Antineoplastic agents. 509. Synthesis of fluorcombstatin phosphate and related 3-halostilbenes

George Pettit, Mathew D. Minardi, Heidi J. Rosenberg, Ernest Hamel, Michael C. Bibby, Sandie W. Martin, M. Katherine Jung, Robin Pettit, Timothy J. Cuthbertson, Jean Chapuis

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1450-1458
Number of pages9
JournalJournal of Natural Products
Volume68
Issue number10
DOIs
StatePublished - Oct 2005

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Stilbenes
stilbenes
antineoplastic agents
tubulin
Antineoplastic Agents
Phosphates
Cells
cell lines
phosphates
Tubulin
Cell Line
synthesis
Potassium
Tubulin Modulators
Salts
potassium
salts
Lymphoid Leukemia
cell free system
halogens

ASJC Scopus subject areas

  • Plant Science
  • Chemistry (miscellaneous)
  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Antineoplastic agents. 509. Synthesis of fluorcombstatin phosphate and related 3-halostilbenes. / Pettit, George; Minardi, Mathew D.; Rosenberg, Heidi J.; Hamel, Ernest; Bibby, Michael C.; Martin, Sandie W.; Jung, M. Katherine; Pettit, Robin; Cuthbertson, Timothy J.; Chapuis, Jean.

In: Journal of Natural Products, Vol. 68, No. 10, 10.2005, p. 1450-1458.

Research output: Contribution to journalArticle

Pettit, G, Minardi, MD, Rosenberg, HJ, Hamel, E, Bibby, MC, Martin, SW, Jung, MK, Pettit, R, Cuthbertson, TJ & Chapuis, J 2005, 'Antineoplastic agents. 509. Synthesis of fluorcombstatin phosphate and related 3-halostilbenes', Journal of Natural Products, vol. 68, no. 10, pp. 1450-1458. https://doi.org/10.1021/np058038i
Pettit, George ; Minardi, Mathew D. ; Rosenberg, Heidi J. ; Hamel, Ernest ; Bibby, Michael C. ; Martin, Sandie W. ; Jung, M. Katherine ; Pettit, Robin ; Cuthbertson, Timothy J. ; Chapuis, Jean. / Antineoplastic agents. 509. Synthesis of fluorcombstatin phosphate and related 3-halostilbenes. In: Journal of Natural Products. 2005 ; Vol. 68, No. 10. pp. 1450-1458.
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