Design, Synthsis And Bioacvity Evaluation Of Novel Blood Oxygen Regulators

In clinic,many factors can lead to the disorder of oxygen release in blood,resulting in insufficient oxygen supply in tissues,which has serious adverse effects.For example,circulatory hypoxia caused by decreased tissue blood flow due to abnormal cardiac function,such as cardiovascular disease.Hypotensive hypoxia,such as respiratory diseases and acute altitude sickness,is caused by decreased arterial partial pressure of oxygen.Blood hypoxia caused by changes in the quantity and nature of hemoglobin,such as hemoglobin disease,carbon monoxide poisoning,and long-term storage of blood.Acute kidney injury,nonalcoholic fatty liver disease,tumors and other diseases can cause tissue hypoxia.Promoting the effective dissociation of blood oxygen is one of the most direct means to solve the above-mentioned diseases.At present,the main oxygen regulators are organic phosphoric acid,aromatic propionic acid,5-hydroxymethyl furfural and so on.Hemoglobin（Hb）in red blood cells（RBCs）is the main carrier of oxygen transport and release.The physiological process of oxygen release from RBCs is regulated by allosteric regulators.Endogenous Hb allosteric regulator 2,3-diphosphate glyceric acid（2,3-DPG）can reduce the oxygen affinity of Hb by binding with Hb,and promote the effective release of oxygen by Hb at hypoxic partial pressure.In view of this,based on the structural characteristics of 2,3-diphosphate glyceric acid（2,3-DPG）,a new type of oxygen regulator was designed and synthesized,and its role in oxygen regulation was evaluated.According to the structural characteristics of glyceric acid 2,3-diphosphate,a new type of diphosphate was designed by retaining the key diphosphate and carboxyl groups.The corresponding 2,3-DPG analogues can be obtained in a high yield（43%）by three simple steps:esterification,phosphorus esterification and palladium-carbon catalytic reduction.Different phosphates（compound L-12）can be obtained by reacting with different bases.The results of nuclear magnetic resonance analysis showed that the obtained phosphate did not decompose in aqueous solution for 15days and had high stability.The synthetic method is simple,the raw materials are cheap and easy to obtain,and the conditions are mild.It provides a new synthetic method for the efficient synthesis of new blood oxygen regulators.After the target compounds were obtained,its role in blood oxygen regulation was evaluated in vivo and in vitro.Compound L-12b-NH₄ can significantly prolong the exhaustion time of mice in swimming exhaustion test,compound L-12b-NH₄ can significantly prolong the survival time of mice in acute hypoxia model under normal pressure.It was found that compound L-12b-NH₄ could significantly shift the oxygen dissociation curve of mice to the right.The partial pressure of oxygen(P₅₀)at 50%oxygen saturation increased by 29.8%,indicating that the affinity of hemoglobin to oxygen decreased and the release of oxygen increased in tissues with low partial pressure of oxygen.In conclusion,a series of new phosphate oxygen regulators were designed and synthesized in this paper.It was found that compound L-12b-NH₄ could significantly improve the exercise endurance and anti-hypoxia ability of mice,and could significantly reduce the affinity of hemoglobin to oxygen under hypoxic partial pressure,promote the dissociation of blood oxygen and thus improve the utilization rate of oxygen.This paper provides a theoretical and experimental basis for the design and synthesis of oxygen regulators.These compounds have important clinical application value in the treatment of oxygen regulated diseases.