An overview of tubulin inhibitors that interact with the colchicine binding site

Abstract

Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.

Fig. 1

Tubulin binding sites (BS) of microtubule targeting agents.

Fig. 2

Publications related to CBSIs over last decades from PubMed (data entry implementation date until Dec 30th, 2011).

Fig. 3

Chemical structures of established drugs bound to colchicine binding site and CBSIs in clinical trials (TMP: 3, 4, 5-trimethoxyphenyl).

Fig. 4

Interactions between the pharmacophoric points and the tubulin structure (based on Ref. (60)).

Fig. 5

Chemical structures of chemical modified CA-4 analogs.

Fig. 6

Chemical structures of chemical modified CA-4 analogs (continued).

Fig. 7

Chemical structures of indole, quinolone and thiophene-based CBSIs.

Fig. 8

Chemical structures of chalcone analogs.

Fig. 9

Chemical structures of sulfonamide CBSIs.

Fig. 10

Chemical structures of 2-ME analogs.

Fig. 11

Chemical structures of CBSIs derivatives of natural products.

Fig. 12

Chemical structures of CBSIs covalently binding to tubulin colchicine binding site.

Fig. 13

Chemical structures of screened and synthesized CBSIs.

Fig. 14

Chemical structures of prodrugs of CBSIs.

Fig. 15

Chemical structures of CBSIs with improved solubility.