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Letters in Organic Chemistry


ISSN (Print): 1570-1786
ISSN (Online): 1875-6255

Synthesis of Biologically Potent Novel 5-(2-bromopyridin-3-yl-amino)-2- alkyl/aryl-isoindoline-1,3-dione Analogs Via Buchwald-Hartwig C-N Coupling Reaction

Author(s): Ankur Gupta, Bhagyashree Kamble and Chandrasekar M.J. Nanjan

Volume 10 , Issue 2 , 2013

Page: [139 - 146] Pages: 8

DOI: 10.2174/1570178611310020013

Price: $65


A novel series of N-alkyl/aryl substituted phthalimide analogs containing 2-bromopyridyl functionality were synthesized applying optimized Buchwald-Hartwig amination conditions using palladium acetate, cesium carbonate, and ±BINAP in toluene at 110°C under argon atmosphere. The target heteroaryl phthalimide derivatives were obtained in moderate yield ranging from 40% to 51%. In the extra precision (XP) docking studies, at the ATP site of human topoisomerase IIα (hTopoIIα) (PDB id 1ZXM), we identified that compound 3(a) demonstrated remarkable H-bond interactions with catalytic MG2+, ASN 91, SER 148, SER 149, ALA 167 and compound 3(c) with ARG 162, ASN 163, GLY 164, LSY 168, ASN 95 indicating their significance as a plausible hTopoIIα inhibitors. In the in vitro evaluation of A549 cell line, compounds 3(a) and 3(c) were observed to have only moderate cytotoxicity (IC50 180μg/ml and 210μg/ml respectively). The developed process could be widely employed for the synthesis of novel heterocyclic compounds with one of the components as N-alkyl/aryl substituted phthalimide derivatives and has the potential to be developed as a major route for the identification of active drug candidates.

Keywords: Buchwald-Hartwig (C-N) coupling, BINAP, palladium acetate, phthalimide, topoisomerase II, in silico, in vitro antiproliferation, 1ZXM

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