Ingenol: Highly Strained Natural Product as a Core of Powerful Bioactive Compounds

Ingenol is a diterpene isolated from Euphobia family and its structure was determined in 1970.¹⁾ Although ingenol has a weak activity against protein kinase C,²⁾ ingenol derivatives show wide range of bioactivity. For instance, ingenol 3-mebutate, an angelate ester at 3-hydroxy group of ingenol, is utilized as a therapeutic medicine for solar keratosis (a precancerous skin condition).³⁾ The mechanism of 1 is considered as an activation of protein kinase C, so it has also been reported to indicate an anticancer⁴⁾ and anti-HIV⁵⁾ activities. By the way, ingenol has an “inside-outside structure”, a unique and highly strained structure at a condensed ring moiety of two seven-membered rings, so that it is regarded as a challenging target of total synthesis.^6,7)