Arylthioindole Inhibitors of Tubulin Polymerization. 3. Biological Evaluation, Structure−Activity Relationships and Molecular Modeling Studies

Abstract

The 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 beta-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.

Lewis Acid–Mediated Arylation of N-Protected Bromomethylindoles

“…of ZnBr 2 as well as 20 mol% InBr 3 . Even though the veratylation could be performed with other Lewis acids such as CuCl 2 , NiBr 2 , FeCl 3 , and Sc(OTf) 3 , the yield of the arylated product 2b obtained was found to be somewhat less. Additionally, these Lewis acids also required longer reaction period (13-20 h) for completion of the veratrylation reaction (entries 3-6).…”

“…[2] Recently, 3-arylthioindole analogs also been explored as tubulin polymerase inhibitors. [3] Hence, syntheses of different types of substituted indole derivatives are necessitated to unravel their medicinal activity.…”

Fragment-based QSAR: perspectives in drug design

“…On the other hand, the characterization of the chemical space is an important factor to be considered in order to define the applicability of the constructed HQSAR models. To evaluate this crucial component, we have created statistically robust HQSAR models for a set of 180 indole derivatives presenting potent anticancer activity as a result of their ability to bind to the colchicine site and to inhibit tubulin polymerization (results not shown) [51][52][53][54]. Afterwards, we have analyzed and compared a series of HQSAR prediction statistics to provide meaningful insights that can be used for the determination of optimal cutoff values in VS procedures.…”

Unconventional Knoevenagel-type indoles: Synthesis and cell-based studies for the identification of pro-apoptotic agents

“…Indole derivatives have been described as useful chemical templates in different therapeutic areas, including the treatment of neurodegenerative diseases [3][4][5], psychiatric disorders [6] and inflammation [7,8]. Moreover, indole derivatives were found to be endowed with antiviral [9], antioxidant [10], antiplasmodial [11], antiproliferative and antitumor efficacy [12][13][14][15][16][17][18][19][20]. Recently induction of methuosis, which is one of the most recently acknowledged nonapoptotic cell death phenotype involving the accumulation of cytoplasmic vacuoles derived from macropinosomes, was identified as the mechanism of action of conjugated 3-vinyl indoles [21].…”