A series of novel terpyridine-skeleton molecule derivants inhibit tumor growth and metastasis by targeting topoisomerases

Han Byeol Kwon, Chanmi Park, Kyung Hwa Jeon, Eunyoung Lee, So Eun Park, Kyu Yeon Jun, Tara Man Kadayat, Pritam Thapa, Radha Karki, Younghwa Na, Mi Sun Park, Seung Bae Rho, Eung Seok Lee, Youngjoo Kwon

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

A series of novel terpyridine-skeleton molecules containing conformational rigidity, 14 containing benzo[4,5]furo[3,2-b]pyridine core and 15 comprising chromeno[4,3-b]pyridine core, were synthesized, and their biological activities were evaluated. 3-(4-Phenylbenzo[4,5]furo[3,2-b]pyridin-2-yl)phenol (8) was determined to be a nonintercalative topo I and II dual catalytic inhibitor and 3-(4-phenylchromeno[4,3-b]pyridine-2-yl)phenol (22) was determined to be a nonintercalative topo IIα specific catalytic inhibitor by various assays. These two catalytic inhibitors induced apoptosis in addition to G1 arrest in T47D human breast cancer cells with much less DNA toxicity than etoposide. Compounds 8 and 22 significantly inhibited tumor growth in HCT15 subcutaneously implanted xenografted mice. The modification of compounds 8 and 22 with the introduction of a methoxy instead of a hydroxy group enhanced endogenous topo inhibitory activity, metabolic stability in diverse types of liver microsomes and improved pharmacokinetic parameters in rat plasma such as augmentation of bioavailability (41.3% and 33.2% for 2-(3-methoxyphenyl)-4-phenylbenzofuro[3,2-b]pyridine (8-M) and 3-(4-phenylchromeno[4,3-b]pyridine-2-yl)methoxybenzene (22-M), respectively).

Original languageEnglish
Pages (from-to)1100-1122
Number of pages23
JournalJournal of Medicinal Chemistry
Volume58
Issue number3
DOIs
StatePublished - 12 Feb 2015

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