Arylthioindoles, Potent Inhibitors of Tubulin Polymerization

Abstract

Several arylthioindoles had excellent activity as inhibitors both of tubulin polymerization and of the growth of MCF-7 human breast carcinoma cells. Methyl 3-[(3,4,5-trimethoxyphenyl)thio]-5-methoxy-1H-indole-2-carboxylate (21), the most potent derivative, showed IC(50) = 2.0 microM, 1.6 times more active than colchicine and about as active as combretastatin A-4 (CSA4). Compound 21 inhibited the growth of the MCF-7 cells at IC(50) = 13 nM. Colchicine and CSA4 had 13 nM and 17 nM IC(50) values, respectively, with these cells.

Lead identification of conformationally restricted benzoxepin type combretastatin analogs: synthesis, antiproliferative activity, and tubulin effects

“…The drug concentration required to inhibit the cell growth by 50% (IC 50 ) following incubation of the cells in the culture medium for 72 h was determined and the results are displayed in Table 1. The IC 50 values obtained for combretastatin CA-4 were 0.0031 μM for MCF-7 and 0.043 μM for MDA-MB 231, which are in good agreement with the reported values for combretastatin CA-4 using the MTT assay on human MCF-7 and MDA-MB 231 breast cancer cell lines 11,20,30 . Compounds 11a-e and 11k, which display polymethoxylated aryl substitution, were found to exert modest antiproliferative effects on MCF-7 cells, with IC 50 in the range 4.86-10.70 μM, when compared with our determined values for combretastatin CA-4 (IC 50 = 0.0031 μM).…”

“…Many cis-restricted analogs of CA-4 have been synthesized to improve the solubility, stability, and therapeutic index 4 of these drugs. A number of examples where the olefinic group is replaced by a conformationally restricted ring structure have demonstrated significant antiproliferative activity 13 , including those based on coumarin (1) 14,15 , 2(5H)-furanone (2) 16 , imidazole 17 , 1,3-oxazole (3) 17 , furazan (4) 4 and furan (5) 18 , diarylindole 17,19 , and arylthioindole 20 , illustrated in Figure 1. We have previously reported the application of the benzoxepin 21 and benzothiepin scaffolds 22 for the design of antiproliferative agents as estrogen receptor (ER) antagonists.…”

Synthesis and Evaluation of Azetidinone Analogues of Combretastatin A-4 as Tubulin Targeting Agents

“…The cytotoxicity was assessed using alamar blue dye. and MDA-MB 231 breast cancer cell lines, (see references 7,73,74 ). …”

The production of novolac oligomers

“…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].…”