Asunto(s)

Aminoácidos/síntesis química , Antineoplásicos/síntesis química , Cobalto/química , Oligopéptidos/química , Fosfinas/química , Pirrolidinas/síntesis química , Aminoácidos/química , Antineoplásicos/química , Depsipéptidos , Indicadores y Reactivos , Pirrolidinas/química , Solventes , Estereoisomerismo

RESUMEN

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.

Asunto(s)

Antineoplásicos/síntesis química , Benzofenonas/síntesis química , Difosfatos/síntesis química , Animales , Antiinfecciosos/síntesis química , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Benzofenonas/química , Benzofenonas/farmacología , Biopolímeros , Colchicina/química , Cristalografía por Rayos X , Difosfatos/química , Difosfatos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Modelos Moleculares , Conformación Molecular , Tubulina (Proteína)/química , Células Tumorales Cultivadas