法国斯特拉斯堡大学Hoveyda, Amir H.研究团队报道了能够高效和可编程地获得精确改变吲哚生物碱支架的催化过程。相关研究成果发表在2024年2月19日出版的国际知名学术期刊《自然—化学》。

一种化合物的整体轮廓影响其引发生物反应的能力，从而使人们能够获得形状独特的分子。天然产物的结构可以被修改，但前提是它是丰富的，并且包含适当的可修改官能团。

该文中，研究人员介绍了一种用于稀有桥接多环生物碱精确改变支架简明合成的可编程策略。该方法的核心是一种可扩展的催化多组分工艺，该工艺可提供含有可微分烯基部分的非对映体和对映体富集的叔高烯丙醇。

研究人员使用一种产品对一种天然生物碱及其精确膨胀、收缩和/或扭曲的框架类似物进行了逐步不同的合成（平均步骤数/支架数为7）。体外测试表明，一个亚甲基在两个区域扩展的骨架对四种类型的癌症细胞系具有细胞毒性。机械和计算研究提供了几个意想不到的选择性趋势的解释。

附：英文原文

Title: A catalytic process enables efficient and programmable access to precisely altered indole alkaloid scaffolds

Author: Huang, Youming, Li, Xinghan, Mai, Binh Khanh, Tonogai, Emily J., Smith, Amanda J., Hergenrother, Paul J., Liu, Peng, Hoveyda, Amir H.

Issue&Volume: 2024-02-19

Abstract: A compound’s overall contour impacts its ability to elicit biological response, rendering access to distinctly shaped molecules desirable. A natural product’s framework can be modified, but only if it is abundant and contains suitably modifiable functional groups. Here we introduce a programmable strategy for concise synthesis of precisely altered scaffolds of scarce bridged polycyclic alkaloids. Central to our approach is a scalable catalytic multi-component process that delivers diastereo- and enantiomerically enriched tertiary homoallylic alcohols bearing differentiable alkenyl moieties. We used one product to launch progressively divergent syntheses of a naturally occurring alkaloid and its precisely expanded, contracted and/or distorted framework analogues (average number of steps/scaffold of seven). In vitro testing showed that a skeleton expanded by one methylene in two regions is cytotoxic against four types of cancer cell line. Mechanistic and computational studies offer an account for several unanticipated selectivity trends.

DOI: 10.1038/s41557-024-01455-7

Source: https://www.nature.com/articles/s41557-024-01455-7