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 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.
authors.affiliation: Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8571, Japan. kigoshi@chem.tsukuba.ac.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ohyoshi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Tamura
authors.forename: Ichiro
authors.initials: I
authors.lastname: Hayakawa
authors.forename: Go
authors.initials: G
authors.lastname: Hirai
authors.forename: Yamato
authors.initials: Y
authors.lastname: Miyazawa
authors.forename: Shota
authors.initials: S
authors.lastname: Funakubo
authors.forename: Mikiko
authors.initials: M
authors.lastname: Sodeoka
authors.forename: Hideo
authors.initials: H
authors.lastname: Kigoshi
mesh_terms: D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C559803:13-oxyingenol; D001688:Biological Products; D004224:Diterpenes; C496628:PRKCA protein, human; C497258:PRKCD protein, human; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta