title: Antineoplastic agents. 509: synthesis of fluorcombstatin phosphate and related 3-halostilbenes(1).
abstract: The present SAR study of combretastatin A-3 (3a) focused on replacement of the 3-hydroxyl group by a series of halogens. That approach with Z-stilbenes resulted in greatly enhanced (>10-100-fold) cancer cell growth inhibition against a panel of human cancer cell lines and the murine P388 lymphocytic leukemia cell line. Synthesis of the 3-fluoro-Z-stilbene designated fluorcombstatin (11a) and its potassium 3'-O-phosphate derivative (16c) by the route 7 --> 8a --> 11a --> 14 --> 16c illustrates the general synthetic pathway. The 3'-O-phosphoric acid ester (15) of 3-bromo-Z-stilbene 13a was also converted to representative cation salts to evaluate the potential for improved aqueous solubility, and the potassium salt (16 mg/mL in water) proved most useful. The fluoro (11a), chloro (12a), and bromo (13a) halocombstatins were nearly equivalent to combretastatin A-4 (1a) as inhibitors of tubulin polymerization and of the binding of colchicine to tubulin. The tubulin binding in cell-free systems was also retained in human umbilical vein endothelial cells. All three halocombstatins retained the powerful human cancer cell line inhibitory activity of combretastatin A-4 (1a) and proved superior to combretastatin A-3 (3a). In addition, the halocombstatins targeted Gram-positive bacteria and Cryptococcus neoformans.
authors.affiliation: Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 872404, Tempe, Arizona 85287-2404, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Pettit
authors.forename: Mathew D
authors.initials: MD
authors.lastname: Minardi
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Rosenberg
authors.forename: Ernest
authors.initials: E
authors.lastname: Hamel
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bibby
authors.forename: Sandie W
authors.initials: SW
authors.lastname: Martin
authors.forename: M Katherine
authors.initials: MK
authors.lastname: Jung
authors.forename: Robin K
authors.initials: RK
authors.lastname: Pettit
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Cuthbertson
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Chapuis
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003455:Cryptococcus neoformans / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007941:Leukemia P388; D015394:Molecular Structure; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D006846:Hydrocarbons, Halogenated; D013267:Stilbenes; D014404:Tubulin