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Ingenane Diterpenoids

  • Giovanni AppendinoEmail author
Chapter
Part of the Progress in the Chemistry of Organic Natural Products book series (POGRCHEM, volume 102)

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.

Keywords

Diterpenoids Ingenol Euphorbia Protein kinase C (PKC) Drug discovery 

Notes

Acknowledgments

This chapter could not have been written without the help of many colleagues and friends. In particular, I am very grateful to Siems Karsten, Fotini Tsichritzis and Sven Jakupovic (Analyticon, Potsdam, Germany) and Franck Jescke for providing me with the material that made it possible to discuss the Jakupovic proposal for the biogenesis of phorboids, to Marco Facini (Sandoz, Munich, Germany) for providing many articles from the early literature on ingenol, and to Louis-Félix Nothias-Scaglia (University of Corsica, France) for his suggestions. A special thanks should also be given to Peter Parson (QIMR Berghofer Medical Research Institute, Brisbane, Australia) and Steven Ogbourne (GeneCology Research Centre, University of the Sunshine Coast, Australia) for carefully reading the biological section of this manuscript and for their suggestions on improving it. Finally, I would like to apologize to my daughter Silvia for the time spent with ingenol and not with her during the summer of 2014, when the first draft of this review was prepared.

My wife Enrica, a medical doctor, medicated me on two occasions when, during my early work on ingenol, I experimented on myself the power of its activity. Were she still with us, she would surely be surprised that an ingenol derivative is now a drug. Jasmin Jakupovic always stimulated me with his ingenuity and inspiring insights, and it is an honor for me to dedicate this work to his memory and to the one of my wife. Paraphrasing a comment made on the premature death of the composer Bellini, what Jasmin lacked could be learnt. What he had could not.

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Dipartimento di Scienze del FarmacoNovaraItaly

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