112 inhibitor Substances 0.000 claims description 17
- 230000001939 inductive effect Effects 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 238000002156 mixing Methods 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
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- 238000000034 method Methods 0.000 claims description 8
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- 239000003814 drug Substances 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
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- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
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- 210000004027 cell Anatomy 0.000 description 56
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 12
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- 238000001819 mass spectrum Methods 0.000 description 9
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- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
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- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 4
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- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 description 4
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
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- OEUUFNIKLCFNLN-LLVKDONJSA-N chembl432481 Chemical compound OC(=O)[C@@]1(C)CSC(C=2C(=CC(O)=CC=2)O)=N1 OEUUFNIKLCFNLN-LLVKDONJSA-N 0.000 description 2
- 229940008099 dimethicone Drugs 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- UJHBVMHOBZBWMX-UHFFFAOYSA-N ferrostatin-1 Chemical compound NC1=CC(C(=O)OCC)=CC=C1NC1CCCCC1 UJHBVMHOBZBWMX-UHFFFAOYSA-N 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
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- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- RZJRJXONCZWCBN-UHFFFAOYSA-N octadecane Chemical compound CCCCCCCCCCCCCCCCCC RZJRJXONCZWCBN-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000012679 serum free medium Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- HTFXWAOSQODIBI-UHFFFAOYSA-N 2-benzyl-1,3-dihydropyrrolo[3,4-c]pyridine Chemical compound C1C2=CC=NC=C2CN1CC1=CC=CC=C1 HTFXWAOSQODIBI-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 101710088172 HTH-type transcriptional regulator RipA Proteins 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [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 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
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- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
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- 238000011081 inoculation Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 229940038384 octadecane Drugs 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
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- 230000011664 signaling Effects 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 229940083037 simethicone Drugs 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
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- 238000003809 water extraction Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicinal chemistry, and discloses a Fascaplysin derivative and a preparation method and application thereof. The Fascaplysin derivative has a chemical structural formula shown in formula (I), can induce iron death, induce iron accumulation, induce active oxygen increase, inhibit expression of GPX4, SLC7A11 and FTH1, has good iron death induction effect, can be used as an iron death inducer to induce tumor cell iron death, and can be used for treating tumor.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a Fascaplysin derivative and a preparation method and application thereof.
Background
The marine-derived substance has the characteristics of being different from other medicines, novel structure and unique activity, and is an excellent medicine treasury. At present, more than 3.5 million marine natural products are found globally, and 16 marine innovative medicaments are successfully marketed, wherein 5 medicinal active ingredients are sourced from sponges. Sponges are the oldest, most complex symbiont invertebrates of known organisms, and are enriched in large numbers of microorganisms. Sponges are an important source of active natural products, almost half of the active compounds of marine origin are derived from sponges; nearly a thousand compounds have been isolated from sponges, many of which have biological activities such as antibacterial, antifungal, antitumor, anti-inflammatory, and the like. The long symbiotic interaction survival evolution process of the sponge and the strong chemical defense mechanism of the sponge inevitably lead to high identification and high selectivity of active substances, and are important sources of novel-structure and new-target original drugs.
Fascaplysin is a natural product isolated from marine sponges and exhibits a wide range of biological activities, including antibacterial, antifungal, antiviral, HIV-1-RT, p56 tyrosine kinase, antimalarial, anticancer, etc. Research reports that Fascaplysin shows specific cyclin-de-dependent kinase 4(CDK4) inhibitory activity, and has been shown to prevent cancer cell growth by inhibiting cyclin-dependent kinase 4(Cdk4), Cdk4 is an early-stage cyclin that is mis-regulated in most cancers. Therefore, it is desired to modify the structure of Fascaplysin and to find an effective Fascaplysin derivative.
Disclosure of Invention
The object of the first aspect of the present invention is to provide a Fascaplysin derivative.
The second aspect of the present invention is directed to a method for producing the Fascaplysin derivative of the first aspect.
A third aspect of the present invention is directed to the use of the Fascaplysin derivative of the first aspect, or a pharmaceutically acceptable salt thereof.
