Synthesis, biological evaluation and SAR of 3-benzoates of ingenol for treatment of actinic keratosis and non-melanoma skin cancer

doi:10.1016/j.bmcl.2013.11.073

Bioorganic & Medicinal Chemistry Letters

Volume 24, Issue 1, 1 January 2014, Pages 54-60

https://doi.org/10.1016/j.bmcl.2013.11.073 Get rights and content

Abstract

Ingenol 3-benzoates were investigated with respect to chemical stability, pro-inflammatory effects, cell death induction and PKCδ activation. A correlation between structure, chemical stability and biological activity was found and compared to ingenol mebutate (ingenol 3-angelate) used for field treatment of actinic keratosis. We also provided further support for involvement of PKCδ for induction of oxidative burst and cytokine release. Molecular modeling and dynamics calculations corroborated the essential interactions between key compounds and C1 domain of PKCδ.

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Acknowledgments

We acknowledge Thomas Vifian, Karin Hvidtfeldt Hansen, Svitlana Tkach, Christa Marvig, Carsten Ryttersgaard, Nina Ravn Borch, Ninette Winther Hansen, Nannette Svendsen for skillful assistance.

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Citation Excerpt :
Therefore, the structure of 8 was elucidated as 3β,5β,8α,15β-tetraacetyloxy-7β,9α-dibenzoyloxyjatropha-6(17),11E-diene-14-dione. The known compounds were determined to be 6β,7β-epoxy-3β,4β,5β-trihydroxyl-20-deoxyingenol (2) (Xiao et al., 2018)，kansuinin A (9) (Wang et al., 2002), esulol A (10) (Sekine et al., 1998), kansuinin D (11) (Chen et al., 2008), kansuinin E (12) (Pan et al., 2004), kansuinin G (13) (Pan et al., 2004), kansuinin F (14) (Pan et al., 2004), 3,5,7,15-tetraacetoxy-9-nicotinoyloxy-14-oxojatropha-6(17),11-diene (15) (Hohmann et al., 1999), esulone A (16) (Manners and Wong, 1985), kansuinin B (17) (Wang et al., 2002), kanesulone A (18) (Lee et al., 2016), 3-O-benzoyl-20-deoxyingenol (19) (Zhang et al., 2012), 5-O-benzoyl-20-deoxyingenol (20) (Gotta et al., 1984), 20-deoxyingenol (21) (Pan et al., 1991), kansuiphorin-D (22) (Pan et al., 1991), kansuiphorin-C (23) (Pan et al., 1991), 3-O-benzoyl-13-O- dodecanoylingenol (24) (Wang et al., 2003), 20-O-benzoyl-13-O-dodecanoylingenol (25) (Wang et al., 2003), ingenol (26) (Teng et al., 2009), 20-O-Acetylingenol (27) (Jakupovic et al., 1998) 3-O-benzoyl- 13-O-dodecanoy-20-O-acetyl ingenol (28) (Grue-Sørensen et al., 2014), ingenol-3-benzoate (29) (Grue-Sørensen et al., 2014), 13-hydroxyingenol-3-(2,3-dimethylbutanoate)-13-dodecanoate (30) (Ott and Hecker, 1981), 3-O-(2′E,4′Z-decadienoyl)-20-O-acetylingenol (31) (Wang et al., 2002), 3-O-(2′E, 4′E-decadienoyl)-20-O-acetylingenol (32) (Wang et al., 2002) by comparison of their spectral data with literature values (Fig. 1). The cytotoxic effects of 1–32 against Adr-sensitive HepG2 and Adr-resistant HepG2/Adr cell lines were examined, but none of the compounds showed significant activity (Table 4), except that 3, 8, and 10 showed weak activity against HepG-2 cells (Table 4).
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3-Monoesters of ingenol exhibit high affinity toward PKC [126]. Few studies on the SAR of ingenenes have been made so far [126,127]. Other ingenenes have been isolated from Euphorbiaceae family plants showing modifications in the oxidation state at C3, C4, C5, C12, C13, C16, or C20 positions.
Cancer is among the main causes of death worldwide showing an increasing incidence and a growing mortality in our aging population. Natural products have long been used in popular anticancer treatment. Nowadays, some compounds of natural sources or their semisynthetic derivatives have been used in the clinic as anticancer drugs. Moreover, a huge number of natural metabolites have shown to interact with diverse cellular targets involved in carcinogenesis. The discovery of the natural tumor-promoting phorbol esters (PEs) extracted from the seed oil of the Croton tiglium, as protein kinase C (PKC) activators opened a new research area on the role of PKC proteins in cell growth and tumor promotion. The PKC is a family of serine/threonine kinases composed by 10 structurally and functionally related isoforms divided into three subgroups: classical, novel, and atypical PKCs. Some of the PKC isoforms have been widely implicated in tumor suppression, while other isoforms have been involved in tumor development and invasion. Thus, PKC family isoforms are widely recognized therapeutic targets in anticancer drug development. Several natural compounds have been identified either as inhibitors or activators of the PKC isoforms and used to modulate the PKC activity in tumor cells. Besides the aforementioned PEs that are tigliane diterpenes, the polyoxygenated macrocyclic lactones bryostatins, the staurosporine alkaloids, and the ingenene macrocyclic diterpenes are among the most studied natural PKC modulators. In addition, the daphnane tricyclic diterpenes, the abietane diterpenoids as carnosol and coleon U, the phenolic compounds as curcumin and resveratrol, and the flavonoids as quercetin, have more recently been studied as PKC modulators. Despite this, only two of these compounds reached the clinic, ingenol mebutate and bryostatin 1, in combination with paclitaxel.
This chapter will review the structure and the mechanisms of regulation of PKC isoforms and their role in carcinogenesis, as well as the natural and semisynthetic compounds currently identified as modulators of PKC, particularly their natural sources or semisynthetic processes of preparation, their chemical structures, the structure–activity relationships, those in clinical trials or already approved for therapeutic use.
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Synthesis, biological evaluation and SAR of 3-benzoates of ingenol for treatment of actinic keratosis and non-melanoma skin cancer

Abstract

Graphical abstract

Section snippets

Acknowledgments

Cancer Immunol. Immunother.

Toxins

J. Am. Acad. Dermatol.

J. Drugs Dermatol.

Bioorg. Med. Chem. Lett.

Determ. Org. Struct. Phys. Methods

Chem. Res. Toxicol.

Engl. J. Med.

Expert Rev. Dermatol.

Clin. Cosmet. Invest. Dermatol.

Dermatol. Ther.

J. Am. Acad. Dermatol.

Drugs

Eur. J. Org. Chem.

Planta Med.

Bioorg. Med. Chem. Lett.

J. Am. Chem. Soc.

Mini-Rev. Med. Chem.

Front. Biosci.

Physiol. Rev.

JAMA Dermatol.

J. Nat. Prod.