Design,Synthesis And Activity Evaluation Of Novel Tocotrienol Derivatives As Radioprotective Agents

Radioprotective drug,also known as radioprotective agent,is defined by the compounds or preparations that can reduce radiation-induced damage if administered before or early after radiation.Most countries in the world especially with nuclear powers have always been focus on the research of radioprotective agents.After nearly a century of research,a series of radioprotective agents with good radioprotective effect have been developed internationally.However,due to considerable side effects and inconvenient administration,these radioprotective agents have not been equipped as radioprotective drugs in the army.In the 1980 s,the radioprotective drugs “523”,“500” and “408” have been developed through multiple animal experiments in China,which have been recognized with certain therapeutic effects according to the clinical treatment of patients with radiation accident patients,and have been subsequently equipped to the troops.In recent years,hematopoietic factors such as granulocyte-colony stimulating factor(G-CSF)have been widely used to treat leukopenia in cancer patients receiving radiochemotherapy,which have also shown good efficacy in the treatment of radiation accident victims.Compared with hematopoietic factors,the radioprotective drugs currently equipped are obviously insufficient in terms of recovery of white blood cells,which is difficult to meet the demands of future wars.Therefore,it is a global hot spot to explore new radioprotective drugs with significant radioprotective effects as well as mild side effects that would meet the demands of military health service in recent years.At present,G-CSF is one of the most effective drugs to treat acute radiation sickness.In 2015,G-CSF/neupogen and PEGylated G-CSF/neulasta were approved by the US FDA for the treatment of acute radiation sickness.In recent years,some studies have found that a variety of small molecule radioprotectors against irradiation under research exert protective and preventive roles in radiation by promoting endogenous G-CSF secretion.Vitamin E is a naturally existing small molecule compound,including two major types,tocopherols and tocotrienols in nature.It is reported that ?-and ?-tocotrienol can significantly promote the secretion of endogenous G-CSF in mice,with good radioprotective activity.Because of its low toxic and side effects,it is one of the key candidates for the US military research on radioprotectors against irradiation in recent years.However,tocotrienol is a strong fat-soluble compound,laying great difficulty in formulation,thus,the development process is impeded.In this study,tocotrienol(T3H)was used as a lead compound to obtain a series of T3 H and its derivatives with various structures through T3 H total synthesis and semi-synthesis.By activity screening of endogenous G-CSF production in mice,the structure-activity relationship of T3 H derivative on promoting G-CSF production was confirmed,aiming to find target compounds with good water solubility and strong radioprotective activity.The results showed that: 1 Based on the total synthesis pathway of T3 H,?-T3 H of natural configuration was obtained by enzymatic chemistry.As a result,the G-CSF-promoting activity of ?-T3 H was consistent with that of plant-extracted ?-T3 H.2 ?-T3 H was used as the raw material,the ?-T3 H and ?-T3 H of natural configuration were obtained by methylation of chromogenic mother nucleus.Similarly,the G-CSF-promoting activity of ?-T3 H and ?-T3 H was consistent with that of plant-extracted ?-T3 H.3 Based on the total synthesis pathway of T3 H,a racemic compound of ? and ? configuration with 1 to 3 isopentenyl units in the side chain or a methylidene structure with different-length chains in the side chain were obtained.The activity analysis showed that the G-CSF-promoting activity of T3 H and T2 H with racemic ? configuration was comparable to the natural ?-T3 H activity;while the G-CSF-promoting activity of T3 H and T2 H with racemic ? configuration was significantly superior to that of the natural ?-T3 H,in which racemic ?-T2 H was optimal.However,racemic ?-T1 H and ?-T1 H as well as compounds with methylidene structure in the side chain failed to promote endogenous production of G-CSF.4 When the hydroxyl at the 6-position of the tocotrienol chromane ring was replaced by amidogen,the activities of G-CSF production was reduced;when the aminoethyl,hydroxyethyl and diamino were bonded to the hydroxyl or amidogen in the 6-position of chromane ring,the promoting activity of G-CSF production of these compounds were comparable to that of natural ?-T3 H.5 The T3 H derivative with terminal hydroxyl was phosphate-modified for salt formation to acquire 10 new compounds.The activity evaluation revealed that the G-CSF-producing activity of T3 H derivative basically disappeared after phosphate modification,which restored after salt formation.The promoting effects of G-CSF production in three salt-forming compounds were comparable to that of natural ?-T3 H.The solubility of the bound compounds indicated that the racemic ?-T2 H and ?-T2 H phosphate sodium salts had good water solubility,with potent promoting activity of G-CSF production.Collectively,in this study,T3 H was used as a lead compound to obtain 30 T3 H and its derivatives and 25 new compounds with diverse structures by T3 H total synthesis and semi-synthesis.The structure-activity relationship of T3 H derivative on promoting G-CSF production was confirmed.Moreover,two target compounds with good water solubility and potent promoting activity of G-CSF production were found,namely,racemic ?-T2 H and ?-T2 H phosphate sodium.