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Issue 48, 2016
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Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation

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Abstract

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 insideoutside 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.

Graphical abstract: Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation

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Publication details

The article was received on 18 Oct 2016, accepted on 14 Nov 2016 and first published on 14 Nov 2016


Article type: Paper
DOI: 10.1039/C6OB02268E
Citation: Org. Biomol. Chem., 2016,14, 11426-11437
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    Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation

    T. Ohyoshi, Y. Tamura, I. Hayakawa, G. Hirai, Y. Miyazawa, S. Funakubo, M. Sodeoka and H. Kigoshi, Org. Biomol. Chem., 2016, 14, 11426
    DOI: 10.1039/C6OB02268E

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