Canalesolide A, a Structurally Unique Polyhydroxy Macrolide from the Marine Cyanobacterium Okeania sp. with Potent Antitrypanosomal Activity
Year: 2026
Type: article
Abstract: The discovery of structurally novel natural products remains central to expanding biologically relevant chemical space, particularly within underexplored marine metabolite classes. Herein, we report the discovery and complete structural elucidation of canalesolide A, a new polyhydroxylated macrolide isolated from the marine cyanobacterium Okeania sp. The compound was identified through an integrated workflow combining phenotypic screening against Trypanosoma brucei and LC-MS/MS-based molecular networking, enabling rapid prioritization of bioactive fractions and dereplication of known metabolite families. Spectroscopic analysis revealed that canalesolide A belongs to the bastimolide-related class of macrolides but exhibits a distinct structural architecture. Its structure was established by integrating ultrahigh-resolution NMR spectroscopy, empirical configurational analysis of polyol systems, targeted model compound synthesis, and controlled chemical degradation and derivatization. This combined strategy resolved stereochemical motifs that were inaccessible by direct analysis of the intact macrolide alone, providing a transferable approach for assigning densely oxygenated marine macrolides. Genome mining identified the putative biosynthetic gene cluster and proposed biosynthetic pathway for a bastimolide-related macrolide. Canalesolide A displays potent, low nanomolar antitrypanosomal activity against human-infective subspecies of T. brucei with rapid elimination of parasites within 1 h at 1 μM. Although moderate mammalian cytotoxicity was observed, preliminary in vivo efficacy/toxicity studies in infected mice suggest a narrow therapeutic window highlighting the need for improved selectivity. This study expands the structural and biosynthetic diversity of polyhydroxylated macrolides and establishes a generalizable framework for resolving stereochemically complex natural products.
DOI: 10.1021/jacs.6c11673
Institutions: University of California San Diego, University of Bristol
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: National Science Foundation, University of Bristol, Centre National de la Recherche Scientifique, National Institutes of Health, University of California, San Diego, Materials Research Science and Engineering Center, Harvard University, Engineering and Physical Sciences Research Council, National Institute of General Medical Sciences, Division of Materials Research, Skaggs School of Pharmacy and Pharmaceutical Sciences, Materials Research Science and Engineering Center, University of California, San Diego
Awards: G1186292489, G1417047297, 600 MHz NMR spectrometer with 1.7mm micro-cryoprobe, G4950536974, G5282220012, EPSRC Centre for Doctoral Training in Technology Enhanced Chemical Synthesis, UC San Diego MRSEC: an NSF Materials Research Science and Engineering Center, G8412107296, G8692219177, Unified Computation Tools for Natural Products research
OpenAlex ID: W7204952384