CN112608302B - 低氧还原激活靶向泛素化降解egfr蛋白的喹唑啉类衍生物及其应用 - Google Patents
低氧还原激活靶向泛素化降解egfr蛋白的喹唑啉类衍生物及其应用 Download PDFInfo
- Publication number
- CN112608302B CN112608302B CN202011576814.1A CN202011576814A CN112608302B CN 112608302 B CN112608302 B CN 112608302B CN 202011576814 A CN202011576814 A CN 202011576814A CN 112608302 B CN112608302 B CN 112608302B
- Authority
- CN
- China
- Prior art keywords
- ethoxy
- fluorophenyl
- oxy
- chloro
- amino
- 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
- 230000034512 ubiquitination Effects 0.000 title claims abstract description 9
- 238000010798 ubiquitination Methods 0.000 title claims abstract description 9
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 title claims abstract 3
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 title claims abstract 3
- 230000009467 reduction Effects 0.000 title claims description 6
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract 2
- 229910052760 oxygen Inorganic materials 0.000 title description 5
- 230000015556 catabolic process Effects 0.000 title description 4
- 238000006731 degradation reaction Methods 0.000 title description 4
- 239000001301 oxygen Substances 0.000 title description 3
- 230000003213 activating effect Effects 0.000 title 1
- 206010021143 Hypoxia Diseases 0.000 claims abstract description 21
- 230000007954 hypoxia Effects 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims abstract description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 3
- 239000000460 chlorine Substances 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims abstract description 3
- 239000011737 fluorine Substances 0.000 claims abstract description 3
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 2
- 150000003246 quinazolines Chemical class 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 12
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 10
- 230000004913 activation Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- -1 3-(2-(2-((4-((3-Chloro-4-fluorophenyl)(4-nitrobenzyl)amino)-7-methoxyquinazolin-6-yl)oxy )ethoxy)ethoxy)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propanamide Chemical compound 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 229940080818 propionamide Drugs 0.000 claims description 4
- GCBQLLFQZNNEOQ-UHFFFAOYSA-N COC(C=C(C1=C2)N=CN=C1N(CC(C=C1)=CC=C1[N+]([O-])=O)C(C=C1)=CC(Cl)=C1F)=C2OCCOCCOCCOCCOCCC(NC1=C(CN(C(CCC(N2)=O)C2=O)C2=O)C2=CC=C1)=O Chemical compound COC(C=C(C1=C2)N=CN=C1N(CC(C=C1)=CC=C1[N+]([O-])=O)C(C=C1)=CC(Cl)=C1F)=C2OCCOCCOCCOCCOCCC(NC1=C(CN(C(CCC(N2)=O)C2=O)C2=O)C2=CC=C1)=O GCBQLLFQZNNEOQ-UHFFFAOYSA-N 0.000 claims description 2
