Abilities of 3,4-Diarylfuran-2-one Analogs of Combretastatin A-4 to Inhibit Both Proliferation of Tumor Cell Lines and Growth of Relevant Tumors in Nude Mice

• Published in: Anticancer research 2004-01, Vol.24 (1), p.179-186
• Main Authors: LICHUN SUN, VASILEVICH, Natalya I, FUSELIER, Joseph A, COY, David H
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - toxicity; Biological and medical sciences; Cell Cycle - drug effects; Cell Division - drug effects; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Furans - pharmacology; Furans - toxicity; Growth Inhibitors - pharmacology; Growth Inhibitors - toxicity; Humans; Male; Medical sciences; Mice; Mice, Nude; Stilbenes - pharmacology; Stilbenes - toxicity; Tubulin - metabolism; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0250-7005; 1791-7530

Background: Combretastatin A-4 (CA-4) and its analogs are potent inhibitors of tubulin polymerization and display strong inhibitory activity on both solid tumor and tumor cell growth. Since natural CA-4 is difficult to synthesize and also isomerizes to an inactive form quite readily, a recently reported new 3,4-diarylfuran-2-one-based series of CA-4 analogs was investigated, in the hope of bypassing some of these difficulties. These analogs appear to offer a valuable tool for CA-4 research because of their extremely facile synthesis from readily available starting materials. Materials and Methods: The CA-4 analogs were evaluated by MTT assay, cell cycle analysis, tubulin polymerization and tumor-inhibiting experiments. Results: Various benzene ring substitutions on the furan-2-one skeleton (analogs to the two aromatic rings on the CA-4 styrene skeleton) quickly demonstrated that the structure-activity relationships are quite similar to previously synthesized CA-4 analogs. The most interesting analog appears to be an anilino compound (NV-5-9) which was also quite soluble. Analog NV-5-9 was remarkably potent in all tested tumor cell lines and could strongly inhibit tubulin polymerization at doses as low as 1 mM. Further experiments with tumor-bearing mice indicated that NV-5-9 and other potent analogs (NV-4-82 and NV-4-86) were effective in treating human prostate PC-3 and SCLC NCI-H69 tumors at well below an oral MTD dose of around 200 mg/kg body weight. This suggests some bioavailability by this route. Conclusion: These data strongly support that NV-5-9 is extremely potent, readily synthesizable and apparently suitable for in vivo studies employing transplanted tumors.