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

Takayuki Ohyoshi, Yuki Tamura, Ichiro Hayakawa, Go Hirai, Yamato Miyazawa, Shota Funakubo, Mikiko Sodeoka, Hideo Kigoshi

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2 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)11426-11437
Number of pages12
JournalOrganic and Biomolecular Chemistry
Volume14
Issue number48
DOIs
Publication statusPublished - Jan 1 2016

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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    Ohyoshi, T., Tamura, Y., Hayakawa, I., Hirai, G., Miyazawa, Y., Funakubo, S., Sodeoka, M., & Kigoshi, H. (2016). Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation. Organic and Biomolecular Chemistry, 14(48), 11426-11437. https://doi.org/10.1039/c6ob02268e