Microbial skeletal editing: hints for arene reconstruction from actinobacteria

Covering: up to the end of 2025Organic synthesis is mastering the newly emerged field of skeletal editing-minimal, core-scaffold rewiring-for the fast and efficient modulation of bioactivity in the pursuit of speeding-up drug discovery. The related goal of modulation of bioactivity by structure modification was evolutionary pursued by microorganisms for ages. In this review, we aim to demonstrate that transformations following skeletal editing logic (such as atom swap/addition/deletion) are already operable by the biosynthetic machinery of actinobacteria. The pathways that are utilized to solve the issues of structure editing are analyzed on the selected examples and organized into four distinct groups, namely, carbon-to-oxygen swaps, carbonyl deletions with ring contraction and fully carbocyclic edits, carbon-to-nitrogen swaps and skeletal reorganizations that retain the atomic formula but alter the connectivity. Most of these transformations are guided by monooxygenase enzymes. Among the diverse skeletal editing cases, the modification of angucycline polyketides, in particular, the ring B modification of dehydrorabelomycin is the most "developed"-disclosed transformations include three types of molecular edits. It displays a close analogy to the diversity-oriented skeletal editing: the action of a single homologous enzyme of the AlpJ family initiates the editing and is able to generate high chemical diversity of the bioactive derivatives. Herein, we also compare the disclosed "natural" skeletal editing strategies with the related "chemical" methods that have emerged in recent years, bridging natural and synthetic repertoires. Further analysis of the separate enzymatic steps and the logic behind them could inspire the development of new reactions and methods for the late-stage modification of complex bioactive molecules.