title: Gateway synthesis of daphnane congeners and their protein kinase C affinities and cell-growth activities.
abstract: The daphnane diterpene orthoesters constitute a structurally fascinating family of natural products that exhibit a remarkable range of potent biological activities. Although partial activity information is available for some natural daphnanes, little information exists for non-natural congeners or on how changes in structure affect mode of action, function, potency or selectivity. A gateway strategy designed to provide general synthetic access to natural and non-natural daphnanes is described and utilized in the synthesis of two novel members of this class. In this study, a commercially available tartrate derivative was elaborated through a key late-stage diversification intermediate into B-ring yuanhuapin analogues to initiate exploration of the structure-function relationships of this class. Protein kinase C was identified as a cellular target for these agents, and their activity against human lung and leukaemia cell lines was evaluated. The natural product and a novel non-natural analogue exhibited significant potency, but the epimeric epoxide was essentially inactive.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, California 94305, USA. wenderp@stanford.edu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wender
authors.forename: Nicole
authors.initials: N
authors.lastname: Buschmann
authors.forename: Nathan B
authors.initials: NB
authors.lastname: Cardin
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Jones
authors.forename: Cindy
authors.initials: C
authors.lastname: Kan
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Kee
authors.forename: John A
authors.initials: JA
authors.lastname: Kowalski
authors.forename: Kate E
authors.initials: KE
authors.lastname: Longcore
mesh_terms: D002455:Cell Division; D004224:Diterpenes / Q000138:chemical synthesis* / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*
chemical_list: D004224:Diterpenes; C011309:mezerein; D011493:Protein Kinase C