- WEIVLKTYXPUEST-UHFFFAOYSA-N COC(C=C(C1=C2)N=CN=C1N(CC(C=C1)=CC=C1[N+]([O-])=O)C(C=C1)=CC(Cl)=C1F)=C2OCCOCCOCCOCCOCCC(NC1=C2OC(C(CCC(N3)=O)C3=O)OC2=CC=C1)=O Chemical compound COC(C=C(C1=C2)N=CN=C1N(CC(C=C1)=CC=C1[N+]([O-])=O)C(C=C1)=CC(Cl)=C1F)=C2OCCOCCOCCOCCOCCC(NC1=C2OC(C(CCC(N3)=O)C3=O)OC2=CC=C1)=O WEIVLKTYXPUEST-UHFFFAOYSA-N 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 25
- 230000000694 effects Effects 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 230000008685 targeting Effects 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000004663 cell proliferation Effects 0.000 abstract 1
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- 102000001301 EGF receptor Human genes 0.000 description 24
- 108060006698 EGF receptor Proteins 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 230000000593 degrading effect Effects 0.000 description 5
- 230000001146 hypoxic effect Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000007959 normoxia Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- JAELLLITIZHOGQ-UHFFFAOYSA-N tert-butyl propanoate Chemical compound CCC(=O)OC(C)(C)C JAELLLITIZHOGQ-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- 239000006180 TBST buffer Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940121647 egfr inhibitor Drugs 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- TZZDVPMABRWKIZ-XMOGEVODSA-N (3S)-3-[6-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound OC=1C=C2CC[C@@H]([C@@H](C2=CC=1)C1=CC=C(C=C1)N1CCC(CC1)CN1CCN(CC1)C=1C=C2CN(C(C2=CC=1)=O)[C@@H]1C(NC(CC1)=O)=O)C1=CC=CC=C1 TZZDVPMABRWKIZ-XMOGEVODSA-N 0.000 description 1
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 description 1
- 241000400611 Eucalyptus deanei Species 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
- CLCTZVRHDOAUGJ-UHFFFAOYSA-N N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[[4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl]piperidin-1-yl]pyridazine-3-carboxamide Chemical compound FC1=CC2=C(C=C1N1CCN(CC3CCN(CC3)C3=CC=C(N=N3)C(=O)NC3CCC(CC3)OC3=CC(Cl)=C(C=C3)C#N)CC1)C(=O)N(C1CCC(=O)NC1=O)C2=O CLCTZVRHDOAUGJ-UHFFFAOYSA-N 0.000 description 1
- JLVTVCRXFMLUIF-UHFFFAOYSA-N O-Desmorpholinopropyl Gefitinib Chemical compound C=12C=C(O)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 JLVTVCRXFMLUIF-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012160 loading buffer Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000011865 proteolysis targeting chimera technique Methods 0.000 description 1
