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Cancer Chemotherapy and Pharmacology

, Volume 44, Issue 2, pp 131–137 | Cite as

Structure-activity profiles of eleutherobin analogs and their cross-resistance in Taxol-resistant cell lines

  • Hayley M. McDaid
  • Samit K. Bhattacharya
  • Xiao-Tao Chen
  • Lifeng He
  • Heng-Jia Shen
  • Clare E. Gutteridge
  • Susan Band Horwitz
  • Samuel J. Danishefsky
ORIGINAL ARTICLE

Abstract

Purpose: Eleutherobin, a natural product, is an antimitotic agent that promotes the polymerization of stable microtubules. Although its mechanism of action is similar to that of Taxol, its structure is distinct. A structure-activity profile of synthetic eleutherobin derivatives that have modifications at C3, C8 and C15 was undertaken to define the structural requirements for microtubule stabilization and cross-resistance in Taxol-resistant cell lines. Methods: The biological activity of five eleutherobin analogs was assessed using three techniques; (1) cytotoxicity and drug-resistance in three paired Taxol-sensitive and -resistant cell lines; (2) polymerization of microtubule protein in vitro in the absence of GTP and (3) induction of microtubule bundle formation in NIH3T3 cells. Results: Eleutherobin had an IC50 value comparable to that of Taxol, whereas neo-eleutherobin, which has a carbohydrate domain that is enantiomeric with that of the parent compound, was less cytotoxic and had 69% of the maximum microtubule polymerization ability of eleutherobin. Both of these compounds exhibited cross-resistance in MDR1-expressing cell lines. Removal or replacement of the C15 sugar moiety resulted in reduced microtubule polymerization and cytotoxicity compared to eleutherobin and loss of cross-resistance in the cell lines SKVLB and J7-T3-1.6, both of which express high levels of P-glycoprotein. By contrast, removal of the urocanic acid group at C8 resulted in virtually complete abrogation of biological activity. The compound lost its ability to polymerize microtubules, and its cytotoxicity was reduced by a minimum of 2000-fold in lung carcinoma A549 cells. Conclusions: Removal or modification of the sugar moiety alters the cytotoxic potency of eleutherobin and its pattern of cross-resistance in Taxol-resistant cells, although such compounds retain a small percentage of the microtubule-stabilizing activity of eleutherobin. The N(1)-methylurocanic acid moiety of eleutherobin, or perhaps some other substituent at the C8 position, is essential for Taxol-like activity. These findings will be important for the future design and the synthesis of new and more potent eleutherobin derivatives.

Key words Eleutherobin Microtubules Taxol Structure-activity Drug-resistance 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • Hayley M. McDaid
    • 1
  • Samit K. Bhattacharya
    • 2
  • Xiao-Tao Chen
    • 2
  • Lifeng He
    • 1
  • Heng-Jia Shen
    • 1
  • Clare E. Gutteridge
    • 2
  • Susan Band Horwitz
    • 1
  • Samuel J. Danishefsky
    • 2
  1. 1.Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA Tel. +1-718-430-2163; Fax +1-718-430-8922US
  2. 2.Department of Chemistry, Columbia University, Havemeyer Hall, New York, NY 10027, USAUS

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