The spongistatins, potently cytotoxic inhibitors of tubulin polymerization, bind in a distinct region of the vinca domain.

摘要: The highly cytotoxic, sponge-derived, antimitotic macrolide polyether spongistatin 1 has been previously shown to inhibit microtubule assembly, the binding of vinblastine and GTP tubulin, displacement GDP bound in exchangeable site tubulin. We have now examined detail inhibition by both [3H]vinblastine [3H]dolastatin 10 found be a noncompetitive inhibitor radiolabeled drugs contrast competitive patterns obtained with vincristine versus chiral isomer dolastatin 10. Since is itself vinca alkaloid this implies at least three distinct sites for structurally complex diverse natural products that interfere each others tubulin nucleotide exchange. Spongistatin 1, alkaloids peptide agents like 10, does not induce formation GTP-independent, morphologically distinctive polymer ("aggregate"). also eight compounds closely related (spongistatins 2-9). most their properties were spongistatins 6 8. These two compounds, despite activity comparable as inhibitors polymerization binding, had much reduced exchange binding. Spongistatins compared effects on 10-induced aggregate conjunction was about 4-fold less active than an aggregation over 20-fold