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E Hecker

Publications and source records attributed to E Hecker.

173 records · Page 10Linked to original sources
PubMedDate not supplied

On the active principles of the Euphorbiaceae, XII. Highly unsaturated irritant diterpene esters from Euphorbia tirucalli originating from Madagascar.

The latex of Euphorbia tirucalli originating from Madagascar contains as irritant constituents ingenane- and tigliane-type diterpene esters derived from the parent alcohols ingenol and phorbol. The main irritant constituents are isomeric 12,13-acetates, acylates of phorbol as well as 3-acylates of ingenol. As acyl groups, they carry homologous, highly unsaturated aliphatic acids of the general structure CH3-(CH2)m-(CH = CH)n-COOH (m = 2,4; n = 2,3,4,5; total number N of C-atoms = 2n + m + 2). The lack of 4-deoxyphorbol esters in this latex as compared to latex of South African origin is probably indicative of the existence of chemical races of E. tirucalli. In the acyl moiety of phorbol esters investigated in detail, an increasing number of C-atoms or an increasing number of double bonds at a fixed number of C-atoms leads to an increase of irritant activity. As compared to their saturated analogs, corresponding unsaturated phorbol esters exhibit similar irritant activities. On the other hand, by an increasing number of conjugated double bonds in the acyl moieties of phorbol esters, the promoting activity is decreased, thus indicating that irritant activity is a necessary, but insufficient, requirement for promoting activity of phorbol esters. An assessment of a potential carcinogenic risk involved in mass production and handling of the plant should point to the very weak tumor-promoting activity and the chemical instability demonstrated for the diterpene constituents in the latex and hence in all plant parts.

Animals↗
PubMedDate not supplied

Irritant principles of the mezereon family (Thymelaeaceae), V. New skin irritants and tumor promoters of the daphnane and 1 alpha-alkyldaphnane type from Synaptolepis kirkii and Synaptolepis retusa.

Seventeen mostly new, skin irritant diterpene esters (DTE) of the daphnane and 1 alpha-alkyldaphnane types were isolated from roots of Synaptolepis kirkii and Synaptolepis retusa. The parent alcohols of the daphnane types are shown to be 5 beta-hydroxyresiniferonol-6 alpha,7 alpha-oxide [1] and 5 beta, 12 beta-dihydroxyresiniferonol-6 alpha,7 alpha-oxide [2]. Ten of the daphnane types are 9,13,14-orthoesters and three are conventional esters involving tertiary or secondary hydroxyl groups at C-13 or C-14, respectively. The latter may be considered immediate precursors of corresponding orthoesters. The four 1 alpha-alkyldaphnane types are intramolecular 9,13,14-ortho-(2-hexadecenoic acid)-esters in which, formally, the second to last C atom of the orthoester moiety is linked covalently to C-1 alpha of the diterpene parent alcohols 1 or 2. Thus, in the new structure, a macrocyclic ring bridges the alpha side of the diterpene moiety in an "ansa" type manner. The irritancies on the mouse ear of the DTE obtained cover a wide range (I24 = 0.05-670 nmole-1). Some of them are considerably more irritant than the daphnane type standard simplexin. Structure/activity investigations reveal that an ester group instead of a free hydroxyl group at C-20 ("cryptic types"), or presence of a hydroxy or an acetoxy group in position 12 diminishes the irritancies of the daphnane types isolated, similar to what is known in corresponding tigliane types. In the standardized initiation/promotion protocol on the back skin of mice, some of the irritant DTE exhibit tumor-promoting activities higher than that of simplexin.

Animals↗
PubMedDate not supplied

Irritant principles of the spurge family (Euphorbiaceae). XIII. Oligocyclic and macrocyclic diterpene esters from latices of some Euphorbia species utilized as source plants of honey.

