Synthesis and Biological Evaluation of Resorcylic Acid Lactones

Resorcylic acid lactones (RALs) are a family of fungal polyketides characterised by a β-resorcylic acid moiety embedded in a macrocyclic lactone ring. Their structural diversity arises from varied ring sizes, oxidation states and substitutions, often introduced by semisynthetic modifications. Advances in fermentation, strain engineering and epigenetic manipulation have expanded the availability of RAL scaffolds for chemical derivatisation. Semisynthetic routes enable step-economical access to rare congeners and facilitate structure–activity relationship studies. Biologically, RALs exhibit a broad spectrum of activity including antiparasitic, anticancer, antimicrobial, antifouling and nematicidal effects. Key mechanisms involve irreversible protein kinase inhibition, copper-mediated cell death induction, interference with microbial energy metabolism and selective enzyme targeting. Recent developments have emphasised the translation of RALs into drug leads, agrochemicals and molecular probes, underscoring their global significance in human health and sustainable agriculture.

Research from Nature Portfolio

Seminal work has focused on the semisynthesis and comprehensive bioevaluation of 14-membered RALs and their derivatives. By optimising fermentation to yield gram-scale quantities of two major natural RALs, researchers achieved high-yield semisynthesis of six trace metabolites and a series of 17 analogues. Several semisynthetic derivatives displayed sub-micromolar antiplasmodial potency with high therapeutic indices, alongside selective antileishmanial and antichagasic activities. These studies illustrate the power of combining fermentation scale-up, targeted semisynthesis and rigorous in vitro bioassays to identify lead compounds for neglected tropical diseases.

Synthesis and Biological Evaluation of Resorcylic Acid Lactones publication trend

The graph below shows the total number of articles in synthesis and biological evaluation of resorcylic acid lactones across all publications each year (not limited to Nature Index journals).

Technical terms

Resorcylic acid lactone (RAL): A fungal polyketide built around a dihydroxybenzoic acid unit cyclised into a large lactone ring.

Macrolactone: A macrocyclic ester formed by intramolecular condensation of a hydroxy acid.

Semisynthesis: Chemical modification of a natural product scaffold to generate analogues.

Cuproptosis: A regulated form of cell death triggered by copper accumulation and binding to lipoylated proteins.

Ionophore: A molecule that facilitates transmembrane transport of specific ions.

Polyketide synthase (PKS): An enzyme complex that assembles polyketide natural products via successive condensation of acyl-CoA units.

References

1. Discovery of Natural Resorcylic Acid Lactones as Novel Potent Copper Ionophores Covalently Targeting PRDX1 to Induce Cuproptosis for Triple-Negative Breast Cancer Therapy. ACS Central Science (2025).
2. Semisynthesis, Structure Elucidation and Anti-Mycobacterium marinum Activity of a Series of Marine-Derived 14-Membered Resorcylic Acid Lactones with Interesting Ketal Groups. Marine Drugs (2024).
3. Nematicidal glycosylated resorcylic acid lactones from the fungus Pochonia chlamydosporia PC-170 and their key biosynthetic genes. Frontiers in Microbiology (2024).
4. Discovery, Semisynthesis, Antiparasitic and Cytotoxic Evaluation of 14-Membered Resorcylic Acid Lactones and Their Derivatives. Scientific Reports (2017).