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Gateway synthesis of daphnane congeners and their protein kinase C affinities and cell-growth activities

2011; Nature Portfolio; Volume: 3; Issue: 8 Linguagem: Inglês

10.1038/nchem.1074

1755-4349

Paul A. Wender, Nicole Buschmann, N.B. Cardin, Lisa Jones, Cindy Kan, Jung‐Min Kee, John A. Kowalski, Kate E. Longcore,

Marine Sponges and Natural Products

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. The daphnane diterpene orthoesters constitute a structurally fascinating family of natural products that exhibit remarkable and potent biological activities. A gateway strategy designed to provide general synthetic access to and biological evaluation of natural and non-natural daphnanes is described and used for yuanhuapin analogues.