Study On Aryl Sulfones And Sulfur-containing Analogs Of Their Synthesis And Radioprotective Properties

Despite ionizing radiation brings more and more changes to human life,it also induces great harm to human body.It is the promising field for researchers to study how to protect against ionized radiation effectively.Due to the stability,safety and dosage form of the current antiradiation agents,most of them cannot be used for clinical treatment.So it is urgent for us to explore countermeasure agents which are effective,safe,convenient for administration.Ex-Rad?ON01210?is a novel,small-molecule kinase inhibitor explored by Onconova Therapeutics.It showed attractive protective and therapeutic effect for radiation-induced damage of bone marrow hematopoietic and gastrointestinal system.The aryl sulfone group is to be main pharmacophore of Ex-Rad.In this research work,we designed and synthesized four series of new potent radioprotective compounds as the core group of Ex-Rad being important structural block with the aid of Computer Drug Design.And we screened the radioprotective effect of these compounds,further investigated their possible mechanism.1.Thirty-five new compounds were designed and synthesized,including aryl sulfones analogs?4a-4t?,Tempol analogs?5a-5f?,ferrocenyl analogs?6a-6e?and piperazine analogs?P1-P5?.All of the structures were analyzed by ¹H NMR,¹³C NMR,HR-MS and X-Ray single crystal diffraction.2.The toxicity of these novel compounds were screened by MTT assay using Huvecs cell.Certain range of concentrationa ryl sulfones analogs?4a-4m?,Tempol analogs?5a-5f?and piperazine analogs?P1-P5?were applied to following experiment to study the bioactivties.The result showed that treatment with compound 4a,4b,5b,5d,P2 and P3 two-hour before irradiation can significantly increase the survival rate of damaged cells and reduce the apoptosis.3.We study the radioprotective mechanism of compound 4a,4b,5b,5d,P2 and P3 with western blotting,and further to observe the effect of these compounds on apoptotic protein expression.The result showed compound 4a,4b,5b and 5d can significantly reduce the expression of Bax,Caspase-3,p53 and p-p53 protein and increase the expression of Bcl-2 protein in radiation-damaged huvecs.That means compounds 4a,4b,5b and 5d can reduce apoptosis by influencing the expression of Bcl-2,Bax,Caspase-3,p53 and p-p53,and above compounds have well radioprotective activity to huvecs.