Caylobolide B: Structure Revision, Total Synthesis, Biological Characterization, and Discovery of New Analogues

TL;DR

This paper introduces a new method to study complex marine compounds, enabling structural and biological insights for drug discovery.

Contribution

A unified workflow combining chemogenomic profiling, NMR, and modular synthesis for marine macrolide study.

Findings

Acetylation at C29 reduces caylobolide cytotoxicity and antifungal activity.

Caylobolide B's structure was revised using NMR techniques.

Modular synthesis of caylobolides was successfully developed.

Abstract

The unique potential of marine polyhydroxylated macrolides in chemical biology and drug discovery has long been constrained by their structural complexity and limited material availability, frustrating efforts in stereochemical assignment, synthesis, and mechanism‐of‐action elucidation. Here, we establish an integrated workflow, combining chemogenomic profiling, ultra‐high‐resolution NMR, and modular total synthesis, for the comprehensive functional and structural interrogation of this challenging natural product class. Applying this approach to caylobolides, natural products isolated from scarce samples of Okeania sp., we performed structure‐activity relationship studies revealing that acetylation at C29 markedly reduces both cytotoxicity and antifungal activity, pinpointing a key pharmacophore. Mechanistic profiling suggests that these macrolides disrupt membrane integrity, similar to amantelide A. Using natural compound samples, we simultaneously revised the structure of caylobolide B through 1H, 1D‐selective TOCSY and HSQC NMR, and developed a modular fragment‐based synthesis of these compounds. By providing a unified methodology for genetic sensitivity profiling, precise structure and stereochemistry determination, and modular total synthesis, this work unlocks new opportunities for the discovery and rational design of potent marine‐derived therapeutics.

Marine polyhydroxylated macrolides’ drug discovery potential is limited by structural complexity and scarce material supply, hindering structure assignment, synthesis, and biological studies. Here, we present an integrated workflow that combines chemogenomic profiling, ultra‐high‐resolution NMR‐guided structural revision and stereochemical assignment, and modular total synthesis to enable comprehensive interrogation of the caylobolide B family.

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