Study On The Design,Synthesis And Bioactivity Of SPLA₂-?A-Targeting Inhibitors Against Tumor Cell Migration

Secretory phospholipase A2 group ?A(sPLA2-?A)is a very important enzyme involved in phospholipid metabolism,which is relevant to many diseases,including cancers.Recent studies have shown that sPLA2-?A can bind to the cell membrane adhesion molecule integrin ?v?3 to induce tumor cells migration,whereas the peptidomimetic molecule composed of benzene ring-thiazole-pyrazole-AWD*I can antagonize this protein-protein interaction to inhibit the migration of tumor cells.Based on the this study,we designed and synthesized a series of new analogues of this active molecule and studied their inhibitory activity against cell migration and cytotoxicity.In the aspect of synthesis,the organic acids with different para-substituents on the phenyl ring were synthesized by thiazole formation,benzoyl amidation,Claisen condensation,pyrazole formation and ester hydrolysis reactions(substituents = H,CH3,OCH3,F,Cl,Br).Then the organic acid was conjugated with the tetrapeptide AWD*I by solid phase synthesis to obtain a series of peptidomimetic compounds with different para-substituents on the phenyl ring.And their intermediates were identified by1H-NMR and the peptoid target molecules were identified by MS.In the study on the bioactivity of the target molecules,the migration of anti-breast cancer cells(MDA-MB-231)was studied by scratches and Transwell cell migration assays.The results show that when the substituents were-H,OCH3,Cl and Br,the peptidomimetics demonstrate the effect of inhibiting cell migration.When the substituent is Br,the inhibition effect is the best(when the compound concentration is10?M,the migration inhibition coefficient in the scratch experiment is 5.17,the migration inhibition rate in the Transwell experiment is 50.17%),and its migration inhibition activity is higher than that of the previously identified active molecules.In addition,CCK-8 cytotoxicity assays show that the peptidomimetic compound with a substituent Br is almost non-toxic to the cells(lung cancer cells A549).Thus,when the substituents on the phenyl ring of the peptidomimetic molecule is Br,it has goodanti-migration and no cytotoxicity,and can be used as a lead compound for further related drug research.This paper provides a scientific basis for the development of anti-tumor drug.