Synthesis and evaluation of analogs of (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene as potential cytotoxic and antimitotic agents

• Published in: Journal of medicinal chemistry Vol. 35; no. 12; pp. 2293 - 2306
• Main Authors: Cushman, Mark, Nagarathnam, Dhanapalan, Gopal, D, He, Hu Ming, Lin, Chii M, Hamel, Ernest
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-06-1992
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Breast Neoplasms - drug therapy; Cell Division - drug effects; Chemistry; Colonic Neoplasms - drug therapy; Exact sciences and technology; Humans; Lung Neoplasms - drug therapy; Melanoma - drug therapy; Noncondensed benzenic compounds; Organic chemistry; Preparations and properties; Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - pharmacology; Stilbenes - therapeutic use; Structure-Activity Relationship; Tubulin - metabolism; Tubulin Modulators; Tumor Cells, Cultured; Antineoplastic agent; Wittig reaction; Ether; Structure activity relation; Benzenic compound; Acetylation; Antimitotic; Ethylenic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00090a021

A series of stilbenes has been prepared and tested for cytotoxicity in the five human cancer cell lines A-549 non-small cell lung, MCF-7 breast, HT-29 colon, SKMEL-5 melanoma, and MLM melanoma. The cis stilbenes 6a-f proved to be cytotoxic in all five cell lines, with potencies comparable to that of combretastatin A-4. These cytotoxic compounds were all potent inhibitors of tubulin polymerization. The corresponding trans stilbenes 7b-f were inactive as tubulin polymerization inhibitors and were significantly less cytotoxic in the five cancer cell lines. In the dihydro series, 8b, 8c, and 8f were inactive as tubulin polymerization inhibitors, while 8a, 8d, and 8e were less active than the corresponding cis compounds 6a, 6d, and 6e. The lack of tubulin polymerization inhibitory activity and cytotoxicity displayed by the phenanthrene 23b, which was synthesized as a conformationally rigid analogue of the lead compound 1, indicates that the activity of the stilbenes is not due to a totally planar conformation. Similarly, inactivity of the conformationally restricted analogue 26 suggests that the biologically active conformation of 1a resembles that of the cis alkene 1. Additional inactive compounds prepared include the benzylisoquinoline series 28-32 as well as the protoberberines 38 and 39. Shortening the two-carbon bridge of 1a to a one-carbon bridge in the diphenylmethane 20 resulted in a decrease in cytotoxicity and tubulin polymerization inhibitory activity. Although the corresponding benzophenone 18 was as active as 1a as a tubulin polymerization inhibitor, it was less cytotoxic than 1a, and the benzhydrol 19 was essentially inactive. With the exception of the amide 15c, which displayed low antitubulin activity, all of the phenylcinnamic acid derivatives 14a-c and 15a-f were inactive in the tubulin polymerization inhibition assay. The acid 14b and the ester 15a were cytotoxic in several of the cancer cell cultures in spite of their inactivity as tubulin polymerization inhibitors.