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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：
10380804
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380804
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.

项目摘要该提案的目的是设计新的药剂，其在存在下释放生物效应物。过氧化氢，提供了一种空间精确策略的方法，用于治疗多种医学疾病，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，允许较低的剂量，减轻副作用。这些新试剂是基于过氧化氢介导的α-硼基转化醚和相关结构转化为半缩醛，导致分解形成酮并释放出效应器在该方法中释放的酮副产物是无毒的，提供优异的生物相容性。治疗疾病的机会，其中促进细胞反应，而不是细胞死亡， objective.这一多学科计划将利用有机合成，动力学研究，细胞分析，动物实验，以实现其目标。第一个具体目标是设计释放环在氧化条件下使用二核苷酸以刺激针对肿瘤的免疫应答。的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，降低了所需的辐射剂量，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，为以下方面创造了独特的机会：局部化疾病治疗，同时为开发设计前药的一般策略提供指导释放出结构上完全不同的物质

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Peroxide-Mediated Release of Organophosphates from Boron-Containing Phosphotriesters: A New Class of Organophosphate Prodrugs.

DOI：
10.1021/acs.orglett.3c02036
发表时间：
2023-07-28
期刊：
ORGANIC LETTERS
影响因子：
5.2
作者：
Klootwyk, Brittany M.;Ryan, Amy E.;Lopez, Arbil;McCloskey, Mitchell J. R.;Janosko, Chasity P.;Deiters, Alexander;Floreancig, Paul E.
通讯作者：
Floreancig, Paul E.

Development of a light-activated STING agonist.

光激活 STING 激动剂的开发。