The Design, Synthesis Of Structures Of Nitronyl Nitroxide Radicals Drugs And Their Preliminary Pharmacodynamic Reasearch

Nitronyl nitroxide radicals are a category of functional group structures which includenitronyl nitroxide radical and nitrogen oxygen dipole. This article designed andsynthesised five kinds of new chiral nitronyl nitroxide radicals, then researched theirprotective effects on myocardium ischemia reperfusion injury (MIRI) and radiation. Aftera series of biological experiments, these nitronyl nitroxide radicals can be found certaineffects on myocardium ischemia reperfusion injury protection and radiation protection.Details are as follows.1. Designed and synthesized two kinds of new chiral nitronyl nitroxide radicals whichwere L-1and L-2. They used L-prolinol as the raw material, and there was a phenoxybond between the chiral carbon atom and the imidazole ring of nitroxide radical. Thesynthesis method has also been optimized. The structural characterizations of the twocompounds were carried out by means of MS, IR, EA and EPR spectra.2. Designed and synthesized three kinds of new chiral nitronyl nitroxide radicalswhich were L-3, L-4and L-5. They used L-prolinol as the raw material, and the chiral carbon atom combined with the imidazole ring of nitroxide radical directly. Thesynthesis method has also been optimized. The structures of these three compoundswere also confirmed by MS, IR, EA and EPR spectra.3. Researched the protective effects of L-1and L-2on myocardial ischemia reperfusion.The myocardial ischemia reperfusion animal models were established from healthymale Sprague-Dawley rats. Before and after the experiment, the activity of CK, SODand the contents of MDA, NO in serum were tested. The results showed that after theischemia reperfusion, the activity of CK and contents of MDA in serum were markedlyreduced, but the activity of SOD was significantly enhanced. It indicated that nitroxidescan increase the capacity of eliminating free radical and inhibit the lipid peroxidation.The markedly increased contents of NO in serum indicated that L-1and L-2couldprovide NO. Thus, this part of the experiment demonstrated that L-1and L-2couldameliorate the heart function of model rats, and compared with L-2, L-1had strongereffect on protecting myocardium. In addition, L-1and L-2had the ability of bothscavenging harmful free radicals and providing NO, which was helpful to prevent themyocardial ischemia reperfusion injury.4. Researched the radio-protective properties of chiral nitronyl nitroxide radicalsincluding L-3to L-5.(1) The cytotoxicity research was carried out on C6rat glioma cells. These cells weretreated by6concentrations of these free radicals. The survival rate of the cells wassignificantly decreased when the doses of the free radicals exceeded62.5μg/mL.Therefore, less than or equal to the concentrations of62.5μg/mL were chosen to benon-toxic doses.(2) In the MTT cell experiment, the1.0Gy γ ray was used to C6rat glioma cells, thenthe survival rate of the cells was counted. The three radicals all showed certainresistance to radiation compared with the irradiated group. The cell survival rate of L-3group was higher than L-4and L-5group. Thus L-3was chosen as the drug in animalexperiment.(3) The male konmin mices were used to establish the animal model. The experiment researched the effects of different radiation doses on livability of mice and the effectson spleen, thymus, bone marrow hematopoietic stem cells, polychromatic erythrocytesof mice and the activity of SOD and the contents of MDA in serum. The results showedthat the livability of the mice was significantly improved after L-3treatment. The indexof spleen and thymus, the number of spleen colonies, the number of bone marrow cellsand the level of protein were markedly increased. The activity of SOD, the contents ofMDA in serum and the PCEMNs were significantly reduced. The results indicated thatL-3could reduce the DNA injury caused by radiation and prolong the life of the miceunder the radiation.