Arylthioindoles: design, synthesis and biological activity

Microtubules have essential roles in vital cellular functions, such as motility, division, shape maintenance, and intracellular transport. The microtubules are made of linear rows of alternating alpha- and beta-tubulin, and are the best studied cancer target to date. Recently, we have reported a novel class of tubulin polymerization inhibitors, arylthioindoles (ATIs), that bind to the colchicine site on beta-tubulin close to its interface with -tubulin.1,2 Focusing our attention on some aminoderivatives related to combretastatin A-4, we designed and synthesized new ATI derivatives.3 The new compounds strongly inhibited tubulin polymerization, with activity in the low micromolar range, comparable to the effects of colchicine and combretastatin A-4. Derivatives bearing a halogen atom or a small alkyl or ether group at position 5 of the indole nucleus, were also potent inhibitors of MCF-7 cell growth. For example, 5-bromo-3-[(3,4,5-trimethoxyphenyl)thio]-1H-indole showed tubulin polymerization IC50 = 1.6 microM and growth of MCF-7 cells IC50 = 43 nM, and inhibited [3H]colchicine binding at 65%. The cytotoxicity was resulted well correlated with the binding affinity for the colchicine site on tubulin. Cell cycle analysis revealed an accumulation of HeLa cells in the G2/M phase at 24 h and polyploidization at 48 h. At 24 h, inhibition of tubulin polymerization had not caused extensive apoptosis, suggesting that impaired cell viability might occur through a “mitotic catastrophe”. References (1) De Martino, G.; La Regina, G.; Coluccia, A. et al. J. Med. Chem. 2004, 47, 6120-6123. (2) De Martino, G.; Edler, M. C.; La Regina, G. et al. J. Med. Chem. 2006, 49, 947-954. (3) La Regina, G.; Edler, M. C.; Brancale, A. et al. J. Med. Chem. 2007, ASAP Article.