Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 17, Issue 21, Pages 5897-5901Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2007.07.105
Keywords
cornbretastatins; tubulin; anti-cancer; pyrazolines; CC-1065; duocarmycins; pyrrolobenzodiazepines; achiral; seco-Amino-CBI; dimer
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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 IC50 values of 2.1 and 0.5 mu M 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 EC50 value of 7.1 mu M 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). (c) 2007 Elsevier Ltd. All rights reserved.
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