Synthesis And Biological Activity Of Nucleoside Hypoxia-targeted Anti-tumor Drugs, New Neuropathic Pain Treatment Drugs And New Anti-insulin Resistance Drugs

The research of this dissertation is composed of the following three parts.Research of hypoxia-activated anti-tumor nucleoside analogues:With the environmental pollution outside the world and the changes in lifestyle,cancer is becoming a huge threat to us now.For the treatment of cancer,clinical often use surgery,radiotherapy and chemotherapy,in which chemotherapy is still a primary treatment now.General toxicity of chemotherapeutic drugs and not targeting to the tumor or the targeting to the tumor has less efficacy with chemotherapy is still upset for doctors,which inevitably occurs with over use of chemotherapy drugs and has a lot of side effects.The damage is huge both for doctors and patients,as well as the social economy!Synthesing a new type of tumor-targeting drugs is extremely urgent.Started from metabolic inhibition of antitumor drugs,a series of liver tumor-targeting metabolic antagonist of antitumor nucleoside analogues were synthesised.Compound JH-003 shows a satisfactory plasma metabolic rate,which laid the foundation for later study.Research of the novel therapeutic drugs for neuropathic pain:Neuropathic pain is caused by a somatic sensory nervous system damage,with clinical features such as spontaneous pain,hyperalgesia,abnormal pain and paresthesia.It has a serious damage to the quality of life of modern people,but currently lack of satisfactory clinical drug is known to us all.Looking for a new target for neuropathic pain is becoming more and more popular in drug research.NMDAR-PSD95-nNOS uncoupling agents was found to have a good effect for the treatment of neuropathic pain.Combined with pregabalin,gabapentin by amidation,the new twin drugs existed low pharmacokinetic properties in vivo in the previous study,which greatly reduce the effects of the treatment of neuropathic pain.Based on the previous results,target compounds were redesigned:by introducing the ethylene glycol,a new type of NMDAR-PSD95-nNOS uncoupling agents was synthesized.The target compounds showed better nerve cell protective effect.Pharmacological experiments are ongoing.Research of novel drugs against insulin resistance:With the improvement of people's economy,diabetes and its complications are affecting the quality of human's life.Insulin resistance proved to be a factor of high blood sugar,diabetes and metabolic disorders.Insulin resistance showed to have relationship with some inflammatory signaling pathway in adipose tissue.Inside of the Adipose tissue,containing two subtypes of macrophages(M1 subtype and M2 subtype).The less Class A Scavenger Receptor on the surface of macrophages can reduce insulin resistance.Of course,as an endogenous ligand of Class A Scavenger Receptor,LPC has shown to have activity against insulin resistance.Based on the research,a series of LPC analogues were designed,hoping to have a strong activity to against insulin resistance.The photosensitive probe of MT was also designed and synthesized to explore its target.Pharmacological experiment indicates that MT shows hypoglycemic activity,which laid foundation for further studies.