Conditional Control of Drug Function Through α-Boryl Ether Oxidation

通过α-硼基醚氧化条件控制药物功能

• 批准号: 9750473
• 负责人: Alexander Deiters
• 金额: $ 38.45万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750473
• 关键词: Acute; Alcohols; Aldehydes; Animals; Behavior; Biological; Biological Assay; Biological Process; Cell Death; Cell Membrane Permeability; Cells; Cellular Assay; Charge; Chemicals; Clinical; Complex; Crowding; Cytotoxin; Development; Diabetes Mellitus; Diffuse; Dinucleoside Phosphates; Disease; Dose; Drug Controls; Drug Exposure; Environment; Enzymes; Esters; Ethers; Exhibits; Gene Activation; Hydrogen Peroxide; Immune response; Immunooncology; Injections; Interferon-beta; Ionizing radiation; Ketones; Kinetics; Lead; Localized Disease; Malignant Neoplasms; Masks; Mediating; Medical; Monitor; Nerve Degeneration; New Agents; Organic Synthesis; Oxidative Stress; Pathway interactions; Patients; Periodicity; Permeability; Peroxides; Pharmaceutical Preparations; Physiological; Process; Prodrugs; Production; Protein Synthesis Inhibitors; Quality of life; Radiation; Radiation Dose Unit; Radiation therapy; Reactive Oxygen Species; Reperfusion Injury; Research; Research Personnel; Site; Solid Neoplasm; Stimulator of Interferon Genes; Stimulus; Structure; Sulfhydryl Compounds; Testing; Tissues; Traumatic Brain Injury; Validation; Variant; Virus Diseases; base; cancer therapy; cytotoxic; design; hemiacetal; imaging agent; mouse model; multidisciplinary; novel therapeutics; oxidation; phosphonate; phosphoric diester hydrolase; prevent; programs; quinone methide; radiation response; response; side effect; skills; success; targeted treatment; tumor; tumor microenvironment

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.

项目概要 该提案的目的是设计在存在生物效应物的情况下释放生物效应器的新药剂 过氧化氢，为治疗多种医疗问题提供了一种空间精确策略的方法 以氧化应激为特征的疾病。这些条件包括但不限于 再灌注损伤、病毒感染、神经变性、脑外伤和癌症。空间精确 释放将是有益的，因为它可以最大限度地减少一般药物暴露，从而允许较低的剂量 减轻副作用。新药剂基于过氧化氢介导的 α-硼基转化 醚和半缩醛的相关结构，导致分解形成酮并释放 效应器。这种方法释放的酮副产物是无毒的，提供了优异的 治疗疾病的机会是促进细胞反应而不是细胞死亡 客观的。这个多学科项目将利用有机合成、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循环的药物 氧化条件下的二核苷酸，以刺激针对肿瘤的免疫反应。这 第二个具体目标是将药物释放与放射治疗结合起来，创建一种针对特定部位的方法 癌症治疗。模拟辐射生理反应的释放剂将允许 自感应释放机制可降低所需的辐射剂量并最大限度地减少后期副作用。 这些项目的 PI 和合作者的技能相结合，创造了独特的机会 局部疾病治疗，同时为设计前药的总体策略提供指导 释放结构不同的药剂。