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A Series of Novel Terpyridine-Skeleton Molecule Derivants Inhibit Tumor Growth and Metastasis by Targeting Topoisomerases

Title
A Series of Novel Terpyridine-Skeleton Molecule Derivants Inhibit Tumor Growth and Metastasis by Targeting Topoisomerases
Authors
Kwon, Han-ByeolPark, ChanmiJeon, Kyung-HwaLee, EunyoungPark, So-EunJun, Kyu-YeonKadaya, Tara ManThapa, PritamKarki, RadhaNa, YounghwaPark, Mi SunRho, Seung BaeLee, Eung-SeokKwon, Youngjoo
Ewha Authors
권영주
SCOPUS Author ID
권영주scopus
Issue Date
2015
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0022-2623JCR Link1520-4804JCR Link
Citation
vol. 58, no. 3, pp. 1100 - 1122
Publisher
AMER CHEMICAL SOC
Indexed
SCI; SCIE; SCOPUS WOS scopus
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 II alpha 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).
DOI
10.1021/jm501023q
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약학대학 > 약학과 > Journal papers
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