Institute of Organic Chemistry and Chemical Biology, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany.
Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
Nat Chem. 2022 Sep;14(9):1000-1006. doi: 10.1038/s41557-022-00996-z. Epub 2022 Jul 25.
Modification of polyketides with fluorine offers a promising approach to develop new pharmaceuticals. While synthetic chemical methods for site-selective incorporation of fluorine in complex molecules have improved in recent years, approaches for the biosynthetic incorporation of fluorine in natural compounds are still rare. Here, we report a strategy to introduce fluorine into complex polyketides during biosynthesis. We exchanged the native acyltransferase domain of a polyketide synthase, which acts as the gatekeeper for the selection of extender units, with an evolutionarily related but substrate tolerant domain from metazoan type I fatty acid synthase. The resulting polyketide-synthase/fatty-acid-synthase hybrid can utilize fluoromalonyl coenzyme A and fluoromethylmalonyl coenzyme A for polyketide chain extension, introducing fluorine or fluoro-methyl units in polyketide scaffolds. We demonstrate the feasibility of our approach in the chemoenzymatic synthesis of fluorinated 12- and 14-membered macrolactones and fluorinated derivatives of the macrolide antibiotics YC-17 and methymycin.
氟取代的聚酮类化合物为开发新药物提供了一种很有前途的方法。虽然近年来用于在复杂分子中进行位点选择性氟取代的合成化学方法已有改进，但在天然化合物中进行生物合成氟取代的方法仍然很少。在这里，我们报告了一种在生物合成过程中向复杂聚酮类化合物中引入氟的策略。我们用来自后生动物 I 型脂肪酸合酶的进化上相关但具有底物耐受性的结构域替换了聚酮合酶中作为扩展单元选择的天然酰基转移酶结构域。由此产生的聚酮合酶/脂肪酸合酶杂合体可以利用氟代丙二酰辅酶 A 和氟甲基丙二酰辅酶 A 进行聚酮链延伸，在聚酮支架中引入氟或氟甲基单元。我们通过化学酶合成证明了我们方法的可行性，合成了氟化的 12 元和 14 元大环内酯以及大环内酯抗生素 YC-17 和 methymycin 的氟化衍生物。
