Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells

Ravi Hegde, Padma Thimmaiah, Mayur C. Yerigeri, Gowdahalli Krishnegowda, Kuntebommanahalli N. Thimmaiah, Peter J. Houghton

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Multidrug resistance (MDR) is one of the main obstacles limiting the efficacy of chemotherapy treatment of tumors. Parent acridones 1A and 1B were prepared by the Ullmann reaction followed by cyclization and N-alkylation. N-(ω-Chloroalkyl) analogues were subjected to iodide catalyzed nucleophilic substitution reaction with secondary amines to get the compounds 3A-13A and 3B-13B, which enhanced the uptake of vinblastine in KBCh R-8-5 cells to a greater extent (2.6-13.1-fold relative to control) than verapamil. The study on the structure-activity relationship revealed that substitution of -H at position C-4 in acridone nucleus by -OCH3 increased the cytotoxic and anti-MDR activities. The ability of acridones to inhibit calmodulin dependent cyclic AMP phosphodiesterase has been determined and the results have shown a strong positive correlation between anti-calmodulin activity and cytotoxicity in KBChR-8-5 cells or anti-MDR activity.

Original languageEnglish (US)
Pages (from-to)161-177
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Volume39
Issue number2
DOIs
StatePublished - Feb 2004
Externally publishedYes

Keywords

  • Acridones
  • Anti-MDR activity
  • Anti-calmodulin activity

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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