Design,Synthesis And Biolgical Evaluation Of EGCG Derivatives And Ticagrelor Derivatives Based On Prodrug Strategy

Prodrug is a molecule which does not have any intrinsic biological activity but is capable to generate a biologically active drug when it is catalyzed by specific enzymes or in the specific chemical environment.Prodrug has become an effective strategy in medicinal chemistry due to the useful applications in improving drug water-solubility,lipophicity,absorption membrane permeability,increasing the t1/2,target releasing or reducing side effects and so on.In this paper,we explored anti-vitiligo and anti-thrombotic drugs based on prodrug strategy in order to meet the clinical needs.The results are as follows:Study of EGCG deveriates based on prodrug:Natural prodruct epigallocatechin-3-gallate(EGCG)is one of the main chemical constituents of green tea,which has been intensively investigated for its biological activities including anti-oxidation,anti-inflammatory,anti-cancer,and neuroprotection.In our previous study,we demonstrated that EGCG would be a promisng anti-vitiligo agent.However,due to the presence of eight unprotected phenolic hydroxyl groups,EGCG is notably unstable and is known to have poor membrane permeability leading to limited clinical application.Therefore,prodrug strategy was investigated to overcome the undesirable properties of EGCG.The following modifications were made:1)Introduction of the acyl groups onto the skeleton of EGCG.Most of the compounds showed moderate to good protective effect of melanocytes from H2O2-induced cell damage while 1-21 showed the best activity.2)Peracetylated EGCG deveriates were designed and synthesized.When redusing the number of hydroxyl group on galloyl moiety of EGCG,the compounds showed significantly decreased activity,less than I-21 even at a high concentration,indicating that the number of hydroxyl groups of EGCG is closely associated with activity.3)Introduction of hydroxy-cinnamoyl moiety onto EGC.Peracetylated target compounds showed good protective effect to melanocytes from H2O2-induced cell damage which is consistent with the cell viability.Also we found that I-52 can potently decrease the release of lactate dehydrogenase(LDH)in melanocytes.In addition,the caffeinic deveriates showed good inhibitory activities against JAK(IC50:JAKl:53.5pgM,JAK2:22.6μM,JAK3:0.5μM),indicating that these compounds can protect melanocytes with both anti-oxidant and JAK inhibiting activity.Therefore,we improved the membrane permeability and poor efficacy of EGCG affording promising EGCG deveriates as both anti-oxidant and JAK-inhibiting agents,which provids a notable thought and experiment basis for the development of EGCG deveriates as anti-vitiligo drugs.Study of ticagrelor deveriates based on prodrug:Ticagrelor is a direct,orally active and reversible antagonist of P2Y12,which is a platelet inhibitor.It has been demonstrated that the mean elimination half-lives of ticagrelor in healthy subjects is 7-8.5 hours,so patients need twice per day,while just once a day for irreversible clopidogrel.Therefore,discontinuation of the rapidly reversible drug in patients with poor compliance is likely to increase the risk of acute thrombosis,leading to MI or stroke.Several ticagrelor derivatives were designed and obtained by deuterated metabolic sites of ticagrelor and introduction of oligopeptide transporters substrate valine.The Preliminary pharmacokinetics experiments showed the target compounds improved the PK,and in SD rats models,the half-life of compound 11-31 extended 43.5%,and AUC(O-∞)increased 11.7%.Therefore,in this paper,based on prodrug strategy,we improved the metabolic stability of ticagrelor,and obtained half-life extended ticagrelor derivatives.Also,further work about introduction of additional transporter substrates to enhance their bioavailability is ongoing.In conclusion,based on prodrug strategy,we successfully improved the poor lipophicity of natural product EGCG and enhanced the protective effect of melanocytes from H2O2-induced cell damage which laid a good foundation for further clinical application.Furthermore,it is identified that based on oligopeptide transporters prodrug strategy combination with deuterated strategy,we can improve half-life and bioavailability in response to the rapid metabolism of antiplatelet agents ticagrelor.It is expected to solve the clinical compliance problems and improve the competitive advantage compared to other irreversible P2Y12 receptor inhibitor clopidogrel,which has significant application value.