- Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation
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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 G?6983 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.
- Ohyoshi, Takayuki,Tamura, Yuki,Hayakawa, Ichiro,Hirai, Go,Miyazawa, Yamato,Funakubo, Shota,Sodeoka, Mikiko,Kigoshi, Hideo
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p. 11426 - 11437
(2016/12/18)
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- Total synthesis of (-)-13-oxyingenol and its natural derivative
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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. Copyright
- Ohyoshi, Takayuki,Funakubo, Shota,Miyazawa, Yamato,Niida, Keisuke,Hayakawa, Ichiro,Kigoshi, Hideo
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p. 4972 - 4975
(2012/06/30)
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