新型2-硫代喹唑啉二酮类PARP-1抑制剂的合成及其生物活性
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摘要
分别以苯胺(衍生物)与苯甲醛(衍生物)为起始原料,合成关键中间体5-(6-氟-4-氧代-2-硫-3,4-二氢-2H-喹唑啉基-1-甲基)苯甲酸(6a)、 2-氟-5-(6-氟-4-氧代-2-硫-3,4-二氢-2H-喹唑啉-1-基甲基)苯甲酸(6b)和2-氟-5-{[4-氧代-2-硫代-3,4-二氢吡啶并[2,3-d]嘧啶-1(2H)-基]甲基]}苯甲酸(6c);再经多步反应合成了14个含喹唑啉二酮骨架的PARP-1抑制剂(8a～8n),其结构经~1H NMR和MS(ESI)表征。体外活性测试结果显示:化合物1-{3-[4-(环戊烷羰基)-3-甲基哌嗪-1-羰基]-4-氟苄基}-6-氟-2-硫代-2,3-二氢-1H-喹唑啉-4-酮(8g)和1-{3-[4-(环己烷羰基)-3-甲基哌嗪-1-羰基]-4-氟苄基}-6-氟-2-硫代-2,3-二氢-1H-喹唑啉-4-酮(8h)对人乳腺癌细胞MDA-MB-436的抑制活性最强,IC_(50)分别为64.3 nmol·L~(-1)和86.4 nmol·L~(-1),与阳性对照药奥拉帕尼的抑制活性处于同一数量级(IC_(50)=48.3 nmol·L~(-1))。
The key intermediates, 2-fluoro-5-((4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)benzoic acid(6 a), 2-fluoro-5-((6-fluoro-4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)benzoic acid(6 b)and 2-fluoro-5-((4-oxo-2-thioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)methyl)benzoic acid(6 c), were synthesized from aniline(derivatives) and benzaldehyde(derivatives), respectively. Fourteen PARP-1 inhibitors(8 a～8 n) containing quinazolinedione skeleton were synthesized by multi-step reaction. The structure was characterized by ~1H NMR and MS(ESI). In vitro activity test results showed that the compounds 1-(3-(4-(cyclopentanecarbonyl)-3-methylpiperazine-1-carbonyl)-4-fluorobenzyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one(8 g) and 1-(3-(4-(cyclohexanecarbonyl)-3-methylpiperazine-1-carbonyl)-4-fluorobenzyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one(8 h) have strongest inhibitory activities against human breast cancer cell line MDA-MB-436 with IC_(50) of 64.3 nmol·L~(-1) and 86.4 nmol·L~(-1), which was in the same order of magnitude as the positive control drug olaparib(IC_(50)=48.3 nmol·L~(-1)).
The key intermediates, 2-fluoro-5-((4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)benzoic acid(6 a), 2-fluoro-5-((6-fluoro-4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)benzoic acid(6 b)and 2-fluoro-5-((4-oxo-2-thioxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)methyl)benzoic acid(6 c), were synthesized from aniline(derivatives) and benzaldehyde(derivatives), respectively. Fourteen PARP-1 inhibitors(8 a～8 n) containing quinazolinedione skeleton were synthesized by multi-step reaction. The structure was characterized by ~1H NMR and MS(ESI). In vitro activity test results showed that the compounds 1-(3-(4-(cyclopentanecarbonyl)-3-methylpiperazine-1-carbonyl)-4-fluorobenzyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one(8 g) and 1-(3-(4-(cyclohexanecarbonyl)-3-methylpiperazine-1-carbonyl)-4-fluorobenzyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one(8 h) have strongest inhibitory activities against human breast cancer cell line MDA-MB-436 with IC_(50) of 64.3 nmol·L~(-1) and 86.4 nmol·L~(-1), which was in the same order of magnitude as the positive control drug olaparib(IC_(50)=48.3 nmol·L~(-1)).
