Microtubules are the basic components of cell structure, which take part in a wide number of pivotal cellular functions. Drugs that are able to modulate the microtubule assembly either by inhibition of tubulin polymerization or by blocking microtubule assembly are of great interest in anti-cancer therapy. In the past few years, several small synthetic molecules that have indole nucleus as a core structure have been identified as tubulin inhibitors. Indomethacin, a well-known NSAID, with an indole nucleus was chosen for our study. In order to investigate the Structure Activity Relationship (SAR) between the anti-cancer effect and some potentially relevant chemical properties, we prepared a series of indole derivatives, where the structure of Indomethacin was gradually modulated, varying the carboxylic group nature by substitution with different amide groups and the amide hydrogen nature by introduction of different benzoyl substituents. Interestingly, these modifications resulted to a set of compounds exhibiting higher potency than the parent compound. One of the Indomethacin analogue showed stronger antiproliferative activity against multiple cancer cell lines via interfering with tubulin polymerization. Tubulin polymerization assay indicated that this compound inhibited tubulin assembly at high concentrations, but promoted this process at low concentrations. The binding mode of this compound in tubulin was predicted using the molecular docking simulation. This compound was selected as the lead compound for further SAR study, devoted to the optimization of the cytotoxic effect and other mechanism investigation.

Lead optimization of tubulin inhibitors and further mechanism investigation

246th National Meeting (2013)

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