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.
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.


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.


CONCLUSIONS
These data strongly support that NV-5-9 is extremely potent, readily synthesizable and apparently suitable for in vivo studies employing transplanted tumors.
Sun
Lichun
L
Department of Medicine, Peptide Research Laboratories, Tulane Health Sciences Center, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112-2699, USA. lsun@tulane.edu
Vasilevich
Natalya I
NI
Fuselier
Joseph A
JA
Coy
David H
DH
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005663:Furans / Q000494:pharmacology* / Q000633:toxicity; D006131:Growth Inhibitors / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D013267:Stilbenes / Q000494:pharmacology* / Q000633:toxicity; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; D006131:Growth Inhibitors; D013267:Stilbenes; D014404:Tubulin; C058728:fosbretabulin