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

基本信息

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
项目类别：
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

项目摘要

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病症这些病症包括但不限于：再灌注损伤、病毒感染、神经变性、创伤性脑损伤和癌症。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的新药物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这种方法释放的酮副产物是无毒的，提供了极好的效果。治疗疾病的机会是促进细胞反应而不是细胞死亡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。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模拟辐射生理反应的释放剂将允许癌症治疗。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。