Topology and mechanism in self-immolation chemistry
自焚化学的拓扑和机理
基本信息
- 批准号:RGPIN-2018-06275
- 负责人:
- 金额:$ 2.11万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2018
- 资助国家:加拿大
- 起止时间:2018-01-01 至 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Self immolative (SI) chemistry is a technology that finds use in many “smart” materials, substances that react or sense their environment, such as biodegradable polymers, targeted pro-drugs and a wide variety of sensors and assays for pollutants, enzymes, pH, temperature and light to name but a few. SI chemistry is often employed to deliver a programmed response at a targeted site. A common SI design has “linear topology” where a targeting or immobilizing group is attached to triggering group and then to an SI linker and finally to a reporter molecule that is released to provide the desired effect. The process is started by a triggering event that activates the SI linker that then unravels (or self-immolates) to releases the reporter molecule. Biodegradable polymers may link SI groups together and disintegrate in response to light or pH change or release active substances in response to exposure to an enzyme or some other triggering input. SI is often designed to be fast as it's important that the response is localized but such SI molecules can be rather unstable. In many reported cases in fact, the SI step is in fact rather slow (from minutes to hours) and the triggered intermediate has time to diffuse away from its localized site before the reporter molecule is released and the targeting may be lost. ***Nonetheless, a slow and controlled SI step can be advantageous and provide a sustained localized effect if the targeting integrity can be maintained. An answer to this problem is to design an SI molecule with a “branched” topology where the targeting or immobilizing moiety is separated from the triggering event.***This research program proposes to design stable SI linker technologies with “branched” topology where the targeting or immobilized moiety attached to the SI linker and separated from the triggering moiety. Primary focus will be to provide predictable and “tunable” release (sustained release) of a wide variety of reporter molecules without losing targeting. ***In the shorter term the program will focus on SI cyclization linkers based on ethylenediamine (EDA) and electronic cascade SI linkers based on para-aminobenzyl alcohol (PABA). Through iterative design, synthesis and kinetic analysis on model SI monomers we will 1) determine the best sites for installation of a branching chain for targeting; 2) identify substitutions on the SI linker elements that can be varied to predictably tune rates of SI and reporter molecule release; 3) identify branched SI molecules that are inherently very stable but are triggered for slow release of a reporter molecule by changes in pH. ***In the longer term we will 1) evaluate the effects on SI rates of immobilization into micelles or onto particles and 2) develop new SI linkers to deliver reporter molecules not reliably delivered with current SI technologies.***These program studies will provide principles for design of SI chemistry for sustained response in a wide variety of smart materials.
自焚(SI)化学是一项技术,可用于许多“智能”材料,反应或感知其环境的物质,如可生物降解聚合物,靶向前药物和各种各样的传感器和污染物,酶,pH值,温度和光的分析,仅举几例。SI化学通常用于在目标位点提供程序化反应。常见的SI设计具有“线性拓扑”,其中靶向或固定基团连接到触发组,然后连接到SI连接体,最后连接到释放以提供所需效果的报告分子。这个过程是由一个触发事件启动的,该触发事件激活SI连接体,然后SI连接体解开(或自我牺牲)以释放报告分子。可生物降解的聚合物可以将SI基团连接在一起,并在光照或pH值变化下分解,或在暴露于酶或其他触发输入时释放活性物质。SI通常被设计为快速,因为重要的是响应是局部的,但这样的SI分子可能相当不稳定。事实上,在许多报道的病例中,SI步骤实际上相当缓慢(从几分钟到几小时),在报告分子被释放之前,触发的中间体有时间从其定位位点扩散出去,从而可能失去靶向作用。***尽管如此,如果能够保持靶向完整性,缓慢和受控的SI步骤可能是有利的,并提供持续的局部效果。这个问题的答案是设计一个具有“分支”拓扑结构的SI分子,其中靶向或固定部分与触发事件分开。***本研究计划提出设计具有“分支”拓扑结构的稳定SI连接器技术,其中目标或固定部分附着在SI连接器上并与触发部分分离。主要的焦点将是提供可预测的和“可调的”释放(持续释放)各种报告分子而不失去靶向性。***短期内,该项目将重点关注基于乙二胺(EDA)的硅烷环化连接剂和基于对氨基苄醇(PABA)的电子级联硅烷连接剂。通过对模型SI单体的迭代设计、合成和动力学分析,我们将1)确定用于靶向的分支链的最佳安装位置;2)确定可以改变的SI连接元件上的取代,以可预测地调整SI和报告分子的释放速率;3)鉴定具有分支性的SI分子,这些分子本身非常稳定,但可以通过ph的变化触发报告分子的缓慢释放。***从长远来看,我们将1)评估固定到胶束或颗粒上的SI速率对SI的影响,2)开发新的SI连接剂来传递当前SI技术无法可靠传递的报告分子。***这些项目研究将为在各种智能材料中持续响应的SI化学设计提供原则。
项目成果
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专著数量(0)
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会议论文数量(0)
专利数量(0)
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Young, Robert其他文献
The relative importance of family socioeconomic status and school-based peer hierarchies for morning cortisol in youth: an exporatory study.
