INTERACTION OF 3 SPONGE-DERIVED MACROCYCLIC LACTONE POLYETHERS (SPONGISTATIN-3, HALISTATIN-1 AND HALISTATIN-2) WITH TUBULIN

Macrocyclic lactone polyethers of marine origin include a series of co mpounds which bind to tubulin, the subunit protein of microtubules, an d 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 en hances the time-dependent exposure of hydrophobic areas on the tubulin molecule without affecting the exposure of the sulfhydryl groups, whi le homohalichondrin B has no effect on exposure of hydrophobic areas a nd slightly suppresses exposure of sulfhydryl groups. The spongistatin s (isolated from the marine sponge Spongia sp.) resemble the halichond rins, except for having a smaller ring; spongistatin 1 inhibits vinbla stine binding to tubulin and blocks microtubule assembly. Here, we hav e examined the effect of the closely related spongistatin 3 on the exp osure of tubulin sulfhydryl groups and hydrophobic areas. We have foun d that spongistatin 3 inhibits formation of the same intrachain cross- link in tubulin as is inhibited by vinblastine. Unlike vinblastine, ho wever, spongistatin 3 has no effect on the exposure of either sulfhydr yl groups or hydrophobic areas on the tubulin molecule. In short, spon gistatin 3 resembles maytansine in its effects on tubulin more than it does either halichondrin B or homohalichondrin B. We also examined th e interaction of tubulin with halistatins 1 and 2, which are close str uctural analogues of halichondrin B and homohalichondrin B, respective ly. Halistatins 1 and 2 are isolated, respectively, from the marine sp onges Phakellia carteri and Axinella carteri. We find that both halist atins resemble halichondrin B in that they have no effect on the expos ure of sulfhydryl groups. Our results suggest that very small structur al changes in these compounds can significantly alter the pattern of t heir effects on the tubulin molecule. (C) 1995 Wiley-Liss, Inc.