Synthesis of ingenol analogs wth affinity for protein kinase C

Winkler, Jeffrey D.; Hong, Bor‐Cherng; Bahador, Afshin; Kazanietz, Marcelo G.; Blumberg, Peter M.

doi:10.1016/s0960-894x(01)81232-4

Cited by 22 publications

(15 citation statements)

References 17 publications

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“… 44 In addition, simultaneous removal of the C18/C19 methyl groups and dimethylcyclopropane moiety resulted in substantial loss in activity. 45 , 46 Recent studies have further revealed that IngMeb activity requires hydroxyl groups at the C4 and C5 positions and is maintained with various esters at the C3 position. 44 , 47 The 4-, 5-, and 20-hydroxyl groups, however, also form a framework for acyl migration of the ester, leading to subsequent loss in IngMeb potency.…”

Section: Resultsmentioning

confidence: 99%

Chemical Proteomics Identifies SLC25A20 as a Functional Target of the Ingenol Class of Actinic Keratosis Drugs

et al. 2017

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The diterpenoid ester ingenol mebutate (IngMeb) is the active ingredient in the topical drug Picato, a first-in-class treatment for the precancerous skin condition actinic keratosis. IngMeb is proposed to exert its therapeutic effects through a dual mode of action involving (i) induction of cell death that is associated with mitochondrial dysfunction followed by (ii) stimulation of a local inflammatory response, at least partially driven by protein kinase C (PKC) activation. Although this therapeutic model has been well characterized, the complete set of molecular targets responsible for mediating IngMeb activity remains ill-defined. Here, we have synthesized a photoreactive, clickable analogue of IngMeb and used this probe in quantitative proteomic experiments to map several protein targets of IngMeb in human cancer cell lines and primary human keratinocytes. Prominent among these targets was the mitochondrial carnitine-acylcarnitine translocase SLC25A20, which we show is inhibited in cells by IngMeb and the more stable analogue ingenol disoxate (IngDsx), but not by the canonical PKC agonist 12-O-tetradecanoylphorbol-13-acetate (TPA). SLC25A20 blockade by IngMeb and IngDsx leads to a buildup of cellular acylcarnitines and blockade of fatty acid oxidation (FAO), pointing to a possible mechanism for IngMeb-mediated perturbations in mitochondrial function.

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Section: Resultsmentioning

confidence: 99%

Chemical Proteomics Identifies SLC25A20 as a Functional Target of the Ingenol Class of Actinic Keratosis Drugs

et al. 2017

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“…Ingenol ( Figure 7 i) and ingenol esters are some of the diterpenoids identified from extracts of leafy spurge which are found to be an irritant and a tumour promoter [ 34 ]. Both ingenol and its esters are suggested to induce toxicity due to their structural similarity to diacylglycerol and so mimic diacylglycerol thus activating protein kinase C [ 185 ]. The irreversible activation of protein kinase C has been documented to cause metabolic disruption leading to inflammatory response such as tissue damage, release of histamine causing irritation, unregulated cell growth and differentiation which could cause tumour formation [ 186 ].…”

Section: Rumen Microbial Detoxification Of Plant Toxinsmentioning

confidence: 99%

Toxin Degradation by Rumen Microorganisms: A Review

Loh

Ouwerkerk

Klieve

et al. 2020

Toxins

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Animal feeds may contain exogenous compounds that can induce toxicity when ruminants ingest them. These toxins are secondary metabolites originating from various sources including plants, bacteria, algae and fungi. Animal feed toxins are responsible for various animal poisonings which negatively impact the livestock industry. Poisoning is more frequently reported in newly exposed, naïve ruminants while ‘experienced’ ruminants are observed to better tolerate toxin-contaminated feed. Ruminants can possess detoxification ability through rumen microorganisms with the rumen microbiome able to adapt to utilise toxic secondary metabolites. The ability of rumen microorganisms to metabolise these toxins has been used as a basis for the development of preventative probiotics to confer resistance against the poisoning to naïve ruminants. In this review, detoxification of various toxins, which include plant toxins, cyanobacteria toxins and plant-associated fungal mycotoxins, by rumen microorganisms is discussed. The review will include clinical studies of the animal poisoning caused by these toxins, the toxin mechanism of action, toxin degradation by rumen microorganisms, reported and hypothesised detoxification mechanisms and identified toxin metabolites with their toxicity compared to their parent toxin. This review highlights the commercial potential of rumen inoculum derived probiotics as viable means of improving ruminant health and production.

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“…The corresponding tetradecanoate (30) [110] and benzoate (31) [111] derivatives have also been studied.…”

Section: Ingenol Derivativesmentioning

confidence: 99%

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

Gennäs

Talman²,

Yli‐Kauhaluoma³

et al. 2011

CTMC

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Protein kinase C (PKC) comprises a family of ten isoforms that play roles in diverse cellular processes such as proliferation, apoptosis and differentiation. PKC isoforms respond to Gprotein coupled receptor-and receptor tyrosine kinase-signaling via binding the second messenger diacylglycerol with C1 domains. Aberrant signaling through PKC isoforms and other C1 domain-containing proteins has been implicated in several pathological disorders.Drug discovery concerning C1 domains has exploited natural products and rationally designed compounds. Currently, molecules from several classes of C1 domain-binding compounds are in clinical trials; however, still more have the potential to enter the drug development pipeline. This review gives a summary of the recent developments in C1 domain-binding compounds.

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Synthesis of ingenol analogs wth affinity for protein kinase C

Cited by 22 publications

References 17 publications

Chemical Proteomics Identifies SLC25A20 as a Functional Target of the Ingenol Class of Actinic Keratosis Drugs

Chemical Proteomics Identifies SLC25A20 as a Functional Target of the Ingenol Class of Actinic Keratosis Drugs

Toxin Degradation by Rumen Microorganisms: A Review

Current Status and Future Prospects of C1 Domain Ligands as Drug Candidates

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