RESUMO
The total synthesis of biselide E, a marine polyketide isolated from the Okinawan ascidian, has been accomplished. The highlight of this approach is the use of the ß-elimination reaction of the chloroacetoxy group for the construction of an unstable six-membered α,ß,γ,δ-unsaturated lactone portion at the late stage of the total synthesis.
RESUMO
We have established an efficient synthetic methodology for the 13-oxyingenol natural derivative (13-oxyingenol-13-dodecanoate-20-hexanoate), featuring a ring-closing olefin metathesis reaction for the "direct" construction of a highly strained inside-outside framework and a Mislow-Evans-type [2,3]-sigmatropic rearrangement for the stereoselective introduction of the hydroxy group at C5. We also synthesized artificial analogs of 13-oxyingenol and ingenol by using our synthetic strategy. In vitro activation assays of protein kinase C (PKC) α and δ revealed that the dodecanoyl group at O13 on 13-oxyingenol analogs had a significant role in PKCδ activation. The PKCα- or PKCδ-activating 13-oxyingenol and ingenol analogs induced both distinct morphological changes and increases of CD11b expression in HL-60 cells, which would be typical signs of HL-60 cell differentiation to macrophage-like cells, as expected by previous reports. Intriguingly, however, similar differentiation phenotypes were observed with the use of 13-oxyingenol natural derivatives and 13-oxyingenol-13-dodecanoate showing a remarkably less potent PKCα or PKCδ activation ability, which the PKC inhibitor Gö6983 diminished. This indicated the involvement of other PKC isozymes or related kinase activities. 13-Oxyingenol analogs, which induced HL-60 cell differentiation, also induced HL-60 cell death, similar to the action of a phorbol ester, a strong PKC activator.
Assuntos
Produtos Biológicos/farmacologia , Diterpenos/farmacologia , Produtos Biológicos/síntese química , Produtos Biológicos/química , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos/síntese química , Diterpenos/química , Células HL-60 , Humanos , Modelos Moleculares , Conformação Molecular , Proteína Quinase C-alfa/metabolismo , Proteína Quinase C-delta/metabolismo , Relação Estrutura-AtividadeRESUMO
Ring functionalization: the total synthesis of a natural derivative of (-)-13-oxyingenol, a potent anti-HIV diterpenoid, is reported. The key steps in this synthesis include a ring-closing olefin metathesis and a Mislow-Evans-type [2,3]-sigmatropic rearrangement. This synthesis provides access to (-)-13-oxyingenol and its natural derivative in 21 steps from a synthetic intermediate previously prepared by Kigoshi and co-workers.
