权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结

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。