Synthesis and Biological Evaluation of Novel PARP-1 Inhibitors with Indazole Skeleton
LONG Wei1, QIU Wen-ge1, HU Yun-yan2, SONG Li-yun1, LI Hai-jun2, HE Hong1
1. Beijing Key Laboratory for Green Catalysis and Separation, College of Environmental and Energy Engineering, Beijing University of Technology, Beijing 100124, China; 2. Betta pharmaceuticals Co. Ltd, Beijing 100176, China
Abstract：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.
龙伟, 邱文革, 胡云雁, 宋丽云, 李海军, 何洪. 新型吲唑类PARP-1抑制剂的合成及其生物活性评价[J]. 合成化学, 2016, 24(4): 277-282.
LONG Wei, QIU Wen-ge, HU Yun-yan, SONG Li-yun, LI Hai-jun, HE Hong. Synthesis and Biological Evaluation of Novel PARP-1 Inhibitors with Indazole Skeleton. Chinese Journal of Synthetic Chemistry, 2016, 24(4): 277-282.
2016, Vol. 24 
