Antineoplastic agents 440. Asymmetric synthesis and evaluation of the combretastatin A-1 SAR probes (1S,2S)- and (1R,2R)-1,2-dihydroxy-1-(2 ',3 '-dihydroxy-4 '-methoxyphenyl)-2-(3 '',4 '',5 ''-trimethoxyphenyl)-ethane
Gr. Pettit et al., Antineoplastic agents 440. Asymmetric synthesis and evaluation of the combretastatin A-1 SAR probes (1S,2S)- and (1R,2R)-1,2-dihydroxy-1-(2 ',3 '-dihydroxy-4 '-methoxyphenyl)-2-(3 '',4 '',5 ''-trimethoxyphenyl)-ethane, J NAT PROD, 63(7), 2000, pp. 969-974
The synthetic (E)-isomer (3b) of natural combretastatin A-1 (1a) isolated f
rom the African bushwillow Combretum caffrum was the focus of chiral hydrox
ylation (Sharpless) reactions as part of a structure-activity relationship
study. The resulting (R,R)- and (S,S,)-diols (6 and 7) and synthetic interm
ediates were evaluated against a series of cancer cell lines, microorganism
s, and tubulin. Chiral diols 6 and 7 showed increased activity against the
P-388 murine lymphocytic leukemia cell Line with ED50 values of 3.9 and 2.9
mu g/mL, respectively, when compared to the precursor (E)-stilbene 3b. In
contrast, (E)-stilbene 3b exhibited more potent antibiotic activity than th
e chiral diols (6 and 7). Both diols, (R,R)-6 and (S,S)7, displayed less ca
ncer cell growth inhibition and less antibiotic activity than did natural c
ombretastatin A-1 (1a) (P-388 ED50 0.25 mu g/mL).