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

Research output: Contribution to journalArticle

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

Fingerprint

Protein Kinase C
analogs
Derivatives
proteins
evaluation
HL-60 Cells
synthesis
Laurates
Chemical activation
activation
cells
Cell Differentiation
13-oxyingenol
Protein C Inhibitor
Macrophages
Alkenes
phenotype
Phorbol Esters
macrophages
Cell death

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation. / Ohyoshi, Takayuki; Tamura, Yuki; Hayakawa, Ichiro; Hirai, Go; Miyazawa, Yamato; Funakubo, Shota; Sodeoka, Mikiko; Kigoshi, Hideo.

In: Organic and Biomolecular Chemistry, Vol. 14, No. 48, 01.01.2016, p. 11426-11437.

Research output: Contribution to journalArticle

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, vol. 14, no. 48, pp. 11426-11437. https://doi.org/10.1039/c6ob02268e
Ohyoshi, Takayuki ; Tamura, Yuki ; Hayakawa, Ichiro ; Hirai, Go ; Miyazawa, Yamato ; Funakubo, Shota ; Sodeoka, Mikiko ; Kigoshi, Hideo. / Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation. In: Organic and Biomolecular Chemistry. 2016 ; Vol. 14, No. 48. pp. 11426-11437.
@article{5b2f13829c184094b49ee75523c88ebf,
title = "Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation",
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 G{\"o}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.",
author = "Takayuki Ohyoshi and Yuki Tamura and Ichiro Hayakawa and Go Hirai and Yamato Miyazawa and Shota Funakubo and Mikiko Sodeoka and Hideo Kigoshi",
year = "2016",
month = "1",
day = "1",
doi = "10.1039/c6ob02268e",
language = "English",
volume = "14",
pages = "11426--11437",
journal = "Organic and Biomolecular Chemistry",
issn = "1477-0520",
publisher = "Royal Society of Chemistry",
number = "48",

}

TY - JOUR

T1 - Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation

AU - Ohyoshi, Takayuki

AU - Tamura, Yuki

AU - Hayakawa, Ichiro

AU - Hirai, Go

AU - Miyazawa, Yamato

AU - Funakubo, Shota

AU - Sodeoka, Mikiko

AU - Kigoshi, Hideo

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85004130282&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85004130282&partnerID=8YFLogxK

U2 - 10.1039/c6ob02268e

DO - 10.1039/c6ob02268e

M3 - Article

C2 - 27874143

AN - SCOPUS:85004130282

VL - 14

SP - 11426

EP - 11437

JO - Organic and Biomolecular Chemistry

JF - Organic and Biomolecular Chemistry

SN - 1477-0520

IS - 48

ER -