- 229940124823 proteolysis targeting chimeric molecule Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 108010026668 snake venom protein C activator Proteins 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域，具体涉及一类喹唑啉类衍生物，其结构如下所示：
其中，R1、R2和R3各自独立地选自氢、氯、氟、溴、乙炔基或三氟甲基；X为‑CH2‑或‑C(O)‑；n=1、2、3、4、5或6。药理实验表明，此类衍生物或其药学上可接受的盐具有在肿瘤低氧下被还原活化，靶向泛素化降解EGFR蛋白，从而抑制肿瘤细胞增殖的作用。
Description
技术领域
本发明属于药物化学技术领域，具体涉及一类低氧还原激活靶向泛素化降解EGFR蛋白的喹唑啉类衍生物及其在肿瘤治疗领域的应用。
背景技术
肿瘤是威胁人类健康的重大疑难疾病。科学技术的发展使肿瘤的治疗取得了巨大的进步。近年来，以表皮生长因子受体(EGFR)为靶点，成功开发了第一到第四代EGFR抑制剂，其中前三代EGFR抑制剂均已成功上市，用于非小细胞肺癌等肿瘤的治疗。
蛋白降解靶向联合体(Proteolysis Targeting Chimera，PROTAC)是一类能够通过诱导靶蛋白的多聚泛素化而导致靶蛋白降解的化合物。与以往小分子抑制剂不同(对靶蛋白产生抑制效果而达到抗肿瘤的目的)，PROTAC分子通过将靶蛋白降解而发挥抗肿瘤作用。PROTAC作为双功能分子，是药物研发领域的一个新兴方向。目前，已有数百种PROTAC类分子被开发。其中，靶向雄激素受体的分子ARV-110和雌激素受体的分子ARV-471已于2019年被FDA批准进行I期临床试验(NCT0388612和NCT04072952)，用于肿瘤的治疗。然而，PROTAC分子也存在一些潜在缺陷，此类药物对正常组织通常表现出高于其所连接的靶向性药物的毒性。因此，对PROTAC分子进行优化，使之不仅能够对肿瘤组织产生杀伤作用，而且对正常组织无作用，对于减小PROTAC类药物的毒性，开发具有自主知识产权的药物，解决肿瘤持续恶化的问题，具有显著的科学意义和潜在的应用价值。
肿瘤的类别中，实体瘤占了80％～90％，而低氧是实体瘤发展过程中必经的环境之一(Nature Reviews Clinical Oncology,2012,9,(12),674-687.)。同时，低氧的存在促使部分蛋白大量表达，从而又增加了肿瘤的存活力。比如，研究发现，处于低氧环境下的肺癌A549细胞，其EGFR的表达量是常氧下的2倍以上。因此，可以针对肿瘤低氧的特性，以在低氧下过表达的蛋白(如EGFR)作为靶蛋白，设计一类低氧活化型PROTAC，使之选择性的在肿瘤组织中被还原活化，发挥降解靶蛋白、杀死肿瘤细胞的作用。而在正常组织中由于分子处于非活化状态，从而不发挥作用，减小了副作用。
发明内容
本发明目的在于提供一种低氧还原激活靶向泛素化降解EGFR蛋白的喹唑啉类衍生物(PROTAC分子)，此类衍生物以EGFR为靶蛋白，在肿瘤低氧环境中经还原活化来降解肿瘤细胞中的EGFR，从而抑制肿瘤细胞的增殖；同时在正常组织中，由于氧分供应充足，衍生物处于非活化状态，减小了副作用。
本发明还提供了上述低氧还原激活靶向泛素化降解EGFR蛋白的喹唑啉类衍生物的制备方法及其在制备抗癌(肿瘤)药物中的应用。
为实现上述目的，本发明采用如下技术方案：
一类低氧还原激活靶向泛素化降解EGFR蛋白的喹唑啉类衍生物或其药学上可接受的盐，其结构如下所示：
其中，R1、R2和R3各自独立地选自氢、氯、氟、溴、乙炔基或三氟甲基；X为-CH2-或-C(O)-(羰基)；n＝1、2、3、4、5或6。
进一步的，上述的喹唑啉类衍生物或其药学上可接受的盐优选为下述任意一种化合物：
3-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)-N-(2-(2，6-二氧哌啶-3-基)-1-氧代异吲哚啉-4-基)丙酰胺；
3-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丙酰胺；
3-(2-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)-N-(2-(2，6-二氧代吲哚啉-3-基)-1-氧代异吲哚啉-4-基)丙酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-3，6，9，12-四氧杂十五烷-15-酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-3，6，9，12，15-五氧杂十八烷-18-酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-3，6，9，12，15，18-六氧杂二十一烷-21-酰胺；
3-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)-N-(2-(2，6-二氧杂哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)丙酰胺；
3-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)-N-(2-(2，6-二氧杂哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)丙酰胺；
