jm061479u_si_001.pdf (69.29 kB)
Arylthioindole Inhibitors of Tubulin Polymerization. 3. Biological Evaluation, Structure−Activity Relationships and Molecular Modeling Studies
journal contribution
posted on 2007-06-14, 00:00 authored by Giuseppe La Regina, Michael C. Edler, Andrea Brancale, Sahar Kandil, Antonio Coluccia, Francesco Piscitelli, Ernest Hamel, Gabriella De Martino, Ruth Matesanz, José Fernando Díaz, Anna Ivana Scovassi, Ennio Prosperi, Antonio Lavecchia, Ettore Novellino, Marino Artico, Romano SilvestriThe new arylthioindole (ATI) derivatives 10, 14−18, and 21−24, which bear a halogen atom or a small
size ether group at position 5 of the indole moiety, were compared with the reference compounds colchicine
and combretastatin A-4 for biological activity. Derivatives 10, 11, 16, and 21−24 inhibited MCF-7 cell
growth with IC50 values <50 nM. A halogen atom (14−17) at position 5 caused a significant reduction in
the free energy of binding of compound to tubulin, with a concomitant reduction in cytotoxicity. In contrast,
methyl (21) and methoxy (22) substituents at position 5 caused an increase in cytotoxicity. Compound 16,
the most potent antitubulin agent, led to a large increase (56%) in HeLa cells in the G2/M phase at 24 h, and
at 48 h, 26% of the cells were hyperploid. Molecular modeling studies showed that, despite the absence of
the ester moiety present in the previously examined analogues, most of the compounds bind in the colchicine
site in the same orientation as the previously studied ATIs. Binding to β-tubulin involved formation of a
hydrogen bond between the indole and Thr179 and positioning of the trimethoxy phenyl group in a
hydrophobic pocket near Cys241.