Antineoplastic agents. 443. Synthesis of the cancer cell growth inhibitor hydroxyphenstatin and its sodium diphosphate prodrug

George Pettit, Matthew P. Grealish, Delbert L. Herald, Michael R. Boyd, Ernest Hamel, Robin Pettit

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

A structure - activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (3b) led to the discovery of a potent cancer cell growth inhibitor designated phenstatin (5a). This benzophenone derivative of combretastatin A-4 showed remarkable antineoplastic activity, and the benzophenone derivative of combretastatin A-1 was therefore synthesized. The benzophenone, designated hydroxyphenstatin (6a), was synthesized by coupling of a protected bromobenzene and a benzaldehyde to give the benzhydrol with subsequent oxidation to the ketone. Hydroxyphenstatin was converted to the sodium phosphate prodrug (6e) by a dibenzyl phosphite phosphorylation and subsequent benzyl cleavage (6a → 6d → 6e). While hydroxyphenstatin (6a) was a potent inhibitor of tubulin polymerization with activity comparable to that of combretastatin A-1 (3a), the phosphorylated derivative (6e) was inactive.

Original languageEnglish (US)
Pages (from-to)2731-2737
Number of pages7
JournalJournal of Medicinal Chemistry
Volume43
Issue number14
DOIs
StatePublished - Jul 13 2000

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Growth Inhibitors
Prodrugs
Antineoplastic Agents
Derivatives
Combretum
Tubulin Modulators
Salix
Phosphites
Neoplasms
Phosphorylation
Structure-Activity Relationship
Ketones
Oxidation
hydroxyphenstatin
hydroxyphenstatin diphosphate
benzophenone
fosbretabulin
combretastatin A-1

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Antineoplastic agents. 443. Synthesis of the cancer cell growth inhibitor hydroxyphenstatin and its sodium diphosphate prodrug. / Pettit, George; Grealish, Matthew P.; Herald, Delbert L.; Boyd, Michael R.; Hamel, Ernest; Pettit, Robin.

In: Journal of Medicinal Chemistry, Vol. 43, No. 14, 13.07.2000, p. 2731-2737.

Research output: Contribution to journalArticle

Pettit, George ; Grealish, Matthew P. ; Herald, Delbert L. ; Boyd, Michael R. ; Hamel, Ernest ; Pettit, Robin. / Antineoplastic agents. 443. Synthesis of the cancer cell growth inhibitor hydroxyphenstatin and its sodium diphosphate prodrug. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 14. pp. 2731-2737.
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