Synthesis and cytotoxicity of epoxide and pyrazole analogs of the combretastatins.
Twenty-six epoxide and corresponding pyrazole derivatives, of the structurally related chalcones and combretastatin A-4 (CA-4), were synthesized and tested for in vitro cytotoxicity. These molecules were synthesized by epoxidation of the relevant chalcones, followed by reaction with hydrazine. The structures of epoxides 3 and 7, and pyrazole 17, were confirmed by X-ray diffraction studies. The relatively coplanar conformation of a 3',3'',4',4'',5',5''-hexamethoxypyrazole 17 was in good agreement with the shape for 3',3'',4',4'',5'-pentamethoxypyrazole 16, which was determined from molecular mechanics optimization. In vitro cytotoxicity of each class of compounds was obtained using a 72 h continuous exposure MTT assay against two murine cancer cell lines; B16 melanoma and L1210 leukemia. The effect of substitution in the A-ring is addressed: three methoxy groups versus two, generally increased cytotoxicity across both cell lines. In the majority of cases, the pyrazoles are generally more active than the epoxides, with the most active, 5-(3''-amino-4''-methoxyphenyl)-3-(3',4',5'-trimethoxyphenyl)pyrazole 21, possessing an IC(50) value of 5 and 2.4 microM (B16 and L1210, respectively). Due to their planar conformations, the pyrazoles are typically less active than the corresponding chalcones, which adopt angular conformations similar to CA-4. B-ring modifications confirmed that in general the amino compounds are more active than the corresponding nitro compounds. Varying the number and orientation of methoxy groups on the A-ring did not produce any significant differences in toxicity in the cell lines studied.
LeBlanc
Regan
R
Department of Chemistry, Furman University, Greenville, SC 29613, USA.
Dickson
John
J
Brown
Toni
T
Stewart
Michelle
M
Pati
Hari N
HN
VanDerveer
Don
D
Arman
Hadi
H
Harris
Jeff
J
Pennington
William
W
Holt
Herman L
HL
Lee
Moses
M
D000818:Animals; D001632:Bibenzyls / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D002460:Cell Line; D018360:Crystallography, X-Ray; D004852:Epoxy Compounds / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship
D001632:Bibenzyls; D004852:Epoxy Compounds; D011720:Pyrazoles; D013267:Stilbenes; C031280:pyrazole; C040105:combretastatin