The fourth aspect of the invention aims to provide a product.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
in a first aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof,
in the formula (I), X-Are common anions such as: cl-、F-、Br-、I-、HCO3 -、HSO4 -、H2PO5 -、(0.5)HPO5 2-、(1/3)PO5 3-、(1/6)PF6-、CH3CO2 -、CF3CO2 -、CO2HCO2 -、(0.5)CO2CO2 2-、(0.5)CO2(CH2)nCO2 2-、PhCO2 -、CH3SO3 -、PhSO3 -、CF3SO3 -、(p)-Me-PhSO3 -And the like, wherein n is 1-20;
R1any one selected from the following groups:
Preferably, in the formula (I), X-Is Cl-，R1Is composed of
In a second aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) according to the first aspect, wherein the synthetic route is:
the method comprises the following steps:
(1) mixing the compound S1 with tryptamine, and reacting to obtain a compound S2;
(2) mixing the compound S2 with a brominating agent, and reacting to obtain a compound S3;
(3) compounds S3 and R1-B(OH)2Mixing, carrying out a first reaction to obtain a compound S5, mixing the compound S5 with high-temperature resistant oil, and carrying out a second reaction to obtain S6-Cl;
(4) and carrying out ion exchange on S6-Cl to obtain the compound shown in the formula (I).
Preferably, the brominating reagent in the step (2) is at least one of N-bromosuccinimide (NBS) and bromine.
Preferably, the high temperature resistant oil in the step (3) is at least one of mineral oil, liquid paraffin, octadecane and simethicone; further dimethyl silicone oil.
Preferably, the molar ratio of the compound S1 to the tryptamine in the step (1) is 1 (0.5-1.5); further 1: 1.
Preferably, before the compound S1 is mixed with tryptamine in step (1), the method further comprises the following steps: reacting compound S1 with I2Mixing and reacting for 1-3 h at 80-100 ℃.
Preferably, said compounds S1 and I2The molar ratio of (1) is (0.6-1.4); further 1: 0.8.
Preferably, compounds S1 and I2Before mixing, the compound S1 was dissolved in DMSO.
Preferably, the reaction in the step (1) is carried out for 3-5 hours at the temperature of 80-100 ℃.
Preferably, after the reaction in step (1), the method further comprises the following steps: ethyl Acetate (EA)/water extraction, NaS2O3Cleaning, removing solvent, separating and purifying.
Preferably, the separation and purification is performed by silica gel column chromatography; further preferably, the separation and purification is performed by silica gel column chromatography using 25-35 v/v% Ethyl Acetate (EA)/Petroleum Ether (PE) as an eluent.
Preferably, the molar ratio of the compound S2 to the brominating agent in the step (2) is 1 (0.5-1.5); further 1: 1.
Preferably, compound S2 is dissolved in acetic acid before the compound S2 is mixed with the brominating agent in step (2).
Preferably, the reaction in the step (2) is carried out at room temperature for 1-3 h.
Preferably, after the reaction in step (2), the method further comprises the following steps: EA/saturated NaHCO3Extracting, removing solvent, separating and purifying.
Preferably, the separation and purification is performed by silica gel column chromatography; further preferably, the separation and purification is carried out by silica gel column chromatography with 15-25 v/v% of EA/PE as an eluent.
Preferably, the compounds S3 and R in step (3)1-B(OH)2The molar ratio of (1) is (0.5-1.5); further 1: 1.
Preferably, the compounds S3 and R in step (3)1-B(OH)2Before mixing, the compound S3 was dissolved in dioxane and water.
Preferably, the first reaction in step (3) is performed under argon, Na2CO3And a catalyst.
Preferably, the catalyst is Pd2(dba)3、Pd(dppf)Cl2、Pd(PPh3)4At least one of (a); further Pd (PPh)3)4。
Preferably, the first reaction in the step (3) is carried out for 13-19 hours at the temperature of 80-100 ℃.
Preferably, the first reaction in step (3) further comprises the following steps: removing the solvent, separating and purifying.
Preferably, the separation and purification is performed by silica gel column chromatography; further preferably, the separation and purification is carried out by silica gel column chromatography with 20-30 v/v% of EA/PE as an eluent.
