Antineoplastic agents. 379. Synthesis of phenstatin phosphate

George Pettit, Brian Toki, Delbert L. Herald, Pascal Verdier-Pinard, Michael R. Boyd, Ernest Hamel, Robin Pettit

Research output: Contribution to journalArticle

212 Citations (Scopus)

Abstract

A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A- 4 (1b) directed at maintaining the (Z)stilbene relationship of the olefin diphenyl substituents led to synthesis of a potent cancer cell growth inhibitor designated phenstatin (3b). Initially phenstatin silyl ether (3a) was unexpectedly obtained by Jacobsen oxidation of combretastatin A-4 silyl ether (1c → 3a), and the parent phenstatin (3b) was later synthesized (6a → 3a → 3b) in quantity. Phenstatin was converted to the sodium phosphate prodrug (3d) by a dibenzyl phosphite phosphorylation and subsequent hydrogenolysis sequence (3b → 3c → 3d). Phenstatin (3b) inhibited growth of the pathogenic bacterium Neisseria gonorrhoeae and was a potent inhibitor of tubulin polymerization and the binding of colchicine to tubulin comparable to combretastatin A-4 (1b). Interestingly, the prodrugs were found to have reduced activity in these biochemical assays. While no significant tubulin activity was observed with the phosphorylated derivative of combretastatin A- 4 (1d), phosphate 3d retained detectable inhibitory effects in both assays.

Original languageEnglish (US)
Pages (from-to)1688-1695
Number of pages8
JournalJournal of Medicinal Chemistry
Volume41
Issue number10
DOIs
StatePublished - May 7 1998

Fingerprint

Antineoplastic Agents
Prodrugs
Tubulin
Ether
Assays
Combretum
Tubulin Modulators
Salix
Phosphites
Stilbenes
Growth Inhibitors
Hydrogenolysis
Phosphorylation
Neisseria gonorrhoeae
Colchicine
Alkenes
Structure-Activity Relationship
Bacteria
Phosphates
Derivatives

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Pettit, G., Toki, B., Herald, D. L., Verdier-Pinard, P., Boyd, M. R., Hamel, E., & Pettit, R. (1998). Antineoplastic agents. 379. Synthesis of phenstatin phosphate. Journal of Medicinal Chemistry, 41(10), 1688-1695. https://doi.org/10.1021/jm970644q

Antineoplastic agents. 379. Synthesis of phenstatin phosphate. / Pettit, George; Toki, Brian; Herald, Delbert L.; Verdier-Pinard, Pascal; Boyd, Michael R.; Hamel, Ernest; Pettit, Robin.

In: Journal of Medicinal Chemistry, Vol. 41, No. 10, 07.05.1998, p. 1688-1695.

Research output: Contribution to journalArticle

Pettit, G, Toki, B, Herald, DL, Verdier-Pinard, P, Boyd, MR, Hamel, E & Pettit, R 1998, 'Antineoplastic agents. 379. Synthesis of phenstatin phosphate', Journal of Medicinal Chemistry, vol. 41, no. 10, pp. 1688-1695. https://doi.org/10.1021/jm970644q
Pettit G, Toki B, Herald DL, Verdier-Pinard P, Boyd MR, Hamel E et al. Antineoplastic agents. 379. Synthesis of phenstatin phosphate. Journal of Medicinal Chemistry. 1998 May 7;41(10):1688-1695. https://doi.org/10.1021/jm970644q
Pettit, George ; Toki, Brian ; Herald, Delbert L. ; Verdier-Pinard, Pascal ; Boyd, Michael R. ; Hamel, Ernest ; Pettit, Robin. / Antineoplastic agents. 379. Synthesis of phenstatin phosphate. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 10. pp. 1688-1695.
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