Design, synthesis, and biological testing of pyrazoline derivatives of combretastatin-A4
Johnson, M.; Younglove, B.; Lee, L.; LeBlanc, R.; Holt, H. L., Jr.; Hills, P.; Mackay, H.; Brown, T.; Mooberry, S. L.; Lee, M. Design, synthesis, and biological testing of pyrazoline derivatives of combretastatin-A4. Bioorg. Med. Chem. Lett. 2007, 17, 5897-901.
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).
Bioorganic & Medicinal Chemistry Letters