| Abstract: |
Arylthioindoles (ATIs) that possess a 3-methoxyphenylthio or a 3,5-dimethoxyphenylthio moiety at position 2 of the indole ring were effective tubulin assembly inhibitors, but weak inhibitors of MCF-7 cell growth. ATIs bearing a 3-(3,4,5-trimethoxyphenyl)thio moiety were potent tubulin polymerization inhibitors, with IC50s in the 2.0 (35) to 4.5 (37) μM range. They also inhibited MCF-7 cell growth at nanomolar concentrations. The 3,4,5-trimethoxy substituted ATIs showed potencies comparable to those of the reference compounds colchicine and combretastatin A-4 in both tubulin assembly and cell growth inhibition assays. Dynamics simulation studies correlate well with the observed experimental data. Furthermore, from careful analysis of the biological and in silico data, we can now hypothesize a basic pharmacophore for this class of compounds. © 2006 American Chemical Society. |
| Keywords: |
controlled study; unclassified drug; human cell; antineoplastic agent; mitosis; epidermal growth factor receptor 2; drug screening assays, antitumor; cell line, tumor; drug synthesis; structure activity relation; structure-activity relationship; cancer inhibition; lung small cell cancer; drug mechanism; breast carcinoma; combretastatin a4; heat shock protein 90; microtubule assembly; models, molecular; pharmacophore; indoles; cell strain mcf 7; indole derivative; infrared spectroscopy; molecular model; proton nuclear magnetic resonance; benzene derivatives; tubulin modulators; colchicine; sulfides; thiol derivative; 3 (3,4,5 trimethoxyphenyl)thioindole derivative; 3 methoxyphenylthioindole derivative; 3,5 dimethoxyphenylthioindole derivative
|
