Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

Abstract

The dynamic and crucial role of tubulin in different cellular functions rendered it a promising target in anticancer drug development. Combretastatin A-4 (CA-4), an inhibitor of tubulin polymerization isolated from natural sources, is a lead molecule with significant cytotoxicity against tumour cells. Owing to its non polar nature it exhibits low solubility in natural biological fluids, thereby prompting the development of new CA-4 based derivatives. The modification of this lead molecule was mostly carried out by keeping the crucial cis-orientation of the double bond intact, along with a trimethoxyphenyl aromatic ring, by employing different approaches. The issue of solubility was also addressed by the development of water soluble prodrugs of CA-4. The present review highlights the investigations into the parallel development of both new CA-4 based derivatives and prodrugs in the past few years.

Fig. 1. Stages in assembly of microtubules.

Fig. 2. Naturally occurring inhibitors of tubulin polymerization.

Fig. 3. CA-4 derivatives: cis-olefinic bond replaced with heterocycles.

Fig. 4. CA-4 derivatives: cis-olefinic bond replaced with heterocycles (continued).

Fig. 5. Chemical structures with replacements and substitutions at cis-olefinic bond.

Fig. 6. Chemical structures with modification of both cis-olefinic bond and aromatic ring.

Fig. 7. CA-4 derivatives with modification of ring B.

Fig. 8. Prodrugs of CA-4 in clinical trials.

Fig. 9. Design of prodrugs of CA-4 for selective delivery.

Fig. 10. Prodrugs of CA-4 derivatives.

Zaki S. Seddigi

M. Shaheer Malik

A. Prasanth Saraswati

Saleh A. Ahmed

Ahmed Kamal