- Enantioselective Synthesis and Biological Activity of (3S,4R)- and (3S,4S)-3-Hydroxy-4-hydroxymethyl-4-butanolides in Relation to PGE2
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Compounds 9 and 13 were synthesized, and their structures and stereochemistry were elucidated by spectroscopic methods. In competition binding experiments, specific [3H]-PGE2 binding was significantly displaced by compound 9 and, to a lesser extent, by 13, in a dose-dependent manner. The biological properties of compound 9 were studied on HL-60 cells, and several effects were found related to those of PGE 2. Compound 9 increases c-fos mRNA level as does PGE2 and antagonizes TPA-induced terminal differentiation.
- Miranda, Pedro O.,Estévez, Francisco,Quintana, José,Garcia, Candelaria I.,Brouard, Ignacio,Padrón, Juan I.,Pivel, Juan P.,Bermejo, Jaime
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p. 292 - 295
(2007/10/03)
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- Conformationally constrained analogues of diacylglycerol. Interaction of γ-lactones with the phorbol ester receptor of protein kinase C
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Four 2-deoxy-erythro-1,4-lactones in the D- and L-series and the four corresponding 2-deoxy-threo-1,4-lactones, bearing myristic acid acyl groups at either primary or secondary alcohol functions, were synthesized from L-ascorbic and D-isoascorbic acids. These eight pentonolactones which represent all possible isomers in this series were designed as rigid analogues of 1,2-diacylglycerol (DAG). The inhibition by these compounds of the binding of [3H] phorbol-12,13-dibutyrate to protein kinase C (PK-C) demonstrated the importance in this context of stereochemistry and particularly of the orientation of the fatty acid side chain. The most effective inhibitor (13d, Ki = 2.3 μM) has a fixed conformation which is presumed to be similar to the conformation adopted by DAG when binding to PK-C. A three-point attachment model which has been previously used to rationalize the similar behavior of DAG and phorbol esters was extended to include additional points of equivalence between these two PK-C agonists. This extended model addresses the disposition of the lipophilic myristic acid side chain and the orientation of the lactone carbonyl group which functions as a hydrogen bond acceptor. In this new model, the most active isomer 13d provides the best fit of the eight pentonolactones to phorbol myristate acetate.
- Teng, Kelly,Marquez, Victor E.,Milne, George W. A.,Barchi Jr., Joseph J.,Kazanietz, Marcelo G.,Lewin, Nancy E.,Blumberg, Peter M.,Abushanab, Elie
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p. 1059 - 1070
(2007/10/02)
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