Microwave-assisted synthesis of arylthioindoles and aroylindolesas potent inhibitors of tubulin polymerization

Arylthioindoles and aroylindoles are potent inhibitors of tubulin polymerization and cancer cell growth by binding to the colchicine site on beta-tubulin [1]. Several derivatives were more potent than colchicine, combretastatin-A4, vinblastine and paclitaxel and have potential as novel therapeutic agents to treat cancer. During structure-activity relationship studies, we developed a simple, high-yielding and very fast microwave-assisted protocol to synthesize arylthioindoles and aroylindoles. Sulphur derivatives were prepared within 4 min by treating indoles with disulphides in the presence of sodium hydride in N,N-dimethylformamide under venting-while-heating conditions in a closed vessel [2]. Similarly, reaction of indoles with benzoyl chlorides in the presence of aluminium chloride in 1,2-dichloroethane gave the corresponding ketones in 2 min. Starting indoles were obtained in 2 min by intramolecular cyclization in polyphosphoric acid of aryl hydrazones, that were prepared in 5 min under cooling-while-heating reaction of phenylhydrazines with acetyl derivatives in ethanol in an open vessel [3]. To the best of our knowledge, we reported the first applications of venting-while-heating in a closed vessel and of cooling-while-heating in an open vessel technologies in microwave-assisted organic synthesis. References (1) La Regina G., Bai R., Coluccia A., et al. New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer. J. Med. Chem., 2015, ASAP. (2) La Regina G., Gatti V., Famiglini V., Venting-while-Heating Microwave-Assisted Synthesis of 3-Arylthioindoles, ACS Comb. Sci., 2012, 14, 258−262. (3) La Regina G., Gatti V., Piscitelli P., et al. Open Vessel and Cooling while Heating Microwave-Assisted Synthesis of Pyridinyl N-Aryl Hydrazones. ACS Comb. Sci., 2011, 13, 2–6.