Design, synthesis, and biological evaluation of diminutive forms of (+)-spongistatin 1: lessons learned.
Design, synthesis, and biological evaluation of diminutive forms of (+)-spongistatin 1: lessons learned.
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( )-海绵抑素 1 的小型形式的设计、合成和生物学评价：经验教训。
DOI：
10.1021/ja2046167
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发表时间：
2011
影响因子：
15
通讯作者：
Xu,Qunli
中科院分区：
文献类型：
--
作者：
Smith3rd,AmosB;Risatti,ChristinaA;Atasoylu,Onur;Bennett,ClayS;Liu,Junke;Cheng,Hongsheng;TenDyke,Karen;Xu,Qunli
已经实现了（+）-海绵抑素1的两种小型形式的设计、合成和生物学评价，以及潜在的通用设计策略的开发，以简化高度灵活的大环分子，同时保持生物活性。对（+）-spongistatin 1溶液构象的研究显示，沿包含ABEFrings的西部周边沿着有一个共同的构象偏好。利用小分子识别/结合结构域可能包含配体构象上移动的部分这一假设，设计了类似物，掺入栓系物（蓝色）代替（+）-海绵抑素1大环内酯的CD和ABCD组分，使得保留的（+）-海绵抑素1骨架的构象将模拟天然产物的指定溶液构象。所观察到的纳摩尔细胞毒性和微管去稳定活性的theABEF类似物提供了支持指定的解决方案构象的（+）-spongistatin 1和设计策略的有效性。
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 theABEFrings. 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 theCDand theABCDcomponents 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 theABEFanalogue provide support for both the assigned solution conformation of (+)-spongistatin 1 and the validity of the design strategy.