期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 20, 期 14, 页码 4489-4494出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.05.030
关键词
Topoisomerase; Cytotoxicity; Camptothecin (CPT); Etoposide (VP-16); Epipodophyllotoxin; Conjugates
资金
- NIH [CA17625]
- National Foundation for Cancer Research
- National Cancer Institute [CA63477, A154295-01A1]
Two conjugates (1 and 2) of camptothecin (CPT) and 4 beta-anilino-4'-O-demethylepipodophyllotoxin were previously shown to exert antitumor activity through inhibition of topoisomerase I (topo I). In this current study, two novel conjugates (1E and 2E) with an open E-ring in the CPT moiety were first synthesized and evaluated for biological activity in comparison with their intact E-ring congeners. This novel class of CPT-derivatives exhibits its antitumor effect against CPT-sensitive and -resistant cells, in part, by inhibiting topo I-linked DNA (TLD) religation. An intact E-ring was not essential for the inhibition of TLD religation, although conjugates with an open E-ring were less potent than the closed ring analogs. This lower religation potency resulted in decreased formation of protein-linked DNA breaks (PLDBs), and hence, less cell growth inhibition. In addition to their impact on topo I, conjugates 1E, 2, and 2E exhibited a minor inhibitory effect on topo II-induced DNA cleavage. The novel structures of 1E and 2E may present scaffolds for further development of dual function topo I and II inhibitors with improved pharmacological profiles and physicochemical properties. (C) 2012 Elsevier Ltd. All rights reserved.
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