Preferably, the second reaction in the step (3) is carried out at 250-350 ℃ for 3-5 h.
Preferably, the second reaction in step (3) further comprises washing.
Preferably, when X-Is Cl-When the method for producing the same does not comprise the step (4).
In a third aspect of the invention, there is provided the use of a compound of formula (I) of the first aspect or a pharmaceutically acceptable salt thereof.
The invention also provides application of the compound shown in the formula (I) of the first aspect of the invention or pharmaceutically acceptable salts thereof in preparing an iron death inducer.
The use of a compound of formula (I) according to the first aspect of the invention or a pharmaceutically acceptable salt thereof for inducing iron death.
Preferably, the compound of formula (I) according to the first aspect of the invention or a pharmaceutically acceptable salt thereof is used for inducing iron death in vitro in a non-therapeutic manner.
Preferably, the induction of iron death is induction of cellular iron death.
Preferably, the cell is a non-small cell lung cancer cell.
Secondly, the invention also discloses application of the compound shown in the formula (I) of the first aspect of the invention or pharmaceutically acceptable salts thereof in preparing an iron accumulation inducer.
Preferably, the iron accumulation inducer is an iron ion accumulation inducer.
Preferably, the iron accumulation-inducing agent is used to induce an increase in the intracellular concentration of iron ions.
Preferably, the cell is a non-small cell lung cancer cell.
The use of a compound of formula (I) according to the first aspect of the invention or a pharmaceutically acceptable salt thereof for inducing iron accumulation.
Preferably, the compound of formula (I) according to the first aspect of the invention or a pharmaceutically acceptable salt thereof is used for inducing iron accumulation in vitro in a non-therapeutic destination.
Preferably, the induced iron accumulation is induced by an increase in the intracellular iron ion concentration.
Preferably, the cell is a non-small cell lung cancer cell.
The invention also provides application of the compound shown in the formula (I) of the first aspect of the invention or pharmaceutically acceptable salts thereof in preparing active oxygen inducers.
Preferably, the reactive oxygen species are intracellular reactive oxygen species.
Preferably, the intracellular reactive oxygen species comprises at least one of lipid reactive oxygen species and mitochondrial reactive oxygen species; further lipid active oxygen.
Preferably, the active oxygen inducer is an inducer that promotes the production and accumulation of active oxygen.
The use of a compound of formula (I) according to the first aspect of the invention or a pharmaceutically acceptable salt thereof for inducing an increase in reactive oxygen species.
Preferably, the compound of formula (I) according to the first aspect of the invention or a pharmaceutically acceptable salt thereof is used for inducing an increase in reactive oxygen species in vitro in a non-therapeutic manner.
Preferably, the reactive oxygen species are intracellular reactive oxygen species.
Preferably, the intracellular reactive oxygen species comprises at least one of lipid reactive oxygen species and mitochondrial reactive oxygen species; further lipid active oxygen.
The application of the compound shown in the formula (I) of the first aspect of the invention or the pharmaceutically acceptable salt thereof in preparing the GPX4 inhibitor.
Preferably, the GPX4 inhibitor is an inhibitor that inhibits expression of GPX4 protein.
Preferably, the GPX4 inhibitor is used to inhibit GPX4 protein expression in a cell.
Preferably, the cell is a non-small cell lung cancer cell.
The invention relates to application of a compound shown in a formula (I) of a first aspect or a pharmaceutically acceptable salt thereof in inhibiting expression of GPX 4.
Preferably, the compound of formula (I) of the first aspect of the invention or a pharmaceutically acceptable salt thereof is for use in inhibiting GPX4 expression in vitro in a non-therapeutic setting.
Preferably, the inhibition of GPX4 expression is inhibition of GPX4 protein expression in a cell.
Preferably, the cell is a non-small cell lung cancer cell.
And fifthly, the application of the compound shown in the formula (I) of the first aspect of the invention or the pharmaceutically acceptable salt thereof in preparing the SLC7A11 inhibitor.
Preferably, the SLC7a11 inhibitor is an inhibitor of the expression of SLC7a11 protein.
Preferably, the SLC7a11 inhibitor is used for inhibiting the expression of SLC7a11 protein in a cell.
