Development of Novel Tocotrienol-based Radioprotective Agents

超过50%的癌症患者在癌症治疗期间接受放射治疗; 然而，放射线对正常组织的损伤是放射治疗相关副作用的主要原因 是癌症放射治疗的限制因素。公众对核恐怖分子的关注也越来越多 袭击或工业事故。然而，目前没有安全、有效的FDA批准的辐射防护剂， available.两种维生素E同系物-γ-生育三烯酚（γ-T3）和δ-生育三烯酚（δ-T3）-是一些最重要的 迄今为止已确定的有效的低毒性辐射防护剂。在迄今为止测试的所有天然产物中，γ-T3和 研究发现，δ-T3对暴露于辐射剂量的小鼠具有最高程度的保护作用， 否则是致命的尽管γ-和δ-T3具有潜在的辐射防护作用，但它们的血浆 消除半衰期，如果不通过静脉注射给药，生物利用度低，这限制了其接触 需要在体循环中的时间和浓度，并且需要大剂量给药。短 血浆消除半衰期是由于其对α-生育酚转移蛋白（α-TTP）的低亲和力及其 高代谢率。γ-和δ-T3的低生物利用度至少部分是由它们的高生物利用度引起的。 亲油性和低水溶性。低α-TTP亲和性和低代谢稳定性也是导致细胞凋亡的原因。 γ-和δ-T3的口服生物利用度低，因为口服给药受到显著的首过代谢， 肝脏因此，为了提高γ-和δ-T3作为辐射防护剂的潜在治疗效用，我们建议 设计和合成T3基类似物，其固有的辐射防护性能相当于或优于 但亲脂性降低，α-TTP亲和力增加，代谢增加， 稳定本论文的主要目的是：1）设计合成γ-和δ-T3 类似物; 2）确定γ-和δ-T3类似物的α-TTP结合和肝脏代谢; 3）确定 γ-和δ-T3类似物的抗氧化剂和HMG-CoA还原酶抑制特性;以及4）体外测定 γ-和δ-T3类似物的辐射防护性质。我们的长期目标是将这些化合物开发成 人类使用的防辐射药物。我们预计，这些化合物也将作为研究工具， 研究辐射防护的生化机制。

More than 50% of all cancer patients will receive radiotherapy during the course of their cancer treatments; however, radiation-induced injury to normal tissues is the major cause of radiation treatment–related side effects and is a limiting factor in cancer radiotherapy. There is also growing public concern of nuclear terrorist attacks or industrial accidents. However, no safe, effective, FDA-approved radioprotectants are currently available. Two vitamin E homologues—γ-tocotrienol (γ-T3) and δ-tocotrienol (δ-T3)—are some of the most effective low-toxic radioprotective agents identified to date. Among all natural products tested to date, γ-T3 and δ-T3 were found to give the highest degree of protection to mice exposed to radiation doses that were otherwise lethal. Despite their potential as radioprotectants, γ- and δ-T3 have relatively short plasma elimination half-lives and, if not given by intravenous injection, low bioavailability, which limits their exposure time and concentration in systemic circulation and necessitates administration in large doses. The short plasma elimination half-lives are a result of their low affinity for α-tocopherol transfer protein (α-TTP) and their high rates of metabolism. The low bioavailability of γ- and δ-T3 is caused, at least in part, by their high lipophilicity and low water solubility. Low α-TTP affinity and low metabolic stability are also responsible for the low oral bioavailability of γ- and δ-T3 because oral dosing is subject to significant first-pass metabolism through the liver. Thus, to improve the potential therapeutic utility of γ- and δ-T3 as radioprotective agents, we propose to design and synthesize T3-based analogues with intrinsic radioprotective properties comparable to or better than those of γ- and δ-T3 but with reduced lipophilicity, increased α-TTP affinity, and increased metabolic stability. For this purpose, we will pursue the following Specific Aims: 1) design and synthesize γ- and δ-T3 analogues; 2) determine α-TTP binding and liver metabolism of γ- and δ-T3 analogues; 3) determine antioxidant and HMG-CoA reductase inhibitory properties of γ- and δ-T3 analogues; and 4) determine in vitro radioprotective properties of γ- and δ-T3 analogues. Our long-term goal is to develop these compounds into radioprotective drugs for human use. We expect that such compounds will also serve as research tools for studying biochemical mechanisms of radiation protection.