title: Scaffold-Hopping of Aurones: 2-Arylideneimidazo[1,2-a]pyridinones as Topoisomerase IIα-Inhibiting Anticancer Agents.
abstract: Scaffold-hopping of bioactive natural product aurones has been studied for the first time. 2-Arylideneimidazo[1,2-a]pyridinones as potential topoisomerase IIα (hTopoIIα)-targeting anticancer compounds were considered. A multifunctional activator, polyphosphoric acid, enabled to realize a cascade reaction of 2-aminopyridine with 2,3-epoxyesters toward synthesis of 2-arylideneimidazo[1,2-a]pyridinones. Most of the compounds exhibited hTopoIIα-selective poison activity with efficiency more than etoposide and DNA-binding property, while not interacting with hTopo I. The compounds showed pronounced antiproliferative activities in nanomolar range with relatively poor toxicity to normal cells, inhibition of invasiveness, and apoptotic effect. The activities for inhibition of tubulin assembly, CDK1 and pCDK1, were also observed. Interestingly, the hTopoIIα inhibitory (in vitro and ex vivo studies) and antiproliferative activities of representative potent compounds were found to be manifold higher compared to corresponding parent aurones bearing alike substitutions, indicating the importance of such scaffold-hopping strategy in medicinal chemistry research.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, S. A. S. Nagar, Mohali, Punjab 160062, India.
authors.forename: Garima
authors.initials: G
authors.lastname: Priyadarshani
authors.affiliation: School of Biotechnology, KIIT University , Campus-11, Patia, Bhubaneswar, Orissa 751024, India.
authors.forename: Anmada
authors.initials: A
authors.lastname: Nayak
authors.affiliation: Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, S. A. S. Nagar, Mohali, Punjab 160062, India.
authors.forename: Suyog M
authors.initials: SM
authors.lastname: Amrutkar
authors.affiliation: School of Biotechnology, KIIT University , Campus-11, Patia, Bhubaneswar, Orissa 751024, India.
authors.forename: Sarita
authors.initials: S
authors.lastname: Das
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, S. A. S. Nagar, Mohali, Punjab 160062, India.
authors.forename: Sankar K
authors.initials: SK
authors.lastname: Guchhait
authors.affiliation: School of Biotechnology, KIIT University , Campus-11, Patia, Bhubaneswar, Orissa 751024, India.
authors.forename: Chanakya N
authors.initials: CN
authors.lastname: Kundu
authors.affiliation: Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, S. A. S. Nagar, Mohali, Punjab 160062, India.
authors.forename: Uttam C
authors.initials: UC
authors.lastname: Banerjee
keywords: Scaffold-hopping; anticancer agents; aurones; human topoisomerase IIα; imidazo[1,2-a]pyridine