title: Synthesis of a des-B-ring bryostatin analogue leads to an unexpected ring expansion of the bryolactone core.
abstract: A convergent synthesis of a des-B-ring bryostatin analogue is described. This analogue was found to undergo an unexpected ring expansion of the bryolactone core to generate the corresponding 21-membered macrocycle. The parent analogue and the ring-expanded product both displayed nanomolar binding affinity for PKC. Despite containing A-ring substitution identical to that of bryostatin 1 and displaying bryostatin-like biological function, the des-B-ring analogues displayed a phorbol-like biological function in cells. These studies shed new light on the role of the bryostatin B-ring in conferring bryo-like biological function to bryostatin analogues.
authors.affiliation: Department of Chemistry, University of Utah , Salt Lake City, Utah 84112, United States.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Kraft
authors.forename: Yam B
authors.initials: YB
authors.lastname: Poudel
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: Peter M
authors.initials: PM
authors.lastname: Blumberg
authors.forename: Gary E
authors.initials: GE
authors.lastname: Keck
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054713:Bryostatins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002013:Bryozoa / Q000737:chemistry*; D045744:Cell Line, Tumor; D006801:Humans; D008958:Models, Molecular; D010704:Phorbols / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D054713:Bryostatins; D010704:Phorbols; C046785:bryostatin 1; D011493:Protein Kinase C; C033085:phorbol