Diastereomers of dibromo-7-epi-10-deacetylcephalomannine: crowded and cytotoxic taxanes exhibit halogen bonds.
Diastereomers of dibromo-7-epi-10-deacetylcephalomannine: crowded and cytotoxic taxanes exhibit halogen bonds.
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DOI：
10.1021/jm0509243
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发表时间：
2006-02
影响因子：
7.3
通讯作者：
Yi Jiang;Ana A. Alcaraz;Jian-Min Chen;Hisayoshi Kobayashi;Yang J. Lu;J. Snyder
中科院分区：
文献类型：
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作者：
Yi Jiang;Ana A. Alcaraz;Jian-Min Chen;Hisayoshi Kobayashi;Yang J. Lu;J. Snyder
二溴-7-表-10-脱乙酰头甘露碱（6 和 7）的非对映异构体已被分离和表征。细胞毒性和微管组装测定表明，三尖杉宁类似物 6 具有与紫杉醇非常相似的效力特征，而异构体 7 的活性稍差。通过使用 X 射线晶体学、二维 NMR 实验结合 NAMFIS 分析和 Glide 对接方案，对两种非对映体的固态、溶液和微管蛋白结合构象进行了探测。在晶体中，异构体 7 表现出可能有助于自组装的分子间卤素键。两种晶体结构均未出现在 NAMFIS 溶液分析中，但两种非对映异构体在溶液中均以 T 形紫杉醇构象异构体表示。滑翔对接表明后者能够最好地填充微管蛋白结合袋，正如母体紫杉醇药物所显示的那样。 6 和 7 的结合复合物的每个模型分别呈现从配体之一的溴到靠近 β-微管蛋白 N 末端的 Glu22 或 Asp26 的单一明确的卤素键。紫杉烷和微管蛋白之间卤素键的首次报告可能有助于指导具有类似能力的其他微管稳定剂的设计和合成。
The diastereomers of dibromo-7-epi-10-deacetylcephalomannine (6 and 7) have been isolated and characterized. Cytotoxicity and microtubule assembly assays demonstrate that cephalomannine analogue 6 possesses a potency profile very similar to that of Taxol, while isomer 7 is slightly less active. Solid state, solution, and tubulin-bound conformations of the two diastereomers were probed by using X-ray crystallography, 2-D NMR experiments in conjunction with the NAMFIS analysis, and the Glide docking protocol. In the crystal, isomer 7 exhibits an intermolecular halogen bond that may contribute to self-assembly. Neither crystal structure appears in the NAMFIS solution analysis, but both diastereomers are represented in solution by a T-shaped Taxol conformer. Glide docking demonstrates the latter to best fill the tubulin binding pocket, as has been shown for the parent Taxol drug. Each model of the bound complexes for 6 and 7 presents a single well-defined halogen bond from one of the ligand's bromines to Glu22 or Asp26 near the N-terminus of beta-tubulin, respectively. This first report of a halogen bond between taxanes and tubulin may prove useful in guiding the design and synthesis of other microtubule-stabilizing agents with a similar capacity.