Gr. Pettit et al., Antineoplastic agents. 443. Synthesis of the cancer cell growth inhibitor hydroxyphenstatin and its sodium diphosphate prodrug, J MED CHEM, 43(14), 2000, pp. 2731-2737
A structure-activity relationship (SAR) study of the South African willow t
ree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (3b)
led to the discovery of a potent cancer cell growth inhibitor designated ph
enstatin (5a). This benzophenone derivative of combretastatin A-4 showed re
markable antineoplastic activity, and the benzophenone derivative of combre
tastatin A-1 was therefore synthesized. The benzophenone, designated hydrox
yphenstatin (6a), was synthesized by coupling of a protected bromobenzene a
nd a benzaldehyde to give the benzhydrol with subsequent oxidation to the k
etone. 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 tub
ulin polymerization with activity comparable to that of combretastatin A-1
(3a), the phosphorylated derivative (6e) was inactive.