Preferably, the cell is a non-small cell lung cancer cell.
The invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the inhibition of SLC7A11 expression.
Preferably, the use of a compound of formula (I) according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, for inhibiting the expression of SLC7a11 in vitro in a non-therapeutic setting.
Preferably, said inhibition of expression of SLC7a11 is inhibition of intracellular expression of SLC7a11 protein.
Preferably, the cell is a non-small cell lung cancer cell.
Sixthly, the application of the compound shown in the formula (I) of the first aspect of the invention or the pharmaceutically acceptable salt thereof in preparing the FTH1 inhibitor.
Preferably, the FTH1 inhibitor is an inhibitor that inhibits expression of FTH1 protein.
Preferably, the FTH1 inhibitor is used to inhibit expression of FTH1 protein in a cell.
Preferably, the cell is a non-small cell lung cancer cell.
The use of a compound of formula (I) according to the first aspect of the invention, or a pharmaceutically acceptable salt thereof, for inhibiting expression of FTH 1.
Preferably, the compound of formula (I) of the first aspect of the invention or a pharmaceutically acceptable salt thereof is used for inhibiting expression of FTH1 in vitro in a non-therapeutic manner.
Preferably, said inhibition of FTH1 expression is inhibition of intracellular FTH1 protein expression.
Preferably, the cell is a non-small cell lung cancer cell.
Seventhly, the compound shown in the formula (I) of the first aspect of the invention or the pharmaceutically acceptable salt thereof is applied to preparing antitumor drugs.
Preferably, the tumor is lung cancer; further non-small cell lung cancer.
In a fourth aspect of the invention, there is provided a product comprising a compound of formula (I) according to the first aspect of the invention or a pharmaceutically acceptable salt thereof.
Preferably, the product is at least one of a pharmaceutical product and an agent.
Preferably, the product has any one of functions (w1) to (w 7):
(w1) treating tumors;
(w2) induction of iron death;
(w3) inducing iron accumulation;
(w4) inducing an increase in reactive oxygen species;
(w5) inhibits GPX4 expression;
(w6) inhibits SLC7a11 expression;
(w7) inhibits FTH1 expression.
Preferably, the tumor is lung cancer; further non-small cell lung cancer.
The invention has the beneficial effects that:
the invention discloses a Fascaplysin derivative, the chemical structural formula of which is shown in formula (I), the Fascaplysin derivative can induce iron death, induce iron accumulation, induce active oxygen increase, inhibit the expression of GPX4, SLC7A11 and FTH1, has good iron death induction effect, can be used as an iron death inducer to induce the death of tumor cells, and is used for treating tumors.
The invention also discloses a preparation method of the Fascaplysin derivative, which has the advantages of simple preparation method, mild reaction conditions, convenient operation and control, low energy consumption, high yield, low cost, suitability for industrial production, higher bioactivity of the prepared compound and wide market prospect.
Drawings
FIG. 1 is a scheme for the synthesis of Fascaplysin derivative (Mar-5) in example 1.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of S2 in example 1.
FIG. 3 is a mass spectrum of S2 in example 1.
Fig. 4 is a partially enlarged view of the mass spectrum of S2 in example 1.
FIG. 5 is a NMR spectrum of S3 in example 1.
FIG. 6 is a mass spectrum of S3 in example 1.
Fig. 7 is a partial enlarged view of the mass spectrum of S3 in example 1.
FIG. 8 is a NMR spectrum of S6 in example 1.
FIG. 9 is a mass spectrum of S6 in example 1.
Fig. 10 is a partial enlarged view of the mass spectrum of S6 in example 1.
FIG. 11 is a graph showing the effect of Mar-5 on H358 cells.
FIG. 12 is a graph of the effect of Mar-5 on GPX4, SLC7A11, FTH1 in H358 cells: wherein, A is a WesternBlot result chart of the effect of Mar-5 on GPX4, SLC7A11 and FTH1 in H358 cells; b is a graph of the statistics of the effect of Mar-5 on the relative expression of GPX4 in H358 cells; c is a statistical plot of the effect of Mar-5 on the relative expression of SLC7A11 in H358 cells; d is a graph of the statistical results of the effect of Mar-5 on the relative expression of FTH1 in H358 cells; p < 0.05; denotes p < 0.01.
