Interaction of three sponge‐derived macrocyclic lactone polyethers (spongistatin 3, halistatins 1 and 2) with tubulin

Richard F. Ludueña, Mary Carmen Roach, Veena Prasad, George R. Pettit, Zbigniew A. Cichacz, Cherry L. Herald

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Macrocyclic lactone polyethers of marine origin include a series of compounds which bind to tubulin, the subunit protein of microtubules, and inhibit microtubule assembly and vinblastine binding to tubulin. We have previously studied two of these compounds: halichondrin B and the very similar homohalichondrin B. We have found that halichondrin B enhances the time‐dependent exposure of hydrophobic areas on the tubulin molecule without affecting the exposure of the sulfhydryl groups, while homohalichondrin B has no effect on exposure of hydrophobic areas and slightly suppresses exposure of sulfhydryl groups. The spongistatins (isolated from the marine sponge Spongia sp.) resemble the halichondrins, except for having a smaller ring; spongistatin 1 inhibits vinblastine binding to tubulin and blocks microtubule assembly. Here, we have examined the effect of the closely related spongistatin 3 on the exposure of tubulin sulfhydryl groups and hydrophobic areas. We have found that spongistatin 3 inhibits formation of the same intrachain cross‐link in tubulin as is inhibited by vinblastine. Unlike vinblastine, however, spongistatin 3 has no effect on the exposure of either sulfhydryl groups or hydrophobic areas on the tubulin molecule. In short, spongistatin 3 resembles maytansine in its effects on tubulin more than it does either halichondrin B or homohalichondrin B. We also examined the interaction of tubulin with halistatins 1 and 2, which are close structural analogues of halichondrin B and homohalichondrin B, respectively. Halistatins 1 and 2 are isolated, respectively, from the marine sponges Phakellia carteri and Axinella carteri. We find that both halistatins resemble halichondrin B in that they have no effect on the exposure of sulfhydryl groups. Our results suggest that very small structural changes in these compounds can significantly alter the pattern of their effects on the tubulin molecule. © 1995 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)40-48
Number of pages9
JournalDrug Development Research
Volume35
Issue number1
DOIs
StatePublished - May 1995

Keywords

  • anti‐tumor drug
  • microtubule
  • tubulin

ASJC Scopus subject areas

  • Drug Discovery

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