分别以5-溴-2-氟苯甲腈(1a)和3-溴苯甲腈(1b)为原料,经Sonogashira偶联,脱三甲基硅基保护基,三分子偶联及水解等5步反应制得中间体2-氟-5-[(4-氧代-3,4-二氢吡咯[1,2-d][1,2,4]三嗪-1-基)甲基]苯甲酸(6a)和3-[(4-氧代-3,4-二氢吡咯[1,2-d][1,2,4]三嗪-1-基)甲基]苯甲酸(6b).环烷基甲酸经酰氯化,缩合和脱Boc保护基3步反应制得环烷基哌嗪-1-基甲酮(7a~7c).6a与NCS(1 eq.)反应制得5-[(6-氯-4氧代-3,4二氢吡咯[1,2-d][1,2,4]三嗪-1-基)甲基]-2氟-苯甲酸(6c);6a与NCS(2 eq.)反应制得5-[(6,7-二氯-4氧代-3,4二氢吡咯[1,2-d][1,2,4]三嗪-1-基)甲基]-2氟-苯甲酸(6d).6a~6d,6a~6c分别与7a~7c和1-(2-嘧啶基)哌嗪在TBTU(缩合剂),DIPEA(碱)的作用下合成了13个新型吡咯并三嗪酮类PARP-1抑制剂(8a~8m),其结构经1H NMR和MS(ESI)表征.采用Alarm blue法研究了8a~8m对肿瘤细胞MDA-MB-436的抑制活性(IC50).结果表明:8f,8g,8i和8j对MDA-MB-436有较强的抑制活性(IC50=30.5~69.3 nmol·L-1).%The intermediates, 2-fluoro-5-[(4-oxo-3,4-dihydropyrrolo[1,2-d] [1,2,4] triazin-1-yl) methyl]benzoic acid(6a) and 3-[(4-oxo-3,4-dihydropyrrolo[1,2-d] [1,2,4] triazin-1-yl) methyl] benzoic acid(6b) were obtained by a five-step reaction of Sonogashira coupling, deprotection, triplet coupling, hydrolysis, etc, using 5-bromo-2-fluorobenzonitrile(1a) and 3-bromobenzonitrile(1b) as the materials, respectively. Cycloalkylpiperazin-1-ylmethanone(7a ~7c) were prepared by a three-step reaction of chlorination, condensation and deprotection from cycloalkylcarboxylic acid. 5-(6-Chlo-ro-4-oxo-3,4-dihydropyrrolo[1,2-d][1,2,4] triazin-1-yl)-2-fluoro-benzoic acid(6c) and 5-[(6,7-dichloro-4-oxo-3,4-dihydropyrrolo [1,2-d][1,2,4]-yl) methyl]-2-fluoro-benzoic acid(6d) were ob-tained by the reaction of 6a with NCS(1 eq. or 2 eq. ). Thirteen novel PARP-1 inhibitors(8a~8m) with pyrazolotriazinone skeleton were synthesized by the condensation reaction of 6a~6d, 6a~6c with 7a~7c or 1-(2-pyrimidyl) piperazine, using TBTU as condensation agent and DIPEA as base. The structures were characterized by 1H NMR and MS(ESI). The inhibition activities(IC50) of 8a~8m a-gainst tumor cells MDA-MB-436 were investigated by the Alarm blue method. The results indicated that8f, 8g, 8i and 8j exhibited well activities with IC50 of 30. 5~69. 3 nmol·L-1 .
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