3-(2-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)-N-(2-(2，6-二氧杂哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)丙酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)-3，6，9，12-四氧杂十五烷-15-酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)-3，6，9，12，15-五氧杂十八烷-18-酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)-3，6，9，12，15，18-六氧杂二十一烷-21-酰胺。
本发明还提供了上述喹唑啉类衍生物或其药学上可接受的盐在制备抗癌(肿瘤)药物中的应用，即用于肿瘤的治疗。
进一步的，本发明述还提供了上述喹唑啉类衍生物或其药学上可接受的盐在制备预防和治疗肺癌药物中的应用。
和现有技术相比，本发明的有益效果如下：
本发明创新性的提供了一类低氧还原激活靶向泛素化降解EGFR蛋白的喹唑啉类衍生物(PROTAC)分子，该类衍生物以EGFR为靶蛋白，在肿瘤低氧环境中经还原活化来降解肿瘤细胞中的EGFR，而在正常组织中，由于氧分供应充足，衍生物处于非活化状态，从而减小了副作用。试验结果显示：本发明所涉及靶向泛素化降解EGFR蛋白的喹唑啉类衍生物具有在肿瘤低氧环境下经还原活化后降解EGFR的作用，从而发挥肿瘤增殖抑制作用，可用于癌症尤其是肺癌的预防和治疗。
附图说明
图1为实施例5化合物的氢谱数据；
图2为实施例5化合物选择性在低氧下降解EGFR蛋白的作用机制；
图3为实施例5化合物在常氧和低氧下对EGFR蛋白的降解作用。
具体实施方式
以下结合实施例对本发明的技术方案作进一步地详细介绍，但本发明的保护范围并不局限于此。
实施例1：制备3-(2-(2-(2-(甲苯磺酰氧代)乙氧基)乙氧基)乙氧基)丙酸叔丁酯(1)
将对甲苯磺酰氯(0.75g,3.95mmol)加入到含有3-(2-(2-(2-羟基乙氧基)乙氧基)丙酸叔丁酯(1.0g，3.59mmol)和三乙胺(1.45g，14.36mmol)的二氯甲烷(10mL)混合液中，反应液在室温下搅拌约2h。待反应结束后，反应液中加入10mL二氯甲烷，用饱和食盐水(3x20mL)萃取，有机相用无水硫酸钠干燥，浓缩。所得粗品经硅胶柱色谱(石油醚：乙酸乙酯＝3:1)纯化，得纯品1.47g(收率：94.8％)。1H NMR(400MHz,CDCl3)δ7.78(d,J＝8.1Hz,2H),7.32(d,J＝8.0Hz,2H),4.18–4.10(m,2H),3.81–3.48(m,12H),2.59–2.37(m,5H),1.42(s,9H)。
实施例2：制备3-(2-(2-(2-((4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯(2)
将3-(2-(2-(2-(甲苯磺酰氧代)乙氧基)乙氧基)乙氧基)丙酸叔丁酯(1.0g,2.31mmol)加入到含有4-((3-氯-4-氟苯基)氨基)-7-甲氧基喹唑啉-6-醇(0.70g,2.20mmol)和碳酸钾(0.18g,1.32mmol)的无水二甲基甲酰胺(DMF，10mL)混合液中，在80℃反应约1h。待反应结束后，蒸除反应体系中溶剂，加入乙酸乙酯(30mL)，用饱和食盐水(6x20mL)萃取，有机相浓缩得粗品，硅胶柱色谱分离纯化(二氯甲烷:甲醇＝100:3)得纯品，为无色油状物(1.26g,收率：98.5％)。1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.45(s,1H),7.94–7.89(m,1H),7.67–7.60(m,1H),7.52(s,1H),7.28(s,1H),7.20–7.06(m,2H),4.27–4.21(m,2H),3.91–3.84(m,5H),3.74–3.64(m,4H),3.63–3.57(m,4H),3.57–3.52(m,2H),2.42-2.35(m,2H),1.38(s,9H)。
实施例3：制备3-(2-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯(3)
将3-(2-(2-(2-((4-((3-氯-4-氟苯基)氧基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯(350mg,0.60mmol)和1-(溴甲基)-4-硝基苯(391mg,1.8mmol)同时加入含有碳酸铯(Cs2CO3，205mg,0.63mmol)的无水二甲基甲酰胺(10mL)混合液中，室温反应约3h。待反应结束后，反应体系中加入乙酸乙酯(40mL)，用饱和食盐水萃取(6x20mL)，收集有机相，无水硫酸钠干燥，浓缩，得粗品，硅胶柱色谱分离纯化(二氯甲烷:乙酸乙酯＝2:1)得淡黄色油状物(271mg,收率：63.2％)。1H NMR(400MHz,CDCl3)δ8.73(s,1H),8.18–8.13(m,2H),7.59–7.52(m,2H),7.22(s,1H),7.20–7.16(m,1H),7.14–7.08(m,1H),6.98–6.92(m,1H),6.49(s,1H),5.45(s,2H),3.97(s,3H),3.76–3.55(m,14H),2.52-.48(m,2H),1.44(s,9H)。
实施例4：制备3-(2-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)乙氧基)丙酸(4)
