A. Tudor Evans

Daphnane diterpenes of Thymelaea hirsuta

Five 12-hydroxy-daphnane esters were isolated from the leaves and twigs of Egyptian Thymelaea hirsuta. These compounds were identified as gnidicin, gniditrin, genkwadaphnin, the aliphatic C-12 ester, 12-O-heptadecenoyl-5-hydroxy-6,7-epoxy-resiniferonol-9,13,14-orthobenzoate and the novel aliphatic C-12 ester 12-O-butenyl-5-hydroxy-6,7-epoxy-resiniferonol-9,13-14-orthobenzoate.

Sapintoxin A. A fluorescent phorbol ester that is a potent activator of protein kinase C but is not a tumour promoter

In this communication we report on the activity of the naturally occurring, highly fluorescent phorbol ester Sapintoxin A (12-o-[2-methylaminobenzoate]-4-deoxyphorbol 13-acetate). This compound potently activates the enzyme protein kinase C (PKC) (Ka 76 nM) but is neither a complete nor second-stage tumour promoter in traditional Berenblum tests. Sapintoxin A has properties in common with promoters such as 12-o-tetradecanoylphorbol 13-acetate (TPA) in that it will induce erythema in vivo, induce lymphocyte mitogenesis in vitro and cause aggregation of human and rabbit platelets. Accordingly, Sapintoxin A is a suitable negative control compound for biochemical studies concerning the involvement of PKC in tumour promotion and cell proliferation.

The potent irritancy of the daphnane orthoester, resiniferatoxin, exhibits features of a mixed aetiology

Abstract— Resiniferatoxin‐induced erythema of mouse ear was shown to possess characteristics of both a phorbol ester‐mediated response and that induced by the neurogenic irritant, capsaicin. Whereas the response to the phorbol ester, sapintoxin D, was delayed and prolonged, and was augmented by capsaicin pretreatment, the response to resiniferatoxin was biphasic, with the early phase being antagonized by capsaicin desensitization. However, resiniferatoxin was most potent in inducing a delayed erythema which, unlike the capsaicin response, was sensitive to inhibition by low dose hydrocortisone treatment, but not to chronic capsaicin desensitization. It is concluded that the erythema response to resiniferatoxin has a mixed aetiology, which may explain the unique potency of this toxin.

Properties of a Resiniferatoxin-stimulated, Calcium Inhibited but Phosphatidylserine-dependent Kinase, which is Distinct from Protein Kinase C Isotypes α, β1γ, δ, ε and η

We have separated a resiniferatoxin‐stimulated histone‐kinase activity from human neutrophils, elicited mouse macrophages and murine alveolar macrophages by hydroxyapatite chromatography.

An ingenane diterpene from belizian Mabea excelsa

The new ingenane diterpene, 5-deoxy-13-hydroxyingenol, was isolated from the alcohol preserved fresh latex of the stems of Mabea excelsa and characterized from its semi-synthetic triacetate. This is the first instance of an ingenane diterpene obtained from species other than those of Euphorbia and Elaeophorbia. This diterpene occurred in the latex in the form of an inseparable mixture of six aliphatic mono-esters of the tertiary C-13 hydroxy group.

The Different Calcium Requirements of the Mitogenic Effects Elicited in Primary Neonatal Rat Hepatocytes by the Diterpene Phorbol Esters 12-O-Tetradecanoylphorbol-13-Acetate and Sapintoxin A

A single exposure to a wide range of concentrations (10−13−10−5 mol/L) of the powerful, complete tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulated 4-day-old primary neonatal rat hepatocytes to synthesize new DNA and to divide within 24 hours independently on the actual (either high [1.8 mmol/L] or low [0.01 mmol/L]) concentration of calcium (Ca2+) in the surrounding HiWoBa2000 synthetic growth medium. Conversely, the exposure to the same range of doses of sapintoxin A (SAP A; a fluorescent phorbol ester activating the Ca2+/phospholipid-dependent protein kinase [PK-C]) without acting by itself either as a complete or as a second-stage tumour promoter) enhanced the proliferative activity of primary hepatocytes only on condition that a high level of Ca2+ was present in the growth medium. On the other hand, studies on the kinetics of the inhibition of new DNA synthesis showed that the induction of the G0/G1 and G1/S transitions by TPA in hepatocytes incubated in the Ca2+-devoid HiWoBa20000 medium still required cellular Ca2+-, CaM-, and PK-C-dependent metabolic events. Hence, the diverse conditioning of the mitogenic activity of tumour promoting and non-promoting phorbol esters by the level of extracellular Ca2+ suggests as a quite likely event the involvement in the process of differently Ca2+-dependent isoenzymes of their receptor PK-C.