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
Author(s)
이응석권한별[권한별]박찬미[박찬미]전경화[전경화]이은영[이은영]박소은[박소은]전규연[전규연]타라만카다얏프리텀다빠라다깔끼나영화[나영화]박미선[박미선]노승배[노승배]권영주[권영주]
Keywords
DNA CLEAVABLE COMPLEX; II-ALPHA; CATALYTIC-ACTIVITY; BREAST-CANCER; IN-VITRO; 2,4,6-TRIPHENYL PYRIDINES; ANTICANCER AGENTS; CELL-MIGRATION; CYTOTOXICITY; DERIVATIVES
Issue Date
201502
Publisher
AMER CHEMICAL SOC
Citation
JOURNAL OF MEDICINAL CHEMISTRY, v.58, no.3, pp.1100 - 1122
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).
URI
http://hdl.handle.net/YU.REPOSITORY/33602http://dx.doi.org/10.1021/jm501023q
ISSN
0022-2623
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약학대학 > 약학부 > Articles
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