title: Synthesis of seco-B-ring bryostatin analogue WN-1 via C-C bond-forming hydrogenation: critical contribution of the B-ring in determining bryostatin-like and phorbol 12-myristate 13-acetate-like properties.
abstract: The seco-B-ring bryostatin analogue, macrodiolide WN-1, was prepared in 17 steps (longest linear sequence) and 30 total steps with three bonds formed via hydrogen-mediated C-C coupling. This synthetic route features a palladium-catalyzed alkoxycarbonylation of a C2-symmetric diol to form the C9-deoxygenated bryostatin A-ring. WN-1 binds to PKCα (Ki = 16.1 nM) and inhibits the growth of multiple leukemia cell lines. Although structural features of the WN-1 A-ring and C-ring are shared by analogues that display bryostatin-like behavior, WN-1 displays PMA-like behavior in U937 cell attachment and proliferation assays, as well as in K562 and MV-4-11 proliferation assays. Molecular modeling studies suggest the pattern of internal hydrogen bonds evident in bryostatin 1 is preserved in WN-1, and that upon docking WN-1 into the crystal structure of the C1b domain of PKCδ, the binding mode of bryostatin 1 is reproduced. The collective data emphasize the critical contribution of the B-ring to the function of the upper portion of the molecule in conferring a bryostatin-like pattern of biological activity.
authors.affiliation: Department of Chemistry and Biochemistry, University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Andrews
authors.forename: John M
authors.initials: JM
authors.lastname: Ketcham
authors.forename: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Noemi
authors.initials: N
authors.lastname: Kedei
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lewin
authors.forename: Megan L
authors.initials: ML
authors.lastname: Peach
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krische
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054713:Bryostatins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002013:Bryozoa / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006865:Hydrogenation; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism; D008958:Models, Molecular; D051571:Protein Kinase C-alpha / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D054713:Bryostatins; C046785:bryostatin 1; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate