Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, Department of Chemistry, University of Pennsylvania , Philadelphia, 19104, United States.
J Am Chem Soc. 2011 Sep 7;133(35):14042-53. doi: 10.1021/ja2046167. Epub 2011 Aug 12.
The design, synthesis, and biological evaluation of two diminutive forms of (+)-spongistatin 1, in conjunction with the development of a potentially general design strategy to simplify highly flexible macrocyclic molecules while maintaining biological activity, have been achieved. Examination of the solution conformations of (+)-spongistatin 1 revealed a common conformational preference along the western perimeter comprising the ABEF rings. Exploiting the hypothesis that the small-molecule recognition/binding domains are likely to comprise the conformationally less mobile portions of a ligand led to the design of analogues, incorporating tethers (blue) in place of the CD and the ABCD components of the (+)-spongistatin 1 macrolide, such that the conformation of the retained (+)-spongistatin 1 skeleton would mimic the assigned solution conformations of the natural product. The observed nanomolar cytotoxicity and microtubule destabilizing activity of the ABEF analogue provide support for both the assigned solution conformation of (+)-spongistatin 1 and the validity of the design strategy.
已经实现了两种（+）-海绵抑素 1 的小型化形式的设计、合成和生物评价，同时还开发了一种潜在的通用设计策略，可在保持生物活性的同时简化高度灵活的大环分子。（+）-海绵抑素 1 的溶液构象研究揭示了一个共同的构象偏好，沿着西部边界包含 ABEF 环。利用小分子识别/结合结构域可能包含配体中构象移动性较小部分的假设，设计了类似物，用系链（蓝色）代替（+）-海绵抑素 1 大环内酯的 CD 和 ABCD 部分，从而保留的（+）-海绵抑素 1 骨架的构象将模拟天然产物的指定溶液构象。ABE 类似物的纳米级细胞毒性和微管去稳定活性观察结果为（+）-海绵抑素 1 的指定溶液构象和设计策略的有效性提供了支持。
