New phospholipase A2 inhibitor: synthesis and inhibition mechanism of oxazolidinone phospholipid analog

(R)-3-Dodecanoyl-4-phosphatidylcholino-hydroxymethyl-2-oxazolidino ne (7), which is a new glycerophospholipid analog, was synthesized starting from (S)-glycidol through a 4-alkylsilyoxymethyl derivative and N-acyl-4-hydroxymethyl derivative. The cyclic amide analog 7 showed strong inhibitory activity toward both Group I and II PLA25, but the inhibitory potency of 7 was slightly weaker than that of the linear amide analog (R)-1, which had been developed by de Haas et al. (Biochem. Biophys. Acta 1990, 1043, 67). The interactions of 7 with human secretory PLA2 was investigated by computer modeling in comparison with those of the linear amide analog 1. The results of the computer modeling were very compatible with those of the inhibitory activities toward PLA2S, and the both results showed that the binding mode of the oxazolidinone analog 7 was very similar to that of the genuine substrate and was different from that of the linear amide analog 1.