将三氟乙酸(1mL)逐滴加入到3-(2-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)乙氧基)丙酸叔丁酯(271mg)的DCM(5mL)溶液中，室温反应1h。待反应结束后，减压蒸除反应液，对残余物进行硅胶柱色谱分离纯化(二氯甲烷:甲醇＝100:4)，得黄色油状物(215mg，收率：86.0％)。1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.16(d,J＝8.6Hz,2H),7.68(s,1H),7.49(d,J＝8.6Hz,2H),7.43–7.37(m,1H),7.36–7.28(m,1H),7.16–7.09(m,1H),6.30(s,2H),5.57(s,2H),4.00(s,3H),3.79–3.48(m,14H),2.59–2.44(m,2H)。
实施例5：制备3-(2-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧代异吲哚啉-4-基)丙酰胺(5)
将2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU，171mg,0.45mmol)和N,N-二异丙基乙胺(DIEA，116mg,0.90mmol)加入到含有3-(2-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)乙氧基)丙酸(200mg,0.30mmol)和来那度胺(82mg,0.32mmol)的无水二甲基甲酰胺(3mL)混合液中，室温反应约5h。待反应结束后，反应体系中加入乙酸乙酯(20mL)，用饱和食盐水萃取(6x10mL)，收集有机相，无水硫酸钠干燥，浓缩，得粗品，柱分(二氯甲烷:甲醇＝100:3)得棕色胶状物(72mg,收率：26.7％)。1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.76(s,1H),8.70(s,1H),8.16(d,J＝8.7Hz,2H),7.72(d,J＝7.9Hz,1H),7.67(d,J＝7.5Hz,1H),7.57(d,J＝8.7Hz,2H),7.41(t,J＝7.7Hz,1H),7.26(s,1H),7.20(dd,J＝6.4,2.7Hz,1H),7.10(t,J＝8.6Hz,1H),7.00–6.93(m,1H),6.41(s,1H),5.47(s,2H),5.18(dd,J＝13.2,5.2Hz,1H),4.42(s,2H),3.94(s,3H),3.84(t,J＝5.5Hz,2H),3.77–3.47(m,12H),2.91–2.13(m,6H)，详见图1。
以上述实施例5制备获得的化合物3-(2-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)乙氧基)-N-(2-(2,6-二氧哌啶-3-基)-1-氧代异吲哚啉-4-基)丙酰胺(5)为例，进行相关的肿瘤试验，具体如下。
应用试验：Western-blot测定EGFR蛋白降解方法
将人肺癌细胞HCC4006从液氮中取出，复苏，传代，均匀铺于细胞培养板，第二天加入不同浓度的药物，分别在常氧(20％O2)或低氧(1％O2)条件下，37℃孵育24h后收集，用生理盐水洗涤2次，每孔加入SDS裂解液(SDS:double distilled water＝2:1000比例配置)120uL，室温放置5min，金属浴100℃，30min，离心涡旋取全液，即细胞总蛋白。用BCA法定量检测蛋白量，用5x蛋白上样缓冲液稀释蛋白后100℃变性5min。蛋白在SDS-PAGE电泳分离，转膜，TBST稀释获得5％的脱脂奶粉封闭液(5g/100mL)封闭1h，一抗(Anti-GAPDH大鼠单克隆抗体和EGFR抗体)4℃孵育过夜。TBST洗膜，二抗(HRP标记山羊抗小鼠lgG和HRP标记山羊抗兔lgG，1:1000稀释)室温孵育1h，化学发光仪曝光显影，得到EGFR的蛋白印记条带，结果见图3。
从图3的结果可看出：在常氧条件下，实施例5所示化合物对HCC4006细胞中EGFRDel19基本无降解作用；而在低氧条件下，实施例5所示化合物在10μM浓度下，对EGFRDel19的降解率超过50％，低氧下降解EGFR蛋白的作用机制见图2。由此说明，该化合物能够在肿瘤低氧环境下被激活，降解EGFRDel19，发挥肿瘤增殖抑制作用，而在常氧下无明显作用。由于正常组织多处于常氧状态，因此，本发明化合物可以降低对正常组织的毒性。
综上，本发明喹唑啉类衍生物能够在低氧环境下经还原活化后降解EGFR，发挥肿瘤增殖抑制作用，可用于癌症尤其是肺癌的预防和治疗。
Claims (4)
1.一类低氧还原激活靶向泛素化降解EGFR蛋白的喹唑啉类衍生物或其药学上可接受的盐，其结构如下所示：
其中，R1、R2和R3各自独立地选自氢、氯、氟、溴、乙炔基或三氟甲基；X为-CH2-或-C(O)-；n=1、2、3、4、5或6。
2.根据权利要求1所述的喹唑啉类衍生物或其药学上可接受的盐，其特征在于，所述喹唑啉类衍生物为下述任意一种化合物：
3-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)-N -(2-(2，6-二氧哌啶-3-基)-1-氧代异吲哚啉-4-基)丙酰胺；
3-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)丙酰胺；
