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  • Title: 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.
    Author: Sun L, Vasilevich NI, Fuselier JA, Coy DH.
    Journal: Anticancer Res; 2004; 24(1):179-86. PubMed ID: 15015595.
    Abstract:
    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.
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