Rf. Luduena et al., INTERACTION OF 3 SPONGE-DERIVED MACROCYCLIC LACTONE POLYETHERS (SPONGISTATIN-3, HALISTATIN-1 AND HALISTATIN-2) WITH TUBULIN, Drug development research, 35(1), 1995, pp. 40-48
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.