The latices of the three South African species Euphorbia ledienii, Euphorbia coerulescens, and Euphorbia triangularis, belonging to a group of cactiform Euphorbias locally called "Noors," were shown to contain four 12-mono- and three 13,20-diesters of the tetracyclic tigliane type parent alcohol 12-deoxyphorbol [1]. In addition, two 13,16-di- and two 13,16,20-triesters of the related 12-deoxy-16-hydroxyphorbol [9] were obtained. Ester groups in 1 and 9 are made up of acetic, isobutyric, tiglic, angelic, and 2-methylbutyric acid; their positions in the parent alcohols were identified. The free parent alcohols were not detected in the latices. On the mouse ear all esters isolated showed moderate irritant activity as compared to the tigliane-type standard TPA. In addition to the oligocyclics listed above, the latex of E. ledienii also yielded five esters of the macrocylic, lathyrane type parent alcohol ingol [14]. In the two triesters and three teraesters the ester groups were made up of acetic, tiglic, and 2-methylbutyric acid (positions in 14 unidentified). None of the ingol esters showed irritant activity.

Diterpenes↗
PubMedDate not supplied

On the active principles of the spurge family (Euphorbiaceae). XI. [1] The skin irritant and tumor promoting diterpene esters of Euphorbia tirucalli L. originating from South Africa.

The irritant and tumor-promoting constituents of latex of Euphorbia tirucalli L. originating from South Africa were isolated. They were identified as irritant ingenane and tigliane type diterpene esters derived from unsaturated aliphatic acids and acetic acid and the polyfunctional diterpene parent alcohols 4-deoxyphorbol, phorbol and ingenol, respectively. The irritant and tumor-promoting esters of 4-deoxyphorbol are predominant and were fully characterized chemically and biologically. They are positionally isomeric 12,13-acylates, acetates e.g. Euphorbiafactors Ti1-Ti4. As acyl groups they carry homologous, highly unsaturated aliphatic acids of the general structure CH3-(CH2)m-(CH = CH)n-COOH (m = 2,4; n = 1,2, 3,4,5; N = 2n + m + 2). Corresponding diesters of 4-deoxy-4 alpha-phorbol are also present which are biologically inactive. Comparison of structures and biological activities of 12,13-diesters of 4-deoxyphorbol indicates that--for a distinct total number of C-atoms (N) in the acyl moiety--an increasing number of conjugated double bonds (n) may increase the irritant but decrease the tumor-promoting activity. Replacement of the hydroxyl function at C-4 (phorbol-12,13-diesters) by hydrogen (corresponding 4-deoxyphorbol-12,13-diesters) does not essentially alter biological activities. Epimerization of 4-deoxyphorbol-12,13-diesters at C-4 abolishes biological activities. The specific chemical properties demonstrated for the diterpene ester irritants contained in the latex of E. tirucalli and hence in all plant parts may be useful in trials to abolish the potential risk of cancer involved especially in occupational mass production and handling of the plant. Some of the structure activity relations of the Euphorbia factors isolated made them excellent tools in experimental cancer research for the analysis of mechanisms of tumorigenesis.

Carcinogens↗
PubMedDate not supplied

Mechanistically different acting tumor promoters induce consistent qualitative and quantitative changes in protein expression patterns of murine epidermis.

Systematic screening of different organs has shown that induction of particular proteins by 12-0-tetradecanoyl-phorbol-13-acetate is specific for mouse skin. Different compartments of skin showed all the same expression. For experimental reasons we focused the analysis performed thereafter on the epidermis. As an end- point of mouse skin tumorigenesis papilloma and carcinoma were also screened for changes in protein expression. We focused our efforts on the characterization and identification of selected, de novo expressed proteins induced by various tumor promoters in murine epidermis. The analysis presented here consists of functional characterization. Having found differences in protein expression in TPA-treated murine epidermis compared with acetone-treated control mice, we then tried to correlate the expression to the signal transduction pathway which the tumor promoter exerts its activity through. For this reason we screened protein expression patterns after topical administration of mechanistically differently acting tumor promoters, which were inflammatives not bearing tumor promoting activity anti-promoters or a combination of tumor promoters with modulators of tumor promotion. The epidermis of untreated newborn mice served as a model for high cellular proliferation and differentiation. Alterations were compared with changes observed after tumor promoter application.

