Cytotoxic N-(fluorenyl-9-methoxycarbonyl) (Fmoc)-dipeptides: Structure–activity relationships and synergistic studies

• Published in: European journal of medicinal chemistry 2010-06, Vol.45 (6), p.2494-2502
• Main Authors: Yen, Chiao-Ting, Wu, Chin-Chung, Lee, Jin-Ching, Chen, Shu-Li, Morris-Natschke, Susan L., Hsieh, Pei-Wen, Wu, Yang-Chang
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Ca9-22; Cell Line, Tumor; Cytotoxicity; Dipeptides - chemical synthesis; Dipeptides - chemistry; Dipeptides - pharmacology; Doxorubicin - pharmacology; Drug Synergism; Fluorenes - chemistry; Fmoc-based dipeptide; General aspects; HepG2; Human cancer cell line; Humans; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2010.02.035

The synthesis and cytotoxic evaluation of a series of Fmoc-based dipeptides are described. Among the thirty compounds, 4a, 8a, 12a, 2b, 4b, 10b, 3c, 4c and 6c showed potent activity against HepG2, Hep3B, MCF-7, MDA-MB-231, A549 and Ca9-22 human cancer cell lines. The most active compounds ( 10a and 10c) showed relatively good sensitivity toward HepG2 and Ca9-22 cell lines with IC 50 values of 1.0 and 0.4 μM, respectively. Additionally, compound 10c was threefold more potent than doxorubicin, the positive control, against the Ca9-22 cell line. Furthermore, 10c showed a synergistic effect and increased the cytotoxicity of doxorubicin against the MDA-MB-231 cancer cell line. Therefore, 10c could be used as a new lead compound for therapeutic development. Thirty Fmoc-based dipeptides were designed and synthesized. The pharmacological results showed compounds 10a and 10c with IC 50 values of 1.0 and 0.4 μM against HepG2 and Ca9-22, respectively. [Display omitted]