Design, synthesis, and biological testing of pyrazoline derivatives of combretastatin-A4

被引：154

作者：

Johnson, Marlie

Younglove, Brent

Lee, Lauren

LeBlanc, Regan

Holt, Herman, Jr.

Hills, Patrice

Mackay, Hilary

Brown, Toni

Mooberry, Susan L.

Lee, Moses ^{[1
]}

机构：

[1] Hope Coll, Dept Chem, Div Nat & Appl Sci, Holland, MI 49423 USA

[2] Furman Univ, Dept Chem, Greenville, SC 29613 USA

[3] Univ N Carolina, Dept Chem, Asheville, NC 28804 USA

[4] SW Fdn Biomed Res, Dept Physiol & Med, San Antonio, TX 78227 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 21期

关键词：

cornbretastatins; tubulin; anti-cancer; pyrazolines; CC-1065; duocarmycins; pyrrolobenzodiazepines; achiral; seco-Amino-CBI; dimer;

D O I：

10.1016/j.bmcl.2007.07.105

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：5897 / 5901

页数：5

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