title: 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 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.
authors.affiliation: Smithsonian Marine Station, 701 Seaway Drive, Fort Pierce, Florida, 34949, USA.
authors.forename: Sarath P
authors.initials: SP
authors.lastname: Gunasekera
authors.affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, 518055, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, Florida, 32610, USA.
authors.forename: Ranjala
authors.initials: R
authors.lastname: Ratnayake
authors.affiliation: Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, Florida, 32610, USA.
authors.forename: Danmeng
authors.initials: D
authors.lastname: Luo
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, 32610, USA.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Lo
authors.affiliation: Department of Chemistry, Texas A & M University, College Station, Texas, 77843, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Reibenspies
authors.affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, 518055, P.R. China.
authors.forename: Zhengshuang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida, 32610, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clare-Salzler
authors.affiliation: Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, 518055, P.R. China. yet@pkusz.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.affiliation: Smithsonian Marine Station, 701 Seaway Drive, Fort Pierce, Florida, 34949, USA. paul@si.edu.
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Paul
authors.affiliation: Department of Medicinal Chemistry and Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, Florida, 32610, USA. luesch@cop.ufl.edu.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001409:Bacillus cereus / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D000458:Cyanobacteria / Q000737:chemistry* / Q000378:metabolism; D019281:Dimerization; D004353:Drug Evaluation, Preclinical; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry; D006031:Glycosylation; D045325:HCT116 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000633:toxicity; D018942:Macrolides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D000067996:RAW 264.7 Cells; D013237:Stereoisomerism
chemical_list: D000900:Anti-Bacterial Agents; D006027:Glycosides; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008070:Lipopolysaccharides; D018942:Macrolides; C000625201:cocosolide; D009569:Nitric Oxide
keywords: glycosides; macrolides; marine natural products; structure elucidation; total synthesis