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: George R Pettit, Mathew D Minardi, Heidi J Rosenberg, Ernest Hamel, Michael C Bibby, Sandie W Martin, M Katherine Jung, Robin K Pettit, Timothy J Cuthbertson, Jean-Charles Chapuis
• Journal: Journal of natural products (J Nat Prod) Vol. 68 Issue 10 Pg. 1450-8 (Oct 2005) ISSN: 0163-3864 [Print] United States
• PMID: 16252907 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Antineoplastic Agents, Phytogenic
• Hydrocarbons, Halogenated
• Stilbenes
• Tubulin

Topics

• Animals
• Anti-Bacterial Agents (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents, Phytogenic (chemical synthesis, chemistry, pharmacology)
• Cryptococcus neoformans (drug effects)
• Drug Screening Assays, Antitumor
• Humans
• Hydrocarbons, Halogenated (chemical synthesis, chemistry, pharmacology)
• Leukemia P388
• Molecular Structure
• Stereoisomerism
• Stilbenes (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tubulin (drug effects)
• Tumor Cells, Cultured