FIG. 13 is a graph of the effect of Mar-5 on lipid reactive oxygen species content in H358 cells: wherein A is a flow cytogram of the effect of Mar-5 on lipid reactive oxygen species content in H358 cells; b is a graph of the statistics of the effect of Mar-5 on lipid reactive oxygen species content in H358 cells; p < 0.05; denotes p < 0.01.
FIG. 14 is a graph showing the effect of Mar-5 on iron concentration in H358 cells; the scale bar is 50 μm.
Detailed Description
The present invention will be described in further detail with reference to specific examples.
It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The materials, reagents and the like used in the present examples are commercially available reagents and materials unless otherwise specified.
The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. The materials, reagents and the like used in the present examples are commercially available reagents and materials unless otherwise specified. The room temperature in this embodiment is 23 to 30 ℃.
EXAMPLE 1 preparation of Fascaplysin derivative (Mar-5)
The synthesis route of Fascaplysin derivative (Mar-5) is shown in FIG. 1, and the specific steps are as follows:
(1) to a DMSO solution (50mL) containing S1(1.55g, 10mmol) was added I2(2.03g, 8mmol) to give mixture A, which is heated at 90 ℃ for 2 hours; tryptamine (1.6g, 10mmol) was then added to mixture A to give mixture B, which was heated at 90 deg.C for 4 hours, extracted with Ethyl Acetate (EA)/water, and NaS2O3(5 wt% aqueous solution) washing; the solvent was removed and the residue was purified by column chromatography on silica gel (30 v/v% Ethyl Acetate (EA)/Petroleum Ether (PE)) to give S2(220mg, yield 72%); the hydrogen spectrum of S2 is shown in fig. 2:1h NMR (400MHz, DMSO) δ 12.19(s,1H),8.45(q, J ═ 4.9Hz,2H),8.34(d, J ═ 7.8Hz,1H), 7.90-7.82 (m,1H),7.63(dd, J ═ 13.1,7.6Hz,2H),7.57(t, J ═ 5.6Hz,2H),7.50(dd, J ═ 9.2,4.1Hz,1H),7.34(t, J ═ 7.5Hz, 1H); the mass spectrum is shown in FIGS. 3 and 4：HRMS(ESI)(M+H)/z＝307.1。
(2) S2(154mg,0.5mmol) was added to a solution of acetic acid (AcOH) (5mL) and N-bromosuccinimide (NBS, 154mg,0.5mmol) was slowly added to the solution of acetic acid containing S2 at room temperature to give mixture C; the mixture was stirred at room temperature for C2 h and passed through EA (100 mL)/saturated NaHCO3Extracting with solution (100 mL); the solvent was removed and the residue was purified by column chromatography on silica gel (20 v/v% EA/PE) to give S3(85mg, yield 35%); the hydrogen spectrum of S3 is shown in fig. 5:1h NMR (400MHz, DMSO) δ 12.33(s,1H),8.63(d, J ═ 1.2Hz,1H),8.52(d, J ═ 4.9Hz,1H),8.48 to 8.44(m,1H),7.82 to 7.74(m,2H),7.63 to 7.60(m,1H),7.57(dd, J ═ 4.7,1.6Hz,2H),7.52 to 7.48(m, 1H); the mass spectrum is shown in FIGS. 6 and 7: hrms (esi) (M + H)/z 385.
