Barboni L, Datta A, Dutta D, Georg G I, Vander Velde D G, Himes R H, Wang M, Snyder J P
Department of Medicinal Chemistry and Drug Discovery Program, Higuchi Biosciences Center, University of Kansas, Lawrence, KS 66045, USA.
J Org Chem. 2001 May 18;66(10):3321-9. doi: 10.1021/jo0015467.
Four new D-secopaclitaxel analogues were synthesized from paclitaxel. The key step of the synthesis involved the opening of the D-ring by Jones oxidation. Two of the compounds had been predicted to be nearly as active as paclitaxel in a minireceptor model of the binding site on tubulin, but all were biologically inactive in an in vitro cytotoxic assay and a tubulin assembly assay. The biological results identify a weakness in our predictive minireceptor model and suggest a corrective remedy in which additional amino acids are needed to accommodate ligand-protein steric effects around the oxetane ring. These changes to the model lead to correct predictions of the bioactivity. Conformational analysis and dynamics simulations of the compounds showed that the 4-acetyl substituent is as important as the oxetane in determining the A ring conformation.
从紫杉醇合成了四种新的D-去甲紫杉醇类似物。合成的关键步骤是通过琼斯氧化打开D环。在微管蛋白结合位点的微型受体模型中，预测其中两种化合物的活性几乎与紫杉醇相同，但在体外细胞毒性试验和微管蛋白组装试验中，所有化合物均无生物活性。生物学结果揭示了我们预测性微型受体模型的一个弱点，并提出了一种纠正方法，即需要额外的氨基酸来适应氧杂环丁烷环周围的配体-蛋白质空间效应。对模型的这些修改导致了对生物活性的正确预测。对这些化合物的构象分析和动力学模拟表明，4-乙酰基取代基在决定A环构象方面与氧杂环丁烷同样重要。
