The Mechanism of the Interactions of Pironetin Analog/Combretastatin A-4 Hybrids with Tubulin

Abstract

We here report an investigation of the interactions with tubulin of two types of molecules of a hybrid structural type consisting in a combretastatin A-4 moiety and a simplified pironetin fragment. The cytotoxicities of the molecules on two reference tumoral cell lines were measured. In addition, the effects of the compounds on the cell cycle and on microtubule assembly were observed. The dynamics of microtubule polymerization was investigated by means of immunofluorescence assays. It was thus established that at least some of the compounds under study exert their cytotoxic action by means of interaction with tubulin. The interactions with tubulin of several cytotoxic pironetin analog/combretastatin A-4 hybrids were investigated. Even though the natural products pironetin and combretastatin A-4 are known to interact with tubulin at different sites, only some of the synthetic hybrid molecules show such type of interactions, which are in addition dependent on the length of the spacer fragment.