Design, Synthesis And Biological Activity Of Targeted Small Molecules And The Thiol-related Reactions

In this dissertation, based on new drug molecular targets RSK2and PPARy, three series of novel small molecules were designed and synthesized, and their corresponding biology activities were evaluated. These new scaffold moleculars exhibited good biological activity, such as indole ketone derivatives, benzotriazole derivatives could inhibit RSK2kinase,2-thioxo-4-thiazolidinones could be considered as new promising molecular probes with excellent binding activities to PPARy.In the first section, a series of novel indolin-2-ones inhibitors against p90ribosomal S6protein kinase2(RSK2) were designed and synthesized and their structure-activity relationship (SAR) was studied. The most potent inhibitor, compound3s, exhibited potent inhibition against RSK2with an IC50value of0.5μM and presented a satisfactory selectivity against23kinases. The interactions of these inhibitors with RSK2were investigated based on the proposed binding poses with molecular docking simulation. Four compounds and six compounds exhibited moderate anti-proliferation activities against PC3cells and MCF-7cells respectively.In the second section, a series of novel benzotriazole derivatives were designed and synthesized. These benzotriazole derivatives exhibited potent inhibitory activities against RSK2, and can be modified for further optimization.In the third section, we designed and synthesized a series of2-thioxo-4-thiazolidinone derivatives and evaluated them on Peroxisome Proliferator Activated Receptor gamma (ppar-y) binding activities. The biological assay results showed compound20and48were highlighted with Ki values of12.15nM and14.46nM, respectively. The structure-activity relationship (SAR) was analyzed for screening privileged structural modifications. Moreover, molecular fitting of these compounds onto the approved drug Rosiglitazone in the PPARy ligand binding domain was taken to elucidate the SAR and explore potential receptor-ligand interactions. These results demonstrate that the2-thioxo-4-thiazolidinones can be considered as new promising molecular probes with excellent binding activities to PPARy.In the fifth section, benzalcyanoacetamides were designed and synthesized as reversible thiol addition conjugate acceptors. These thia-conjugate additions can rapidly and reversibly achieve equilibrium in aqueous condition at neutral pH. Kinetic studies show that electron-withdrawing groups at the4-position of the phenyl ring of benzalcyanoacetamides promoted the conjugate addition at equilibrium. The dynamic thiol exchanges of these conjugate acceptors are faster than singly-activated α, β-unsaturated carbonyls. These thia-conjugate additions can be assembled as potentially useful components in Dynamic Combinatorial Chemistry.