- DOI:
10.1016/j.socscimed.2009.12.006 - 发表时间:
2010-04 - 期刊:
- 影响因子:5.4
- 作者:
West, Patrick;Sweeting, Helen;Young, Robert;Kelly, Shona - 通讯作者:
Kelly, Shona
Toward more efficient protein expression
- DOI:
10.1385/mb:34:2:151 - 发表时间:
2006-10-01 - 期刊:
- 影响因子:2.6
- 作者:
Kalwy, Stephan;Rance, James;Young, Robert - 通讯作者:
Young, Robert
Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery
- DOI:
10.1093/neuonc/not085 - 发表时间:
2013-09-01 - 期刊:
- 影响因子:15.9
- 作者:
Boothe, Dustin;Young, Robert;Beal, Kathryn - 通讯作者:
Beal, Kathryn
The Relationship between Dietary Fiber Intake and Lung Function in the National Health and Nutrition Examination Surveys
- DOI:
10.1513/annalsats.201509-609oc - 发表时间:
2016-05-01 - 期刊:
- 影响因子:8.3
- 作者:
Hanson, Corrine;Lyden, Elizabeth;Young, Robert - 通讯作者:
Young, Robert
A longitudinal study of alcohol use and antisocial behaviour in young people.
- DOI:
10.1093/alcalc/agm147 - 发表时间:
2008-03 - 期刊:
- 影响因子:2.8
- 作者:
Young, Robert;Sweeting, Helen;West, Patrick - 通讯作者:
West, Patrick
Young, Robert的其他文献
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{{ truncateString('Young, Robert', 18)}}的其他基金
Topology and mechanism in self-immolation chemistry
自焚化学的拓扑和机制
- 批准号:
RGPIN-2018-06275 - 财政年份:2022
- 资助金额:
$ 2.11万 - 项目类别:
Discovery Grants Program - Individual
Topology and mechanism in self-immolation chemistry
自焚化学的拓扑和机制
- 批准号:
RGPIN-2018-06275 - 财政年份:2021
- 资助金额:
$ 2.11万 - 项目类别:
Discovery Grants Program - Individual
Topology and mechanism in self-immolation chemistry
自焚化学的拓扑和机理
- 批准号:
RGPIN-2018-06275 - 财政年份:2020
- 资助金额:
$ 2.11万 - 项目类别:
Discovery Grants Program - Individual
Topology and mechanism in self-immolation chemistry
自焚化学的拓扑和机理
- 批准号:
RGPIN-2018-06275 - 财政年份:2019
- 资助金额:
$ 2.11万 - 项目类别:
Discovery Grants Program - Individual
Asymptotic geometry, filling functions, and non-positive curvature
渐近几何、填充函数和非正曲率
- 批准号:
399394-2011 - 财政年份:2015
- 资助金额:
$ 2.11万 - 项目类别:
Discovery Grants Program - Individual
Asymptotic geometry, filling functions, and non-positive curvature
渐近几何、填充函数和非正曲率
- 批准号:
399394-2011 - 财政年份:2014
- 资助金额:
$ 2.11万 - 项目类别:
Discovery Grants Program - Individual
Optimization of novel dual action prodrugs for treatment of osteoporosis
治疗骨质疏松症的新型双重作用前药的优化
- 批准号:
414137-2012 - 财政年份:2013
- 资助金额:
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Collaborative Health Research Projects
Asymptotic geometry, filling functions, and non-positive curvature
渐近几何、填充函数和非正曲率
- 批准号:
399394-2011 - 财政年份:2013
- 资助金额:
$ 2.11万 - 项目类别:
Discovery Grants Program - Individual
Optimization of novel dual action prodrugs for treatment of osteoporosis
治疗骨质疏松症的新型双重作用前药的优化
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414137-2012 - 财政年份:2012
- 资助金额:
$ 2.11万 - 项目类别:
Collaborative Health Research Projects
Proof of concept molecules and molecular probes in drug discovery
药物发现中的概念分子和分子探针的证明
- 批准号:
341724-2008 - 财政年份:2012
- 资助金额:
$ 2.11万 - 项目类别:
Discovery Grants Program - Individual
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