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

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.

• Authors: G R Pettit, M P Grealish, D L Herald, M R Boyd, E Hamel, R K Pettit
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 43 Issue 14 Pg. 2731-7 (Jul 13 2000) ISSN: 0022-2623 [Print] United States
• PMID: 10893310 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Infective Agents
• Antineoplastic Agents
• Benzophenones
• Biopolymers
• Diphosphates
• Tubulin
• hydroxyphenstatin
• hydroxyphenstatin diphosphate
• Colchicine

Topics

• Animals
• Anti-Infective Agents (chemical synthesis, chemistry, pharmacology)
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzophenones (chemical synthesis, chemistry, pharmacology)
• Biopolymers
• Colchicine (chemistry)
• Crystallography, X-Ray
• Diphosphates (chemical synthesis, chemistry, pharmacology)
• Drug Screening Assays, Antitumor
• Humans
• Mice
• Models, Molecular
• Molecular Conformation
• Tubulin (chemistry)
• Tumor Cells, Cultured