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Synthesis of benzo[3,4]azepino[1,2-b]isoquinolin-9-ones from 3-arylisoquinolines via ring closing metathesis and evaluation of topoisomerase i inhibitory activity, cytotoxicity and docking study

Title
Synthesis of benzo[3,4]azepino[1,2-b]isoquinolin-9-ones from 3-arylisoquinolines via ring closing metathesis and evaluation of topoisomerase i inhibitory activity, cytotoxicity and docking study
Authors
Van H.T.M.Khadka D.B.Yang S.H.Le T.N.Cho S.H.Zhao C.Lee I.-S.Kwon Y.Lee K.-T.Kim Y.-C.Cho W.-J.
Ewha Authors
권영주
SCOPUS Author ID
권영주scopus
Issue Date
2011
Journal Title
Bioorganic and Medicinal Chemistry
ISSN
0968-0896JCR Link
Citation
vol. 19, no. 18, pp. 5311 - 5320
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Benzo[3,4]azepino[1,2-b]isoquinolinones were designed and developed as constraint forms of 3-arylisquinolines with an aim to inhibit topoisomerase I (topo I). Ring closing metathesis (RCM) of 3-arylisoquinolines with suitable diene moiety provided seven membered azepine rings of benzoazepinoisoquinolinones. Spectral analyses of these heterocyclic compounds demonstrated that the methylene protons of the azepine rings are nonequivalent. The shielding environment experienced by these geminal hydrogens differs unusually by 2.21 ppm. As expected, benzoazepinoisoquinolinones displayed potent cytotoxicity. However, cytotoxic effects of the compounds were not related to topo I inhibition which is explained by non-planar conformation of the rigid compounds incapable of intercalating between DNA base pairs. In contrast, flexible 3-arylisoquinoline 8d attains active conformation at drug target site to exhibit topo I inhibition identical to cytotoxic alkaloid, camptothecin (CPT). © 2011 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.bmc.2011.08.006
Appears in Collections:
약학대학 > 약학과 > Journal papers
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