Discovery,Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide,a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria |
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| Authors: | Dr Sarath P Gunasekera Yang Li Dr Ranjala Ratnayake Danmeng Luo Dr Jeannette Lo Dr Joseph H Reibenspies Dr Zhengshuang Xu Prof Dr Michael J Clare‐Salzler Prof Dr Tao Ye Dr Valerie J Paul Prof Dr Hendrik Luesch |
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| Institution: | 1. Smithsonian Marine Station, Fort Pierce, Florida, USA;2. Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, P.R. China;3. Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, Florida, USA;4. Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, USA;5. Department of Chemistry, Texas A & M University, College Station, Texas, USA |
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| 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 spectroscopy, 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 also suppressed the proliferation of anti‐CD3‐stimulated T‐cells in a dose‐dependent manner. |
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| Keywords: | glycosides macrolides marine natural products structure elucidation total synthesis |
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