Structure-activity profiles of eleutherobin analogs and their cross-resistance in Taxol-resistant cell lines |
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| Authors: | Hayley M McDaid Samit K Bhattacharya Xiao-Tao Chen Lifeng He Heng-Jia Shen Clare E Gutteridge Susan Band Horwitz Samuel J Danishefsky |
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| Institution: | (1) Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA Tel. +1-718-430-2163; Fax +1-718-430-8922, US;(2) Department of Chemistry, Columbia University, Havemeyer Hall, New York, NY 10027, USA, US;(3) Laboratory for Bioorganic Chemistry, The Sloan-Kettering Institute for Cancer Research, 1275 York Ave., Box 106, New York, NY 10021, USA, US |
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| 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.
Received: 15 October 1998 / Accepted: 17 December 1998 |
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| Keywords: | Eleutherobin Microtubules Taxol Structure-activity Drug-resistance |
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