Department of Chemistry, University of Missouri, 125 Chemistry Building Columbia, MO 65211, United States.
Bioorg Med Chem. 2013 Jan 1;21(1):235-41. doi: 10.1016/j.bmc.2012.10.021. Epub 2012 Oct 27.
Leinamycin (1) is a Streptomyces-derived natural product that displays nanomolar IC(50) values against human cancer cell lines. In the work described here, we report the synthesis and characterization of a small leinamycin analogue 19 that closely resembles the 'upper-right quadrant' of the natural product, consisting of an alicyclic 1,2-dithiolan-3-one 1-oxide heterocycle connected to an alkene by a two-carbon linker. The results indicate that this small analogue contains the core set of functional groups required to enable thiol-triggered generation of both redox active polysulfides and an episulfonium ion intermediate via the complex reaction cascade first seen in the natural product leinamycin. The small leinamycin analogue 19 caused thiol-triggered oxidative DNA strand cleavage in a manner similar to the natural product, but did not alkyate duplex DNA effectively. This highlights the central role of the 18-membered macrocycle of leinamycin in driving efficient DNA alkylation by the natural product.
雷那霉素（1）是一种来源于链霉菌的天然产物，对人癌细胞系具有纳摩尔 IC（50）值。在本文所描述的工作中，我们报告了一种与天然产物的“右上象限”非常相似的小雷那霉素类似物 19 的合成和表征，它由一个通过两个碳连接体连接到烯烃的脂环 1,2-二硫戊环-3-酮 1-氧化物杂环组成。结果表明，这种小类似物包含了一组核心官能团，这些官能团是通过复杂的反应级联反应使硫醇触发产生氧化多硫化物和一个表硫翁离子中间体所必需的，这种反应级联首先在天然产物雷那霉素中观察到。小雷那霉素类似物 19 以类似于天然产物的方式引发硫醇触发的氧化 DNA 链断裂，但不能有效地烷化双链 DNA。这突出了雷那霉素的 18 元大环在驱动天然产物有效 DNA 烷化中的核心作用。
