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

As part of our effort to develop potential topoisomerase II alpha (topo II alpha) targeting anticancer agents, we systematically designed a new series of hydroxy and chloro-substituted 2,4-diphenyl 5H-chromeno[4,3-b] pyridines. Total eighteen compounds were synthesized and tested for their ability to inhibit the function of topo I and II alpha, and proliferation of human breast (T47D), colorectal (HCT15), and cervix (HeLa) cancer cells. Except compound 11, all of the tested compounds displayed selective topo II alpha inhibitory activity. Compounds 8-18, 22, 24, and 25 showed excellent topo II alpha 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 II alpha 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. (C) 2018 Elsevier Ltd. All rights reserved.