Department of Biochemistry, Chemistry and Pharmacology, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Bioorg Med Chem Lett. 2010 Mar 1;20(5):1787-91. doi: 10.1016/j.bmcl.2010.01.009. Epub 2010 Jan 11.
In an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (NSAIDs) has been synthesized and evaluated for activity versus Trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. It was discovered that coupling of NSAIDs to podophyllotoxin increased the potencies of both compounds over 1300-fold. The compounds were shown to be cytostatic in nature and seem to act via de-polymerization of tubulin in a manner consistent with the known activities of podophyllotoxin. The potencies against T. brucei correlated directly with LogP values of the compounds, suggesting that the conjugates are acting as hydrophobic tags allowing podophyllotoxin to enter the cell.
为了发现新型抗锥虫化合物，我们合成了一系列与非甾体抗炎药（NSAIDs）偶联的鬼臼毒素类似物，并对其针对布鲁氏锥虫和一系列人类细胞系的活性进行了评估，发现了具有低纳摩尔效力的化合物。我们发现，将 NSAIDs 与鬼臼毒素偶联可使这两种化合物的效力提高 1300 多倍。这些化合物具有细胞生长抑制作用，似乎通过微管蛋白的解聚起作用，这与鬼臼毒素的已知活性一致。化合物对 T. brucei 的效力与化合物的 LogP 值直接相关，这表明这些缀合物充当疏水性标记，允许鬼臼毒素进入细胞。