3-(2-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)乙氧基)-N-(2-(2，6-二氧代吲哚啉-3-基)-1-氧代异吲哚啉-4-基)丙酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-3，6，9，12-四氧杂十五烷-15-酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-3，6，9，12，15-五氧杂十八烷-18-酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1-氧代异吲哚啉-4-基)-3，6，9，12，15，18-六氧杂二十一烷-21-酰胺；
3-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)-N -(2-(2，6-二氧杂哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)丙酰胺；
3-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)-N-(2-(2，6-二氧杂哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)丙酰胺；
3-(2-(2-(2-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)乙氧基)乙氧基)乙氧基)-N-(2-(2,6-二氧杂哌啶-3-基)-1,3-二氧杂吲哚啉-4-基)丙酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)-3，6，9，12-四氧杂十五烷-15-酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)-3，6，9，12，15-五氧杂十八烷-18-酰胺；
1-((4-((3-氯-4-氟苯基)(4-硝基苄基)氨基)-7-甲氧基喹唑啉-6-基)氧基)-N-(2-(2，6-二氧代哌啶-3-基)-1，3-二氧杂吲哚啉-4-基)-3，6，9，12，15，18-六氧杂二十一烷-21-酰胺。
3.权利要求1或2所述的喹唑啉类衍生物或其药学上可接受的盐在制备抗癌药物中的应用。
4.权利要求1或2所述的喹唑啉类衍生物或其药学上可接受的盐在制备预防和治疗肺癌药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011576814.1A CN112608302B (zh) | 2020-12-28 | 2020-12-28 | 低氧还原激活靶向泛素化降解egfr蛋白的喹唑啉类衍生物及其应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011576814.1A CN112608302B (zh) | 2020-12-28 | 2020-12-28 | 低氧还原激活靶向泛素化降解egfr蛋白的喹唑啉类衍生物及其应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112608302A CN112608302A (zh) | 2021-04-06 |
| CN112608302B true CN112608302B (zh) | 2022-05-24 |
Family
ID=75248468
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011576814.1A Active CN112608302B (zh) | 2020-12-28 | 2020-12-28 | 低氧还原激活靶向泛素化降解egfr蛋白的喹唑啉类衍生物及其应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112608302B (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022061348A1 (en) * | 2020-09-16 | 2022-03-24 | Biotheryx, Inc. | Sos1 protein degraders, pharmaceutical compositions thereof, and their therapeutic applications |
| CN117924286B (zh) * | 2024-03-20 | 2024-05-24 | 四川大学华西医院 | 一类喹唑啉-吡咯烷类衍生物及其制备方法 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20060079121A (ko) * | 2004-12-31 | 2006-07-05 | 에스케이케미칼주식회사 | 당뇨 및 비만 치료예방에 유효한 퀴나졸린 유도체 |
| PH12012500097A1 (en) * | 2009-07-21 | 2011-01-27 | Shanghai Inst Organic Chem | Potent small molecule inhibitors of autophagy, and methods of use thereof |
| MX389264B (es) * | 2015-06-04 | 2025-03-20 | Arvinas Operations Inc | Moduladores de proteolisis basados en imida y metodos de uso asociados. |
| US20190016703A1 (en) * | 2015-12-30 | 2019-01-17 | Dana-Farber Cancer Institute, Inc. | Bifunctional compounds for her3 degradation and methods of use |
