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

Bioorg Med Chem. 2012 Jul 15;20(14):4489-94. doi: 10.1016/j.bmc.2012.05.030. Epub 2012 May 19.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / toxicity
  • Camptothecin / chemistry*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Topoisomerases, Type I / chemistry*
  • DNA Topoisomerases, Type I / metabolism
  • Drug Resistance, Neoplasm / drug effects
  • Humans
  • Podophyllotoxin / chemistry*
  • Stereoisomerism
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / chemistry*
  • Topoisomerase I Inhibitors / toxicity

Substances

  • Antineoplastic Agents
  • Topoisomerase I Inhibitors
  • DNA Topoisomerases, Type I
  • Podophyllotoxin
  • Camptothecin