Gordge, Philip Charles; (1992) Potential agonists and inhibitors of protein kinase C. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Daphnane and tigliane diterpenoid hydrocarbon nuclei were isolated from the latex of Euphorbia poissonii.Pax.Euphorbiaceae using the techniques of liquid-liquid partition, column chromatography, centrifugal liquid chromatography (CLC) and preparative partition and adsorption thin layer chromatography. Six naturally occurring diterpene esters were isolated from the latex and a further eight were semi-synthesised by selective esterification of the C20 primary alcohol of these resiniferonol and 12-deoxyphorbol nuclei. These compounds were characterised by their 1H-NMR, mass spectral, UV and IR properties. Computer-assisted molecular modelling of these compounds in conjunction with standard phorbol ester probes enabled the assessment of their minimum free energy values; resiniferonol derivatives were found to have much lower minimum free energy levels than corresponding 12-deoxyphorbol derivatives. The molecular coordinates of the potent irritant, resiniferatoxin, were also assigned. An in vivo mouse ear erythema assay was used to evaluate the pro-inflammatory response of these compounds and the ability of some resiniferonol derivatives to inhibit erythema induced by phorbol ester and neurogenic (capsaicin) irritants. The pro-inflammatory response induced by resiniferatoxin was found to be of mixed aetiology, comprising of neurogenic and phorbol ester components. The ability of the semi-synthetic compounds to induce epidermal hyperplasia of mouse skin was assessed as a potential correlation for tumour promotion activity. To further understand the biochemical mechanisms of action of these synthetic compounds, their ability to activate or inhibit a mixed isozymic pool of the phorbol ester receptor protein, protein kinase C, isolated from rat brain was studied. The ability of 12-deoxyphorbol-13-O-phenylacetate-20-O-acetate (DOPPA) to selectively activate isozymic forms of protein kinase C isolated from human platelets was also assessed.

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