title: Scaffold-hopping of bioactive flavonoids: Discovery of aryl-pyridopyrimidinones as potent anticancer agents that inhibit catalytic role of topoisomerase IIα.
abstract: A strategy of scaffold-hopping of bioactive natural products, flavones and isoflavones, leading to target-based discovery of potent anticancer agents has been reported for the first time. Scaffold-hopped flavones, 2-aryl-4H-pyrido[1,2-a]pyrimidin-4-ones and the scaffold-hopped isoflavones, 3-aryl-pyrido[1,2-a]pyrimidin-4-ones were synthesized via Pd-catalyzed activation-arylation methods. Most of the compounds were found to exhibit pronounced human topoisomerase IIα (hTopoIIα) inhibitory activities and several compounds were found to be more potent than etoposide (a hTopoIIα-inhibiting anticancer drug). These classes of compounds were found to be hTopoIIα-selective catalytic inhibitors while not interfering with topoisomerase I and interacted with DNA plausibly in groove domain. Cytotoxicities against various cancer cells, low toxicity in normal cells, and apoptotic effects were observed. Interestingly, compared to parent flavones/isoflavones, their scaffold-hopped analogs bearing alike functionalities showed significant/enhanced hTopoIIα-inhibitory and cytotoxic properties, indicating the importance of a natural product-based scaffold-hopping strategy in the drug discovery.
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
authors.forename: Garima
authors.initials: G
authors.lastname: Priyadarshani
authors.affiliation: Department of Pharmaceutical Technology (Biotechnology), National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
authors.forename: Suyog
authors.initials: S
authors.lastname: Amrutkar
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, SAS Nagar, Mohali, Punjab 160062, India.
authors.forename: Uttam C
authors.initials: UC
authors.lastname: Banerjee
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 Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar, Mohali, Punjab 160062, India. Electronic address: skguchhait@niper.ac.in.
authors.forename: Sankar K
authors.initials: SK
authors.lastname: Guchhait
mesh_terms: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009361:Neoplasm Invasiveness; D011744:Pyrimidinones / Q000737:chemistry*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D005419:Flavonoids; D011744:Pyrimidinones; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II
keywords: Anticancer agent; Drug discovery; Flavonoids; Human topoisomerase IIα; Pyrido[1,2-a]pyrimidin-4-ones; Scaffold-hopping