1. Academic Validation
  2. Antineoplastic agents. 509: synthesis of fluorcombstatin phosphate and related 3-halostilbenes(1)

Antineoplastic agents. 509: synthesis of fluorcombstatin phosphate and related 3-halostilbenes(1)

  • J Nat Prod. 2005 Oct;68(10):1450-8. doi: 10.1021/np058038i.
George R Pettit 1 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
Affiliations

Affiliation

  • 1 Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, P.O. Box 872404, Tempe, Arizona 85287-2404, USA.
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.

Figures