Study On The Diversity Synthesis And Activity Of Benzoylated 3-(2-aminothiazolyl)-pyrazole-5-AWD*I Peptidomimetics As Cell Migration Inhibitor

Cancer is a major killer of human health,and it is easy to metastasize and difficult to cure.And the metastasis of cancer is based on cell migration.So if we can develop drugs which inhibit the migration of cancer cells,with the current treatment,we will reduce the risk of cancer metastasis and recurrence.Peptidomimetic compounds are one of the hot research areas in migration inhibitors due to their low toxicity,non-degradability and easy diversification.Based on the previous studies on benzoylated 3-?2-Aminothiazolyl?-pyrazole-5-AWD*I cell migration inhibitors,we designed a new rout which was consist of thiazole ring formation,Boc protection of amino groups,Claisen condensation,pyrazole ring formation,deprotection,diversified amide condensation and ester hydrolysis reactions.Then 10heterocyclic organic acid intermediates with different substituents were successfully synthesized through this new route.Finally,by condensation of the intermediates and the AWD*I tetrapeptide in the liquid phase,10different substituents of the benzoylated 3-?2-Aminothiazolyl?-pyrazole-5-AWD*I peptidomimetic target compounds were obtained.In terms of biological activity research,cytotoxicity experiments showed that the most target compounds were less cytotoxic,which indicated that the inhibition of cell migration by compounds might be achieved by affecting related migration signaling molecules.In addition,the results of the scratch test and the migration experiment were basically the same,showing the following trends:1)In the compounds of 4-H,4-CH₃,4-OCH₃,4-tBu substituents,the anti-migration effect first decreased and then increased,and the anti-migration effect of 4-OCH₃ was the smallest.It showed that within a certain size,compounds with large substituent sizes and strong electron donating ability had poor anti-migration activity,but beyond a certain size,anti-migration activity of large-sized compounds becomes better;2)In the compounds of 4-F,4-Cl,4-Br,and 4-I substituents,the anti-migration effect was gradually decreased,indicating that the compound having large electronegativity and small atomic radius had good activity;3)Among 4-Br,3-Br,and 2-Br substituents,the target compound of 3-Br had the best anti-migration effect,which might be due to the fact that the meta position of the benzene ring was favorable for the formation of hydrophobic interaction.Finally,the target was found by molecular docking reversed with AutoDock Vina.Docking results showed that the affinity trend of the target compounds with integrin?_??₃ was basically consistent with the trend of their anti-migration effect,indicating that?_??₃ might be the target and signal molecule of the compounds action.In view of the important role of cancer cell migration in cancer recurrence,the results of this paper will provide a reference for the development of targeted anticancer drugs.