Ingenane Diterpenoids

Giovanni Appendino

Research output: Contribution to journalReview articlepeer-review

Abstract

Despite a more recent isolation and chemical characterization when compared to phorbol, along with its chemical instability, limited distribution in Nature, and scarce availability, ingenol is the only Euphorbia diterpenoid that has undergone successful pharmaceutical development, with ingenol 3-angelate (ingenol mebutate, Picato(®)) entering the pharmaceutical market in 2012 for the treatment of actinic keratosis. The phytochemical, chemical, and biological literature on members of the ingenane class of diterpenoids is reviewed from their first isolation in 1968 through 2015, highlighting unresolved issues both common to phorboids (biogenesis, relationship between molecular targets, and in vivo activity) and specific to ingenol derivatives (two-dimensional representation, in-out stereoisomerism, versatility of binding mode to PKC, and inconsistencies in the structural elucidation of some classes of derivatives). The biogenesis of ingenol is discussed in the light of the Jakupovic proposal of a dissection between the formation of the macrocyclic Euphorbia diterpenoids and the phorboids, and the clinical development of ingenol mebutate is chronicled in the light of its "reverse-pharmacology" focus.

Original languageEnglish
Pages (from-to)1-90
Number of pages90
JournalProgress in the chemistry of organic natural products
Volume102
DOIs
Publication statusPublished - 1 Jan 2016
Externally publishedYes

Keywords

  • Diterpenoids
  • Drug discovery
  • Euphorbia
  • Ingenol
  • Protein kinase C (PKC)

Fingerprint

Dive into the research topics of 'Ingenane Diterpenoids'. Together they form a unique fingerprint.

Cite this