引文
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[22] 彭评志. MTT法检测乳腺癌细胞的体外药物敏感率[J].广西医学,2008,30(12):1904-1905.
[2] RAJESH M, MUKHOPADHYAY P, GODLEWSKI G, et al. Poly(ADP-ribose)polymerase inhibition decreases angiogenesis[J].Biochem Biophys Res Commun,2006,350(4):1056-1062.
[3] 来芳芳,李杰,季鸣,等. 奥拉帕尼对Taxol抗乳腺癌4T1的增敏作用[J].药学学报,2016,51(6):907-912.
[4] ROULEAN M, PATEL A, HENZEL M J, et al. PARP inhibition:PARP-1 and beyond[J].Nat Rev Cancer,2010,10(4):293-301.
[5] VYAS S, CHANG P. New PARP targets for cancer therapy[J].Nat Rev Cancer,2014,14(7):502-509.
[6] HE J X, YANG C H, MIAO Z H. Poly(ADP-ribose) polymerase inhibitors as promising cancer therapeutics[J].Acta Pharmacol Sinica,2010,31(9):1172-1180.
[7] BECK C, ROBERT I, REINA-SAN-MARTIN B, et al. Poly(ADP-ribose) polymerases in double-strand break repair:Focus on PARP1,PARP2 and PARP3[J].Exp Cell Res,2014,329(7):18-25.
[8] SCOTT L J. Niraparib:First global approval[J].Drugs,2017,77(9):1029-1034.
[9] SYED Y Y. Rucaparib:First global approval[J].Drugs,2017,77(5):585-592.
[10] NIRMALL S, AMTESHWAR S J. Poly(ADP-dibose) polymerase-1(PARP-1)and its therapeutic implications[J].Vascul Pharmacol,2010,53(3):77-78.
[11] LANGELIER M F, SERVENT K M, Rogers E E, et al. A third zinc-binding domain of human poly(ADP-dibose) polymerase-1 coordinates DNA-dependent enzyme activation[J].J BioChem,2008,283(7):4105-4114.
[12] ROULEAU M, PATEL A, HENDZE M J, et al. PARP inhibition:PARP1 and beyond[J].Nat Rev Cancer,2010,10(4):293-301.
[13] 陈静,宋东伟. 奥拉帕尼的合成工艺改进[J].天津化工,2016,30(03):32-33.
[14] 季鸣,姚海平,周洁,等. 新型PARP1/2抑制剂YHP-743的抗肿瘤作用[J].药学学报,2018,53(06):938-943.
[15] 刘志雄,王小龙,薛鑫,等. 新型吡咯并三嗪酮类PARP-1抑制剂的设计、合成及其生物活性评价[J].合成化学,2017,25(2):99-106.
[16] 齐静,刘宁波,赵路军. 聚腺苷二磷酸-核糖聚合酶抑制剂研究进展[J].中国肿瘤临床,2018,45(10):521-524.
[17] 张曦文,李乐乐,江素鑫,等. 环磷酰胺生殖毒性的研究进展[J].中国研究型医院,2018,5(01):27-32.
[18] 李福卫. 新型PARP-1抑制剂的设计、合成以及抗肿瘤活性研究[D].南京:南京中医药大学,2016.
[19] 杨燕,胡万福. MTT法检测复方大果木姜子软胶囊抗肿瘤作用[J].三峡大学学报(自然科学版),2017,39(S1):15-17.
[20] 王小龙,李福卫,唐小航,等. 2#硫代喹唑啉二酮衍生物:CN 201610098627.4[P].2016.
[21] 覃超. MTT法检测脑胶质瘤原代细胞对不同浓度多柔比星的体外药物敏感性研究[D].桂林:桂林医学院,2017.
[22] 彭评志. MTT法检测乳腺癌细胞的体外药物敏感率[J].广西医学,2008,30(12):1904-1905.