Design, synthesis, and biological testing of pyrazoline derivatives of combretastatin-A4.
Fourteen N-acetylated and non-acetylated 3,4,5-tri- or 2,5-dimethoxypyrazoline analogs of combretastatin-A4 (1) were synthesized. A non-acetylated derivative (5a) with the same substituents as CA-4 (1) was the most active compound in the series, with IC(50) values of 2.1 and 0.5 microM in B16 and L1210 cell lines, respectively. In contrast, a similar compound with an acetyl group at N1 of the pyrazoline ring (6g) showed poor activity in the cell lines studied. A cell-based assay indicated that compound 5a caused extensive microtubule depolymerization with an EC(50) value of 7.1 microM in A-10 cells while no activity was seen with the acetylated compound. Molecular modeling studies showed that these compounds possess a twisted conformation similar to CA-4 (1).
Johnson
Marlie
M
Department of Chemistry, Division of Natural and Applied Sciences, Hope College, MI 49423, USA.
Younglove
Brent
B
Lee
Lauren
L
LeBlanc
Regan
R
Holt
Herman
H
Hills
Patrice
P
Mackay
Hilary
H
Brown
Toni
T
Mooberry
Susan L
SL
Lee
Moses
M
D000818:Animals; D002460:Cell Line; D015195:Drug Design; D051379:Mice; D008958:Models, Molecular; D011720:Pyrazoles / Q000737:chemistry*; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*