Phospholipase A ₂ And Sphingomyelin Synthase Bifunctional Inhibitors In The Design, Synthesis And Activity Evaluation

Atherosclerosis (AS) is a chronic inflammatory disease which related to dysbolism of lipids. Its pathogenesis refers to several aspects. As the development of medicine, the therapeutic targets of AS has focused on correlative receptors, biomacromolecules and key enzymes from lipid metabolism to thrombosis, inflammation, immunomodulation, oxidative stress. Nowadays, the selective mono-target drugs, including lipid regulating agents and anti-oxidant agents, are used to AS clinical therapy. Although they show good effects to selective targets, they are also limited in the whole disease. So the "one-molecule, one-target" strategy is unsuitable to AS therapy.We focused on the key enzymes--secretory phospholipase A2(sPLA2) and sphingomyelin synthase (SMS), which influence the lipid metabolism and inflammation in AS. We analyzed the SAR of known inhibitors, designed and synthesized10dual-functional ligands by rational multiple ligands design. Their biological activities were assessmented. The fluorescence assay by ANS as an interfacial probe was used for sPLA2evaluation and HPLC assay by NBD labeled ceramide was used for SMS evaluation. The biological assessment showed some compounds displayed moderate inhibitory activities against both sPLA2and SMS. These results corroborate our initial design strategy and have great guidance to further modification.