Conditional Control of Drug Function Through α-Boryl Ether Oxidation

项目摘要 这项建议的目标是设计新的试剂，在存在的情况下释放生物效应器 过氧化氢，为治疗大量医疗疾病提供了一种空间精确策略的方法 以氧化应激为特征的条件。这些条件包括但不限于， 再灌注损伤、病毒感染、神经变性、创伤性脑损伤和癌症。空间精确度 释放将是有益的，因为它可以最大限度地减少一般药物的暴露，允许较低的剂量 减轻副作用。新试剂是基于过氧化氢介导的α-硼基的转化 醚和相关结构到半缩醛，导致分解形成酮并释放 效应器。在这种方法中释放的酮副产品是无毒的，提供了极好的 治疗疾病的机会，其中促进细胞反应，而不是细胞死亡，是 目标。这一多学科计划将利用有机合成、动力学研究、细胞分析和 动物研究，以实现其目标。第一个具体目标是设计释放环状化合物的试剂 在氧化条件下的二核苷酸，以努力刺激对肿瘤的免疫反应。这个 第二个具体目标是将药物释放与放射治疗相结合，以创建一种针对特定部位的方法 癌症治疗。模拟对辐射的生理反应的释放剂将允许 自动感应释放机制，可降低所需的辐射剂量并将晚期副作用降至最低。 PI和合作者在这些项目上的技能结合在一起，创造了独特的机会 本地化疾病治疗，同时为制定设计前药的一般战略提供指导 释放出结构完全不同的毒剂。

Project Summary The objective of this proposal is to design new agents that release biological effectors in the presence of hydrogen peroxide, providing an approach to spatially precise strategies for treating a multitude of medical conditions that are characterized by oxidative stress. These conditions include, but are not limited to, reperfusion injury, viral infection, neurodegeneration, traumatic brain injury, and cancer. Spatially precise release will be beneficial because it can minimize general drug exposure, allowing for lower doses while mitigating side effects. The new agents are based on the hydrogen peroxide mediated conversion of α-boryl ethers and related structures to hemiacetals, leading to a breakdown that forms a ketone and releases the effector. The ketone by-products that are released in this approach are non-toxic, providing excellent opportunities to treat diseases in which the promotion of cellular responses, rather than cell death, is the objective. This multidisciplinary program will utilize organic synthesis, kinetics studies, cellular assays, and animal studies to achieve its objectives. The first Specific Aim is to devise agents that release cyclic dinucleotides under oxidative conditions in an effort to stimulate an immune response against tumors. The second Specific Aim is to merge drug release with radiation therapy to create a site-specific approach to cancer treatment. Releasing agents that mimic the physiological response to radiation will allow for an autoinductive release mechanism that lowers the required radiation dose and minimizes late stage side effects. The combination of the skills of the PIs and collaborators on these projects creates unique opportunities for localized disease treatment while providing guidance for developing a general strategy for designing prodrugs that release structurally disparate agents.