新型吲唑类PARP-1抑制剂的合成及其生物活性评价

以3-甲基-2-硝基苯甲酸甲酯为起始原料，经两步反应制得中间体1H-吲唑-7-甲酸甲酯(3)； 3分别与三氯氧磷、液溴和碘单质反应制得3的3-位卤代产物(4b~4d)； 4d与氟试剂或氰化锌反应制得3-氟(氰基)-3(4a和4e)； 4d与苯硼酸或甲基硼酸在四三苯基磷钯催化下反应制得3-甲基(苯基)-3(5a和5b)；以氢化钠为碱，3, 4a~4c, 4e, 5分别与4-甲烷磺酰氧基哌啶或3-甲烷磺酰氧基四氢吡咯经缩合反应制得3的2，3-位取代产物(6a～6n)； 6a～6n在甲醇中氨解，随后采用氯化氢气体脱去Boc保护基合成了14个新型吲唑类PARP-1抑制剂(7a～7n)，其结构经¹H NMR和ESI-MS表征。生物活性评价结果显示，有7个目标化合物对PARP-1酶活性抑制IC₅₀低于30 nmol·L^-1,其中2-(四氢吡咯-4-基)-2H-吲唑-7-甲酰胺(7e)和3-氟-2-(四氢吡咯-4-基)-2H-吲唑-7-甲酰胺(7f)的IC₅₀分别为4.2 nmol·L^-1和4.6 nmol·L^-1。

Synthesis and Biological Evaluation of Novel PARP-1 Inhibitors with Indazole Skeleton

Methyl 1H-indazole-7-carboxylate(3) was obtained by two-step reaction from methyl 2-nitro-3-methylbenzoate. 3-Halogenated-3(4b~4d) were prepared by halogenation of 3 with POCl₃, Br₂ or I₂, respectively. 3-Fluoro（cyano)-3(4a, 4e) were prepared by fluorination or cyanation of 4d with selectflor or Zn(CN)₂. 3-Methyl（phenyl）-3(5a, 5b) were obtained by Suzuki coupling of 4d with methylboronic acid or phenylboronic acid catalyzed by Pd(PPh₃)₄. Indazole derivatives(6a~6n) were synthesized by N-alkylation of 3, 4a~4c, 4e and 5. Fourteen novel indazole derivatives(7a~7n) were synthesized by aminolysis and deprotection from 6a~6n. The structures were characterized by ¹H NMR and ESI-MS. The results of biological evaluation indicated that seven target molecules displayed inhibitory activities against PARP-1 with IC₅₀ less than 30 nmol·L^-1. Moreover, the indazoles bearing pyrrolidinyl at 2-position and hydrogen(7e) or fluorin(7f) at 3-position displayed inhibitory activities against PARP-1 with IC₅₀ of 4.2 nmol·L^-1 and 4.6 nmol·L^-1, respectively.