138433-86-0Relevant articles and documents
Conformationally constrained analogues of diacylglycerol. Interaction of γ-lactones with the phorbol ester receptor of protein kinase C
Teng, Kelly,Marquez, Victor E.,Milne, George W. A.,Barchi Jr., Joseph J.,Kazanietz, Marcelo G.,Lewin, Nancy E.,Blumberg, Peter M.,Abushanab, Elie
, p. 1059 - 1070 (2007/10/02)
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.