Animals↗
PubMedDate not supplied

A novel protein (p10) induced by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and other hyperplasiogenic tumor-promoting and non-promoting agents in murine epidermis.

Treatment of murine epidermis with the tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA) shows characteristic and significant changes in protein expression analyzed by 2D PAGE, compared to that of acetone-treated mouse epidermis. Of the seven de novo expressed proteins in TPA treated murine epidermis, one is a 44 kDa protein (p44) located nearby actin, and six proteins are in the low-molecular range between 10-20 kDa (p10, pY, pCa, p1, p2 and p3). Interestingly, the incomplete promoting and inflammative hyperplasiogen 12-O-retinoylphorbol-13-acetate (RPA) and the non-promoting but inflammative and hyperplasiogenic calcium-ionophore A23187 induced the same pattern of proteins observed in the pidermis of mice treated with TPA, with minor quantitative differences. In all cases, p10 expression was quantitative the most abundant. Partial sequencing of this protein has led to the conclusion that it is a novel protein with no such sequences in the database comparisons using FASTA and TFASTA computer programs of Genetics Computer Group. The data presented here do not strictly support the functional role of de novo induced proteins to tumor promotion, but show a causal relationship to hyperplasiogenic potency of TPA, RPA and A23187.

Amino Acid Sequence↗
PubMedDate not supplied

A novel polypeptide p10 expressed in tumor-promoter-treated murine epidermis and in untreated neonatal murine epidermis.

12-O-Tetradecanoyl-phorbol-13-acetate (TPA) has been shown to induce a broad variety of morphological and metabolic changes in mouse skin. These include gross changes in cell growth as well as subtle changes regarding gene expression. Changes in the induction of specific proteins have been described, but it is not yet clear, if there exists a strict causal correlation between the induction of expression of specific proteins and the phenomenon of tumor promotion. At least some of these proteins might also be correlated with an accompanying hyperproliferative effect. This has been shown for protein p10, a 10 kDa protein not found in untreated adult mouse epidermis. The expression of this protein can be induced de novo after the topical administration of TPA. It is also shown, that p10 is expressed in untreated neonatal murine epidermis. Due to the induction of this protein by irritation, hyperproliferation-causing tumor promoters and due to the observable abundance in neonatal epidermis, this protein seems not strictly related to tumor promotion, but rather to proliferation and differentiation.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

12-O-retinoylphorbol-13-acetate (RPA) behaves like a retinoid-derivative in binding to retinol-binding-protein: a correlation with its specific action as an incomplete tumor promoter?

12-O-retinoylphorbol-13-acetate (RPA), an incomplete tumor promoter of the phorbol ester type and protein kinase C (PKC) activator, consists of two characteristic structural elements: the phorbol body and the retinoyl ester chain. Therefore, possible binding of the incomplete tumor promoter RPA to the human transport protein retinol-binding-protein (RBP) has been examined by molecular modeling methods and experimental binding studies. The calculated prediction of binding properties was primarily based on a comparative geometrical approach. It was shown that the beta-ionone-ring of RPA was not altered within the binding pocket of RBP (molecular modeling) compared to retinoic acid (X-ray crystallographic data). The torsion angle C5'-C6'-C7'-C8', determining the conformation of the RBP-beta-ionone-ring relative to the isoprene tail, is rotated by 42 degrees for RPA compared to retinol and to retinoic acid, respectively. Combining all the results from force field calculations, MD simulations and geometrical comparisons, the conclusion could be drawn that RPA should be able to bind to RBP. This interaction should be less strong than that with its natural ligand retinol or with retinoic acid. This prediction was proven experimentally. RPA was able to compete with retinoic acid for binding at RBP in human plasma. The binding properties were investigated using 3H-labeled retinoic acid in homologous and heterologous competition studies in a one-dimensional native polyacrylamide gel electrophoresis system. An approximately 2000-fold weaker binding of RPA to RBP as compared to retinoic acid was determined experimentally, confirming the prediction of the molecular modeling approach. The characteristic behaviour of RPA as an incomplete promoter, due to possible binding to PKC and RBP, is discussed.

Actins↗