Respirantins are 18-membered antimycin-type depsipeptides produced by Streptomyces sp. and Kitasatospora sp. These compounds have shown extraordinary anticancer activities against a panel of cancer cell lines with nanomolar levels of IC₅₀ values. However, further investigation has been impeded by the low titers of the natural producers and the challenging chemical synthesis due to their structural complexity. The biosynthetic gene cluster (BGC) of respirantin was previously proposed based on a bioinformatic comparison of the four members of antimycin-type depsipeptides. In this study, we report the first successful reconstitution of respirantin in Streptomyces albus using a synthetic BGC. This heterologous system serves as an accessible platform for the production and diversification of respirantins. Through polyketide synthase pathway engineering, biocatalysis, and chemical derivatization, we generated nine respirantin compounds, including six new derivatives. Cytotoxicity screening against human MCF-7 and Hela cancer cell lines revealed a unique biphasic dose–response profile of respirantin. Furthermore, a structure–activity relationship study has elucidated the essential functional groups that contribute to its remarkable cytotoxicity. This work paves the way for respirantin-based anticancer drug discovery and development.

中文翻译：

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扩环抗霉素型缩酚肽的工程生物合成及抗癌研究

Respirantins 是由链霉菌属(Streptomyces sp. ) 产生的 18 元抗霉素型缩酚肽。和Kitasatospora sp。这些化合物对一组癌细胞系表现出非凡的抗癌活性，IC ₅₀值达到纳摩尔水平。然而，天然生产者的滴度低以及由于其结构复杂而具有挑战性的化学合成阻碍了进一步的研究。呼吸素的生物合成基因簇（BGC）是先前基于抗霉素型缩酚肽的四个成员的生物信息学比较而提出的。在这项研究中，我们首次报道了使用合成 BGC在白色链霉菌中成功重建呼吸兰汀。这种异源系统可作为呼吸兰汀的生产和多样化的可访问平台。通过聚酮合酶途径工程、生物催化和化学衍生化，我们生成了九种呼吸兰汀化合物，其中包括六种新衍生物。针对人 MCF-7 和 Hela 癌细胞系的细胞毒性筛选揭示了呼吸兰汀独特的双相剂量反应特征。此外，结构-活性关系研究阐明了导致其显着细胞毒性的重要功能基团。这项工作为基于呼吸素的抗癌药物的发现和开发铺平了道路。