New Arylthioindoles:  Potent Inhibitors of Tubulin Polymerization. 2. Structure−Activity Relationships and Molecular Modeling Studies

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 IC(50)s in the 2.0 (35) to 4.5 (37) microM 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.

Iodine-mediated one-pot synthesis of indoles and 3-dimethylaminoindoles via annulation of enaminones

“…Accordingly, moderate to low yields were observed in the case of enaminones 3i-j and 3m-n, and no conversion at all was detected with enaminones 3h and 3k-l (Table 4, entries [8][9][10][11][12][13][14]. In contrast, the cyclization of enaminones 3o-p resulted in good yields of the corresponding indoles 1o-p (Table 4, entries [15][16].…”

“…5 For instance, tryptophan and serotonin are key molecules in the human diet and in neurotransmitters, 6 respectively, while indomethacin, vincristine, and pindolol are typical clinically used drugs. 7 In particular, 2-carboxyindoles are enzyme inhibitors, such as hyaluronidase, 8 tubuline polymerization, 9 HIV-1 integrase, 10 human cytosolic phospholipase A 2  11 and factor Xa. 12 In the case of 3-aminoindoles and cyclic-fused analogues, they have been found to be effective as anticancer, 13 antiplasmodial and cytotoxic agents.…”

Chlorophenols in organic synthesis

“…The number of arylsulphides showed potential clinical application, for example, for the treatment of Alzheimer's disease and Parkinson's disease, for the treatment of asthma and obstructive lung diseases, for the treatment of human immunodeficiency virus (HIV) [39][40][41][42][43][44].…”

MPT0B169, a New Tubulin Inhibitor, Inhibits Cell Growth and Induces G2/M Arrest in Nonresistant and Paclitaxel-Resistant Cancer Cells

“…A number of indole-based compounds such as 3-aroyl-​2-phenylindoles [13] and 3-arylthioindoles-2-carboxylate [14] have shown antiproliferative and antitubulin activities. In this study, we synthesized an indole-based compound, 2-dimethylamino-N-[1-(4-methoxy-benzenesulfonyl)-​2,3-dihydro-1H-indol-7-yl]-acetamide (MPT0B169; fig.…”