Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria

Abstract

A new dimeric macrolide xylopyranoside, cocosolide (1), was isolated from the marine cyanobacterium preliminarily identified as Symploca sp. from Guam. The structure was determined by a combination of NMR, HRMS, X-ray diffraction studies and Mosher’s analysis of the base hydrolysis product. Its carbon skeleton closely resembles that of clavosolides A–D isolated from the sponge Myriastra clavosa, for which no bioactivity is known. We performed the first total synthesis of cocosolide (1) along with its [α,α]-anomer (26) and macrocyclic core (28), thus leading to the confirmation of the structure of natural 1. The convergent synthesis featured Wadsworth–Emmons cyclopropanation, Sakurai annulation, Yamaguchi macrocyclization/dimerization reaction, α-selective glycosidation and β-selective glycosidation. Compounds 1 and 26 potently inhibited IL-2 production in both T-cell receptor dependent and independent manners. Full activity requires the presence of the sugar moiety as well as the intact dimeric structure. Cocosolide (1) also suppressed the proliferation of anti-CD3-stimulated T-cells in a dose-dependent manner.

Marine natural products

“…Similarities between coibamide A and apratoxin A 273 biological outputs (cell morphology, VEGFR2 expression, macroautophagy signalling) suggests these two cyanobacterial metabolites share a common mechanism of action. 274 Other new metabolites of either peptidic or non-peptidic nature were obtained from the genera Hydrocoleum (680 and 681), 275 284 and Symploca (703) 285 and one potentially new genus (704) 286 that is closely related to Trichodesmium, Okeania and Oscillatoria based on 16S rRNA sequence analysis. The structure of caylobolide B 705 was corrected; the E-conguration between C-2/C-3 in the original 2010 paper was amended to a Z-conguration.…”

Total Synthesis of Clavosolide A via Asymmetric Alcohol‐Mediated Carbonyl Allylation: Beyond Protecting Groups or Chiral Auxiliaries in Polyketide Construction

“…While the biological properties of clavosolide A have yet to be determined, the structurally related natural product cyanolide A displays potent molluscicidal activity (LC 50 =1.2 μ m ) against the water snail Biomphalaria glabrata , a vector of the human parasitic disease schistosomiasis. Additionally, in 2016, a closely related macrodiolide xylopyranoside was discovered, cocosolide (not shown), which exhibits immunosuppressive activity . The structure of cocosolide was verified by total synthesis through a 17‐step route (LLS) …”

“…Additionally, in 2016, a closely related macrodiolide xylopyranoside was discovered, cocosolide (not shown), which exhibits immunosuppressive activity . The structure of cocosolide was verified by total synthesis through a 17‐step route (LLS) …”

Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics

“…As stated above, NMR spectroscopy has frequently been used for identification and structure determination. Hence, in recent SAR (structure–activity relationship) profiling of irumamycin-type macrolides [ 70 ], azithromycin acylides [ 71 ] and a new dimeric macrolide cocosolide [ 72 ], one- and two-dimensional NMR techniques have been applied to determine their structure. As elaborated, the structure characterization of free and bound ligands can provide the details about ligand binding modes and other essential information for the design of new and more potent drugs.…”