Three-component Castagnoli-Cushman reaction with ammonium acetate delivers 2-unsubstituted isoquinol-1-ones as potent inhibitors of poly(ADP-ribose) polymerase (PARP)

Journal of Enzyme Inhibition and Medicinal Chemistry

Mikhail Krasavin¹  Petr Zhmurov¹  Alexander Safrygin¹  Dmitry Dar’in¹  Maxim Gureev²  Yulia Zonis³  Sergey Silonov³  Mariia Kasatkina³ 

[1] Chemistry, Saint Petersburg State University, Saint Petersburg, Russi;Digital Biodesign and Personalized Healthcare Research Center, Sechenov First Moscow State Medical University, Moscow, Russi;JSC BIOCAD, Saint Petersburg, Russi;

关键词: Castagnoli-Cushman reaction;    1-oxo-3,4-dihydroisoquinoline-4-carboxamides;    poly(ADP-ribose) polymerase;    PARP1/2 selectivity;    NAD mimetics;    druglikeness;   

DOI  :  10.1080/14756366.2021.1969386

来源: Taylor & Francis

【 摘 要 】

An earlier described three-component variant of the Castagnoli-Cushman reaction employing homophthalic anhydrides, carbonyl compound and ammonium acetate was applied towards the preparation of 1-oxo-3,4-dihydroisoquinoline-4-carboxamides with variable substituent in position 3. These compounds displayed inhibitory activity towards poly(ADP-ribose) polymerase (PARP), a clinically validated cancer target. The most potent compound (PARP1/2 IC50 = 22/4.0 nM) displayed the highest selectivity towards PARP2 in the series (selectivity index = 5.5), more advantageous ADME prameters compared to the clinically used PARP inhibitor Olaparib.

【 授权许可】

CC BY