| JP6968823B2 (ja) * | 2016-04-22 | 2021-11-17 | ダナ−ファーバー キャンサー インスティテュート，インコーポレイテッド | Ｅｇｆｒの分解のための二官能性分子、及び使用方法 |
| CN106432202B (zh) * | 2016-09-22 | 2019-04-02 | 郑州大学第一附属医院 | 喹唑啉类衍生物及其应用 |
| CN110753693A (zh) * | 2016-12-23 | 2020-02-04 | 阿尔维纳斯运营股份有限公司 | Egfr蛋白水解靶向嵌合分子和相关使用方法 |
| CN107698575A (zh) * | 2017-09-26 | 2018-02-16 | 中国药科大学 | cereblon配体介导的新型BET蛋白降解的双功能分子及其制备和应用 |
| CN110372669B (zh) * | 2019-06-19 | 2020-11-24 | 浙江省医学科学院 | 一种基于crbn配体诱导egfr降解的化合物及其制备方法、药物组合物和应用 |
-
2020
- 2020-12-28 CN CN202011576814.1A patent/CN112608302B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN112608302A (zh) | 2021-04-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2021036004A (ja) | Ｒｅｔの阻害剤 | |
| CN101896457A (zh) | 组蛋白脱乙酰基酶抑制剂 | |
| Chen et al. | Design, synthesis and biological evaluation of quinoline derivatives as HDAC class I inhibitors | |
| CA2845127C (en) | Pyrazole compound and pharmaceutical use thereof for inhibiting sglt1 | |
| EP3974422A1 (en) | Compound used as ret kinase inhibitor and application thereof | |
| CN112608302B (zh) | 低氧还原激活靶向泛素化降解egfr蛋白的喹唑啉类衍生物及其应用 | |
| CN103467359A (zh) | 一种含有吲哚的肉桂酰胺类组蛋白去乙酰化酶抑制剂及其制备方法和应用 | |
| US9695181B2 (en) | Hydroximic acid derivatives and medical applications therof | |
| JPH11269140A (ja) | 分化誘導剤 | |
| Ghorab et al. | Biological evaluation, radiosensitizing activity and structural insights of novel halogenated quinazoline-sulfonamide conjugates as selective human carbonic anhydrases IX/XII inhibitors | |
| CN113004251B (zh) | 含2-硝基咪唑的喹唑啉类衍生物及其应用 | |
| CN110627801A (zh) | 一类hdac抑制剂及其用途 | |
| CN113527195B (zh) | 一类5-芳基烟酰胺类lsd1/hdac双靶点抑制剂、其制备方法及应用 | |
| CN103848795A (zh) | 一种l,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂及其制备方法和应用 | |
| Kaur et al. | Design, synthesis, in vitro and in silico evaluation of indole-based tetrazole derivatives as putative anti-breast cancer agents | |
| CN113924288B (zh) | 一种含喹啉基化合物、药物组合物以及其用途 | |
| CN111454229B (zh) | 二氢萘并异噁唑类衍生物及其在抗肿瘤药物中的应用 | |
| CN109293537A (zh) | 磺酰胺类化合物及其医药用途 | |
| WO2018068357A1 (zh) | 一类新型sirt2蛋白抑制剂及其在制药中的用途 | |
| CN107501279A (zh) | 呋喃并喹啉二酮类化合物及其医药用途 | |
| Bouzian et al. | Design and evaluation of novel inhibitors for the treatment of clear cell renal cell carcinoma | |
| CN108530337B (zh) | 一种可选择性抑制胃癌细胞的吲哚酰胺类化合物 | |
| WO2023011416A1 (zh) | 靶向于hdac和nad合成的多靶点抑制剂及其用途 | |
| US10106519B2 (en) | 3-phenyl-7-hydroxy-isocoumarins as macrophage migration inhibitory factor (MIF) inhibitors | |
| CN106496132B (zh) | N-(4-取代苯基)-2-取代乙酰胺类化合物及其作为sirt2蛋白抑制剂的用途 |
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 |