Ingol and Ingenol-Type Diterpenes from Euphorbia trigona Miller with Keratinocyte Inhibitory Activity

Abstract

Ingenol mebutate, isolated from Euphorbia peplus, is an ingenane-type diterpenoid, primarily used for the topical treatment of actinic keratosis, a premalignant skin condition. The aim of our work was to investigate other Euphorbia species to find structurally similar diterpenes that can be used as alternatives to ingenol mebutate. Pharmacological investigation of Euphorbia candelabrum, Euphorbia cotinifolia, Euphorbia ramipressa, and Euphorbia trigona revealed the potent keratinocyte (HPV-Ker cell line) inhibitory activity of these spurge species. From the methanolic extract of the aerial parts of Euphorbia trigona Miller, the most active species, five ingol (1–5) and four ingenane-type diterpenoids (6–9) were isolated by various chromatographic separation techniques, including open column chromatography, vacuum liquid chromatography, thin-layer chromatography, and high-performance liquid chromatography. The structures of the compounds were determined by NMR spectroscopic analysis and by comparison of the assignations with the literature data. The cytotoxic activity of the compounds against keratinocytes was tested in vitro by using ingenol mebutate as a positive control. Among the isolated compounds, two ingenane derivatives (6 and 7) exhibited remarkably stronger cytotoxic activity (IC50 values 0.39 μM and 0.32 μM, respectively) on keratinocytes than ingenol mebutate (IC50 value 0.84 μM). These compounds could serve as starting materials for further investigations to find alternatives to Picato® (with active substance ingenol mebutate), which was withdrawn from marketing authorization in the European Union.

Bioactive Compounds from Euphorbia usambarica Pax. with HIV-1 Latency Reversal Activity

“…Therefore, the intensive study of LRAs is an important topic, especially to discover new candidates from natural sources. For example, a known LRA, ingenol, is isolated originally from Euphorbia peplus [ 64 ] and is a US-FDA-approved topical treatment for actinic keratosis (AK) [ 65 ], showed a significant effect in the reactivation of HIV-1 latency through the PKC pathway [ 65 ]. Both compound 14 and ingenol mebutate are Euphorbia diterpenoids and the potent PKC agonists.…”

Euphorbia neriifolia (Indian Spurge Tree): A Plant of Multiple Biological and Pharmacological Activities

“…Approximately 130 different types of triterpenoids have been isolated so far from the various species of Euphorbia. According to reports, tertracyclic triterpenoids are one of the major triterpenoids in the Euphorbia species and were divided into four classes: cycloartanes , lanostane (85)(86)(87)(88)(89)(90)(91)(92)(93)(94), euphane (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), and tirucallane (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Specifically, 9,19-cyclolanosta...…”

Euphorbiaditerpenoids: isolation, structure, bioactivity, biosynthesis, and synthesis (2013–2021)

“…In this period, a large number of Euphorbia diterpenoids, covering various skeletal types ( e.g. , abietane, 51 kaurane, 119 casbane, 129 jatrophane, 49 lathyrane, 151 ingenane, 142,260,276 tigliane, 174 and myrsinane 272 ), were screened for cytotoxicity, and many of them exhibited moderate or potent antiproliferative activities against a panel of human cancer cells. 27–29,277 In some cases, the in-depth mechanistic studies and in vivo efficacies of the promising leads were investigated.…”