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

Synthesis and Biological Activities of Novel 2-Thioquinazolinedione PARP-1 Inhibitors

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(2 H )-yl)methyl)benzoic acid( 6a ), 2-fluoro-5-((6-fluoro-4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2 H )-yl)methyl)benzoic acid( 6b )and 2-fluoro-5-((4-oxo-2-thioxo-3,4-dihydropyrido[2,3- d ]pyrimidin-1(2 H )-yl)methyl)benzoic acid( 6c ), were synthesized from aniline(derivatives) and benzaldehyde(derivatives), respectively. Fourteen PARP-1 inhibitors( 8a^8n ) containing quinazolinedione skeleton were synthesized by multi-step reaction. The structure was characterized by 1 H 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(1 H )-one( 8g ) and 1-(3-(4-(cyclohexanecarbonyl)-3-methylpiperazine-1-carbonyl)-4-fluorobenzyl)-2-thioxo-2,3-dihydroquinazolin-4(1 H )-one( 8h ) 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 ).