(3) S3(243mg, 0.5mmol) was added to a solution of dioxane (15mL) and water (3mL), and 4-trifluoromethylphenylboronic acid (95mg, 0.5mmol) and Na were added to a solution of dioxane and water containing S3 under argon2CO3(106mg, 1mmol) and Pd (PPh)3)4(40mg) to give mixture D, heating mixture D at 90 ℃ for 16 h, removing the solvent, and purifying the residue by column chromatography on silica gel (25 v/v% EA/PE) to give S5(120mg crude, yield about 70%), dissolving S5(100mg, 0.13mmol) in dimethicone (15mL), heating the solution of dimethicone containing S5 to 300 ℃ for 3-5 h, washing the mixture with PE, 30% EA/PE in that order to give product S6(60mg, yield about 60%), and the hydrogen profile of S6 is shown in FIG. 8:1h NMR (400MHz, DMSO) δ 13.63(s,1H),9.70(s,1H),9.23(s,1H),9.05(s,1H),8.49(d, J ═ 8.0Hz,1H),8.30(s,1H),8.06(d, J ═ 8.0Hz,4H), 7.97-7.87 (m,3H),7.76(d, J ═ 6.8Hz,1H), mass spectra are shown in fig. 9, 10: HRMS (ESI) (M)+)/z＝415.1。
Effects of the embodiment
Mar-5 is dissolved in DMSO to prepare a mother solution with the concentration of 20mM for experiments.
1. H358 cells were cultured in H1640 medium (containing 10 v/v% fetal calf serum and 1 v/v% penicillin/streptomycin) in 5% CO2Culturing in an incubator at 37 ℃; h358 cells were sampled at 1X105After 24 hours of culture, the cells are plated in 12-well plates at a density of one cell/mL and divided into 3 groups, wherein the first group is a blank control group (control), the second group is treated by adding Mar-5 (the final concentration is 2 mu M and Mar-052 mu M), the third group is treated by adding Mar-5 and an iron death inhibitor Fer-1 (the final concentration of Mar-5 is 2 mu M and the final concentration of the iron death inhibitor Fer-1 is 10uM, and the Mar-052 mu M + Fer-110 uM), and after 24 hours of treatment, the cells are photographed and observed by an inverted microscope. The results are shown in FIG. 11: the number of viable cells in the second group (Mar-052. mu.M) was significantly less than that in the first group (control), while the number of viable cells in the third group (Mar-052. mu.M + Fer-110 uM) was significantly greater than that in the second group (Mar-052. mu.M), indicating that Mar-5 induced H358 cell ferrodeath.
2. H358 cells were cultured in H1640 medium (containing 10 v/v% fetal calf serum and 1 v/v% penicillin/streptomycin) in 5% CO2Culturing in an incubator at 37 ℃; h358 cells were sampled at 1X105After culturing for 24 hours, the cells were treated with Mar-5 for 24 hours at four concentration gradients of 0, 0.5, 1 and 2. mu.M, each of which was repeated 3 times, cells were collected by trypsinization at 3000r/min, the supernatant was discarded after centrifugation for 5 minutes, and then lysed with RIPA lysate on ice to collect cellular proteins. And (3) carrying out SDS-PAGE electrophoresis on the collected protein samples, and placing the protein samples in a membrane transfer instrument for membrane transfer. After membrane transfer, primary antibody (1: 1000) GPX4(Cell Signaling Technology, #52455), SLC7A11(Cel l Signaling Technology, #12691), FTH1(abclonal, A1144) and GAPDH (Shanghai Biotech, D110016-0100) were incubated overnight at 4 ℃; washing the membrane the next day, adding diluted (1: 5000) secondary Antibody (Anti-rabbitIgG, HRP-l inked Antibody, CST, 7074S), and incubating at room temperature for 1 h; after the secondary antibody incubation was completed, the image was developed with a developing instrument. The results are shown in FIG. 12: the expression of iron death critical proteins GPX4, FTH1 and SLC7A11 in the H358 cells after Mar-5 treatment is down-regulated, and the reduction is more obvious along with the increase of the concentration of Mar-5.
3. Flow cytometry detection of intracellular lipid reactive oxygen species: h358 cells were selected for the logarithmic phase of growth at 1X105Plating each/mL of the mixture in a 12-well plate, culturing for 24h, treating with Mar-5 at four concentration gradients of 0, 0.5, 1 and 2 mu M for 24h, repeating each treatment for 3 times, and after 24h, using serum-free mediumAfter washing the cells 2 times, the cells were washed with C11-BODIPY 581/591 at a final concentration of 10. mu.M at 37 ℃ in 5% CO2Incubate in incubator for 1 hr. After incubation, the cells were washed twice with PBS to remove excess dye; cells were then trypsinized, resuspended in PBS containing 5% FBS, and finally fluorescence detected by flow cytometry and analyzed. The results are shown in FIG. 13: under the stimulation of Mar-5, the content of intracellular lipid active oxygen increases along with the increase of the concentration of Mar-5, the content of intracellular lipid active oxygen increases, and the accumulation of the lipid active oxygen is a key mark for inducing iron death, which indicates that Mar-5 can effectively induce the H358 cells of the non-small cell lung cancer cell line cells to generate the iron death.
