Combretastatin thiazole analogue

The pyrazole- and thiazole analogues of the 3 -deoxy-3 -amino-4 -methoxy Combretastatin A-4 showed potent antimitotic (IC50 3.0 pM and IC50 10 pM) activity. The former showed also a potent cytotoxic activity (IC50 8.4 nM ). Moderate antimitotic activity (IC50 3.0 pM) and weak cytotoxic activity was observed for a triazole derivative, whereas tetrazole ring confers potent antimitotic (ICso 2.0 pM) as well as cytotoxic activity. Compounds with potent cjdotoxicity were further evaluated in vivo in the Colon murine tumor model. The best antitumor activity in vivo, expressed as tumour growth suppression, was observed for the thiazole and tetrazole derivatives with values comparable to the ones observed for 3 -deoxy-3 -amino Combretastatin A-4 hydrochloride. 

The Combretastatin A-4 analogues, containing a variety of heterocyclic moieties, such as imidazoles, thiazoles and tetrazoles, not only display efficient inhibition of tubulin polymerization but also exert potent cellular growth inhibition in different cancer lines including MDR cancer cells. It is worthy to note that some of Combretastatin A-4 analogues, such as imidazole-based Combretastatin A-4 exhibited oral availability leading to solid tumor regression in vivo tumor models. 

In summary, the Combretastatin A-4 analogues, containing a variety of heterocyclic moieties, such as pyrazoles, imidazoles, thiazoles and tetrazoles, not only display efficient inhibition of tubulin polymerization... 

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