Synthesis and SAR study of new hydroxy and chloro-substituted 2, 4-diphenyl 5H-chromeno[4, 3-b]pyridines as selective topoisomerase IIα-targeting anticancer agents. Issue 8 (1st May 2018)

• Record Type: Journal Article
• Authors: Magar, Til Bahadur Thapa; Seo, Seung Hee; Kadayat, Tara Man; Jo, Hyunji; Shrestha, Aarajana; Bist, Ganesh; Katila, Pramila; Kwon, Youngjoo; Lee, Eung-Seok
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 8(2018)
• Page Start: 1909
• Page End: 1919
• Publication Date: 2018-05-01
• Subjects: Anticancer agents -- 5H-Chromeno[4, 3-b]pyridines -- Hydroxyl and chlorine-substitution -- Selective topoisomerase IIα inhibition -- SAR study; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.02.035
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Highlights: A new series of hydroxy and chloro-substituted 2, 4-diphenyl 5 H -chromeno[4, 3- b ]pyridines were synthesized. Evaluated for topo I and IIα inhibitory activity, and antiproliferative activity. Compounds showed selective topo IIα inhibitory activity. SAR study indicated the importance of hydroxyphenyl-substitution at 4-position. Abstract: As part of our effort to develop potential topoisomerase IIα (topo IIα) targeting anticancer agents, we systematically designed a new series of hydroxy and chloro-substituted 2, 4-diphenyl 5 H -chromeno[4, 3- b ]pyridines. Total eighteen compounds were synthesized and tested for their ability to inhibit the function of topo I and IIα, and proliferation of human breast (T47D), colorectal (HCT15), and cervix (HeLa) cancer cells. Except compound 11, all of the tested compounds displayed selective topo IIα inhibitory activity. Compounds 8 –18, 22, 24, and 25 showed excellent topo IIα inhibitory activity than a positive control, etoposide. Most of the compounds appeared to be superior to reference compounds in their antiproliferative activity. Structure-activity relationship (SAR) study has shown that it is better to place the hydroxyphenyl group at the 4-position of the central pyridine for superior topo IIα inhibition and antiproliferative activity. Similarly, the 3′-, or 4′-hydroxyphenyl substitution at the 2- and 4-positon of pyridine ring is important for better activity than 2′-substitution.