4. Determination of iron concentration: inoculation of 1X10 in 12-well plates5H358 cells, 37 ℃ and 5% CO2The culture was carried out in an incubator for 24 hours. Three experimental groups were set up, wherein the first group was a blank control group (blank control), the second group was treated by adding Mar-5 (final concentration: 2. mu.M, Mar-52. mu.M), the third group was treated by adding iron chelator DFOM and Mar-5 (final concentration: 2. mu.M for Mar-5, final concentration: 50. mu.M for iron chelator DFOM, and final concentration: Mar-052. mu.M + DFOM 50. mu.M), the medium was discarded after culturing for 24 hours, washed 2 times with serum-free medium, and 1mL of 10. mu.M Fe rrOrang probe prepared with serum-free medium was added thereto at 37 ℃ and 5% CO2Incubate in incubator for 30min, take pictures with confocal microscope, and result is shown in fig. 14: the fluorescence intensity of iron ions in H358 cells is obviously stronger after the Mar-5 is added than that of a blank control group, and the fluorescence intensity is weakened after the iron death chelating agent DFOM is added, which shows that the Mar-5 can improve the increase of the iron ions in the H358 cells.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
in the formula (I), X-Selected from Cl-、F-、Br-、I-、HCO3 -、HSO4 -、H2PO5 -、(0.5)HPO5 2-、(1/3)PO5 3-、(1/6)PF6-、CH3CO2 -、CF3CO2 -、CO2HCO2 -、(0.5)CO2CO2 2-、(0.5)CO2(CH2)nCO2 2-、PhCO2 -、CH3SO3 -、PhSO3 -、CF3SO3 -、(p)-Me-PhSO3 -Wherein n is 1-20;
R1any one selected from the following groups:
wherein n is 1-20.
2. A process for the preparation of a compound of formula (I) according to claim 1, which is carried out by the following synthetic route:
the method comprises the following steps:
(1) mixing the compound S1 with tryptamine, and reacting to obtain a compound S2;
(2) mixing the compound S2 with a brominating agent, and reacting to obtain a compound S3;
(3) compounds S3 and R1-B(OH)2Mixing, carrying out the first reaction to obtain a compound S5Mixing the mixture S5 with high temperature resistant oil, and reacting for the second time to obtain S6-Cl;
(4) ion-exchanging S6-Cl to obtain the compound of formula (I) according to claim 1.
3. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 in the preparation of an antitumor medicament.
4. Use according to claim 3, characterized in that:
the tumor is lung cancer.
5. Use of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 in any one of (b1) to (b 2);
(b1) preparing an iron death inducer;
(b2) iron death was induced.
6. Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in any one of (c1) to (c 2);
(c1) preparing an iron accumulation inducer;
(c2) inducing iron accumulation.
7. Use of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof in any one of (d1) to (d 2);
(d1) preparing an active oxygen inducer;
(d2) inducing an increase in active oxygen.
8. Use of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 in any one of (f1) to (f 6);
(f1) preparing a GPX4 inhibitor;
(f2) inhibiting expression of GPX 4;
(f3) preparing an SLC7a11 inhibitor;
(f4) inhibits SLC7a11 expression;
(f5) preparing an FTH1 inhibitor;
(f6) inhibiting expression of FTH 1.
9. A product comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
10. The product of claim 9, wherein:
the product has any one of functions (w1) to (w 7):
(w1) treating tumors;
(w2) induction of iron death;
(w3) inducing iron accumulation;
(w4) inducing an increase in reactive oxygen species;
(w5) inhibits GPX4 expression;
(w6) inhibits SLC7a11 expression;
(w7) inhibiting expression of FTH 1;
preferably, the product is at least one of a pharmaceutical product and an agent.
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