Antitumor agents 294. Novel E-ring-modified camptothecin-4β-anilino- 4′-O-demethyl-epipodophyllotoxin conjugates as DNA topoisomerase i inhibitors and cytotoxic agents

Deyong Ye, Qian Shi, Chung Hang Leung, Seung Whan Kim, Shin Young Park, Elizabeth A. Gullen, Zao Li Jiang, Hao Zhu, Susan L. Morris-Natschke, Yung Chi Cheng, Kuo Hsiung Lee

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Two conjugates (1 and 2) of camptothecin (CPT) and 4β-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.

Original languageEnglish (US)
Pages (from-to)4489-4494
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number14
DOIs
StatePublished - Jul 15 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Keywords

  • Camptothecin (CPT)
  • Conjugates
  • Cytotoxicity
  • Epipodophyllotoxin
  • Etoposide (VP-16)
  • Topoisomerase

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