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Antitumor potential of crown ethers: structure-activity relationships, cell cycle disturbances, and cell death studies of a series of ionophores.

Abstract
The present paper demonstrates the antiproliferative ability and structure-activity relationships (SAR) of 14 crown and aza-crown ether analogues on five tumor-cell types. The most active compounds were di-tert-butyldicyclohexano-18-crown-6 (3), which exhibited cytotoxicity in the submicromolar range, and di-tert-butyldibenzo-18-crown-6 (5) (IC50 values of approximately 2 microM). Also, 3 and 5 induced marked influence on the cell cycle phase distribution--strong G1 arrest, followed by the induction of apoptosis. A computational SAR modeling effort offers insight into possible mechanisms of crown ether biological activity, presumably involving penetration into cell membranes, and points out structural features of molecules important for this activity. The results reveal that crown ethers possess marked tumor-cell growth inhibitory activity, the extent of which depends on the characteristics of the hydrophilic macrocylic cavity and the surrounding hydrophobic ring. Our work supports the hypothesis that crown ether compounds inhibit tumor-cell growth by disrupting potassium ion homeostasis, which in turn leads to cell cycle perturbations and apoptosis.
AuthorsMarko Marjanović, Marijeta Kralj, Fran Supek, Leo Frkanec, Ivo Piantanida, Tomislav Smuc, Ljerka Tusek-Bozić
JournalJournal of medicinal chemistry (J Med Chem) Vol. 50 Issue 5 Pg. 1007-18 (Mar 08 2007) ISSN: 0022-2623 [Print] United States
PMID17300184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Aza Compounds
  • Crown Ethers
  • Ionophores
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Aza Compounds (chemical synthesis, chemistry, pharmacology)
  • Cell Cycle (drug effects)
  • Cell Death (drug effects)
  • Cell Line, Tumor
  • Computer Simulation
  • Crown Ethers (chemical synthesis, chemistry, pharmacology)
  • Drug Screening Assays, Antitumor
  • Humans
  • Ionophores (chemical synthesis, chemistry, pharmacology)
  • Models, Molecular
  • Structure-Activity Relationship

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