Design, synthesis, and biological testing of pyrazoline derivatives of combretastatin-A4
Design, synthesis, and biological testing of pyrazoline derivatives of combretastatin-A4
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DOI：
10.1016/j.bmcl.2007.07.105
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发表时间：
2007-11-01
影响因子：
2.7
通讯作者：
Lee, Moses
中科院分区：
文献类型：
--
作者：
Johnson, Marlie;Younglove, Brent;Lee, Moses
合成了14个考布他汀-A4（1）的N-乙酰化和非乙酰化的3，4，5-三-或2，5-二甲氧基吡唑啉类似物。具有与CA-4（1）相同取代基的非乙酰化衍生物（5a）是该系列中活性最高的化合物，在B16和L1210细胞系中的IC 50值分别为2.1和0.5 μ M。相比之下，在吡唑啉环的N1处具有乙酰基的类似化合物（6 g）在所研究的细胞系中显示出较差的活性。基于细胞的测定表明，化合物5a在A-10细胞中引起广泛的微管解聚，EC 50值为7.1 μ M，而乙酰化化合物没有活性。分子模拟研究表明，这些化合物具有与CA-4类似的扭曲构象（1）。(c)2007爱思唯尔有限公司保留所有权利。
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.