Helmholtz Center for Infection Research (HZI), Department Microbial Drugs, Inhoffenstrasse 7, 38124, Braunschweig, Germany.
Institute for Organic Chemistry, Gottfried Leibniz Universität Hannover.
Angew Chem Int Ed Engl. 2016 Aug 16;55(34):10113-7. doi: 10.1002/anie.201603288. Epub 2016 Jul 12.
Myxobacteria are well-established sources for novel natural products exhibiting intriguing bioactivities. We here report on haprolid (1) isolated from Byssovorax cruenta Har1. The compound exhibits an unprecedented macrolactone comprising four modified amino acids and a polyketide fragment. As configurational assignment proved difficult, a bioinformatic analysis of the biosynthetic gene cluster was chosen to predict the configuration of each stereocenter. In-depth analysis of the corresponding biosynthetic proteins established a hybrid polyketide synthase/nonribosomal peptide synthetase origin of haprolid and allowed for stereochemical assignments. A subsequent total synthesis yielded haprolid and corroborated all predictions made. Intriguingly, haprolid showed cytotoxicity against several cell lines in the nanomolar range whereas other cells were almost unaffected by treatment with the compound.
粘细菌是新型天然产物的重要来源，这些产物具有引人注目的生物活性。我们在此报告了从 Byssovorax cruenta Har1 中分离得到的哈普罗利德（1）。该化合物具有前所未有的大环内酯，包含四个修饰氨基酸和一个聚酮片段。由于构象分配证明具有难度，因此选择生物信息学分析生物合成基因簇来预测每个手性中心的构型。对相应生物合成蛋白的深入分析确定了哈普罗利德的杂合聚酮合酶/非核糖体肽合成酶的起源，并允许进行立体化学分配。随后的全合成得到了哈普罗利德，并证实了所有的预测。有趣的是，哈普罗利德对几种细胞系表现出纳摩尔级的细胞毒性，而其他细胞几乎不受该化合物的影响。
