Querolle Olivier, Dubois Joëlle, Thoret Sylviane, Roussi Fanny, Guéritte Françoise, Guénard Daniel
Institut de Chimie des Substances Naturelles, CNRS, 91190 Gif sur Yvette, France.
J Med Chem. 2004 Nov 18;47(24):5937-44. doi: 10.1021/jm0497996.
Novel C2-C3'N-linked macrocyclic taxoids 4 bearing an aromatic ring at position C2 were synthesized. These compounds, tethered between N3' and the C2-aromatic ring at the ortho, meta, or para position, were constructed by ring-closing metathesis. The para-substituted derivatives were unable to stabilize microtubules, whereas the ortho- and meta-substituted compounds show significant activity in cold-induced microtubule disassembly assay. The meta derivative 4c is the first C2-C3'-linked cyclic analogue to be equipotent to paclitaxel in this assay and to show significant cytotoxicity. Computational studies of the conformational behavior of these compounds indicate that they can adopt several conformations including mainly the "T-shaped" forms. Docking experiments have shown that the "T-shaped" form is preferred for a good interaction of these compounds with the beta-tubulin binding pocket.
合成了在C2位带有芳环的新型C2-C3' N-连接大环紫杉烷4。这些化合物通过闭环复分解反应构建，连接在N3'与邻位、间位或对位的C2-芳环之间。对位取代衍生物无法稳定微管，而邻位和间位取代化合物在冷诱导微管解聚试验中显示出显著活性。间位衍生物4c是该试验中第一个在效力上与紫杉醇相当且显示出显著细胞毒性的C2-C3'-连接环类似物。对这些化合物构象行为的计算研究表明，它们可以采取几种构象，主要包括“T形”形式。对接实验表明，“T形”形式有利于这些化合物与β-微管蛋白结合口袋的良好相互作用。
