Topology and mechanism in self-immolation chemistry

自分解（SI）化学是一种用于许多“智能”材料的技术，这些材料可以反应或感知其环境，例如可生物降解的聚合物，靶向前药和各种传感器以及污染物，酶，pH值，温度和光的测定。SI化学通常用于在靶位点递送程序化反应。常见的SI设计具有“线性拓扑结构”，其中靶向或固定基团连接到触发基团，然后连接到SI接头，最后连接到释放以提供所需效果的报告分子。该过程由激活S1接头的触发事件开始，S1接头然后解开（或自分解）以释放报告分子。可生物降解的聚合物可将SI基团连接在一起，并响应于光或pH变化而分解，或响应于暴露于酶或一些其他触发输入而释放活性物质。SI通常被设计为快速的，因为重要的是响应是局部的，但是这样的SI分子可能相当不稳定。事实上，在许多报道的情况下，SI步骤实际上相当慢（从几分钟到几小时），并且在报告分子释放之前，触发的中间体有时间从其定位位点扩散开，并且靶向可能丧失。* 尽管如此，缓慢和受控的SI步骤可以是有利的，并且如果可以保持靶向完整性，则提供持续的局部效果。这个问题的答案是设计具有“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离。该研究计划提出设计具有“分支”拓扑结构的稳定的SI接头技术，其中靶向或固定化部分连接到SI接头并与触发部分分离。 主要的焦点将是提供可预测的和“可调的”释放（持续释放）的各种报告分子，而不失去靶向。* 在短期内，该计划将专注于基于乙二胺（EDA）的SI环化连接体和基于对氨基苯甲醇（PABA）的电子级联SI连接体。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）确定用于安装用于靶向的分支链的最佳位点; 2）鉴定SI接头元件上的取代，其可以变化以可预测地调节SI和报告分子释放的速率; 3）鉴定固有地非常稳定但通过pH的变化触发缓慢释放报告分子的支链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，2）开发新的SI接头，以递送目前SI技术无法可靠递送的报告分子。这些项目研究将为SI化学设计提供原则，用于各种智能材料的持续响应。

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.