Topology and mechanism in self-immolation chemistry

自焚化学的拓扑和机制

• 批准号: RGPIN-2018-06275
• 负责人: Young, Robert
• 金额: $ 4.23万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748169
• 关键词: Topology; mechanism; self; immolation; chemistry

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)化学是一种技术，它用于许多“智能”材料，即反应或感知其环境的物质，如可生物降解的聚合物、靶向前药物以及各种传感器和污染物、酶、pH、温度和光的分析，仅举几例。硅化学经常被用来在目标位置提供程序化的反应。常见的SI设计具有线性拓扑结构，其中靶向或固定化基团连接到触发基团，然后连接到SI接头，最后连接到释放的报告分子上，以提供所需的效果。这一过程由一个触发事件开始，该事件激活SI连接子，然后该连接子解体(或自焚)以释放报告分子。生物可降解聚合物可将SI基团连接在一起，并响应于光或pH变化而分解，或因暴露于酶或某些其他触发输入而释放活性物质。SI通常被设计成快速的，因为它的反应是局部化的很重要，但这种SI分子可能相当不稳定。事实上，在许多报道的案例中，SI步骤实际上相当缓慢(从几分钟到几个小时)，并且在报告分子被释放之前，触发的中间体有时间扩散离开其定位的位置，从而可能失去靶向。尽管如此，如果能够保持靶向完整性，缓慢且受控的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种具有“分支”拓扑结构的SI分子，其中靶向或固定化部分与触发事件分离。本研究计划提出设计稳定的具有“分支”拓扑结构的SI连接子技术，其中靶向或固定化部分附着在SI连接子上并与触发部分分离。主要的重点将是在不失去靶向性的情况下，提供各种报告分子的可预测和“可调”释放(持续释放)。在短期内，该计划将重点放在基于乙二胺(EDA)的SI环化连接物和基于对氨基苯甲醇(PABA)的级联SI连接物上。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)确定用于靶向的支链的最佳安装位置；2)确定SI连接元件上可以改变的替换以可预测地调节SI和报告分子的释放速率；3)识别本质上非常稳定但被pH变化触发的报告分子缓慢释放的分支SI分子。从长远来看，我们将1)评估固定到胶束或颗粒上对SI速率的影响，以及2)开发新的SI连接物来传递当前SI技术无法可靠传递的报告分子。这些程序研究将为SI化学的设计提供原则，以在各种智能材料中实现持续响应。