"Click ON/OFF" chemistry via sulfonium-activated groups

“点击”反应通过生理学上稳定的化学键以高效率将两个匹配的官能团选择性地偶联在一起。重要的是，由于“点击”反应可以在温和的条件下进行，它们已经彻底改变了我们选择性修饰生物来源的复杂分子并制备其衍生的功能材料的能力。因此，它们是生物技术和制药领域的理想和必要工具。例如，利用生物分子将人工装置与生物流体（例如，生物传感器）或影响身体的功能（例如，治疗学）。我们的研究计划于2013年在加拿大新启动，旨在开发具有上述所有特征的新型“点击”反应，但有一个重要的附加功能-“点击”产物应该能够在精确定义的条件下自发分解，但生理相关的条件。目前，不存在这样的“点击关闭”过程。这样的创新将为方便地制备功能性生物材料提供许多机会，并在不降解整合的生物成分的情况下触发它们的分解。我们的团队最近观察到，某些锍活化的官能团是开发第一组互补“点击开/关”反应的关键。我们的计划将利用这一发现，并开始优化锍活化官能团的结构，以最大限度地提高“点击”和“点击关闭”反应的效率。所提出的化学反应的一个有趣的方面是，“点击关闭”反应原则上可以由特定细胞群中包含的生物学相关刺激引发。更具体地说，它与慢性炎症、神经退行性疾病和癌症密切相关。因此，我们的计划将寻求验证“点击关闭”可以由这些病变细胞启动，并利用这一知识开发新的响应性药物递送系统。总的来说，这是一个多学科的计划，非常适合使用创新的化学平台培训众多研究生。预计这项工作将在生物技术和制药部门得到应用，我们计划将其转化为当地产业，对加拿大人的生活和福祉产生最大影响。

"Click" reactions selectively couple together two matching functional groups with high efficiency via a physiologically stable chemical bond. Importantly, because "Click" reactions can be performed under mild conditions, they have revolutionized our ability to selectively modify complex molecules of biological origin and prepare functional materials derived thereof. They are therefore both ideal and essential tools within the biotechnological and pharmaceutical sectors. For example, biomolecules are exploited to interface artificial devices with biological fluids (e.g., biosensors) or to influence the function of the body (e.g., therapeutics). Our research program, newly initiated in Canada in 2013, seeks to develop new types of "Click" reactions that possess all of the characteristics above, but with one important added feature - the "Click" product should be able to spontaneously disassemble under precisely defined, yet physiologically-relevant conditions. Currently, no such "Click OFF" process exists. Such an innovation would unbridle numerous opportunities for conveniently preparing functional biomaterials, and triggering their disassembly without degrading the integrated biological component.*** Our group has recently observed that certain sulfonium-activated functional groups are the key to developing a first ever set of complementary "Click ON/OFF" reactions. Our program will capitalize on this discovery and begin optimizing the structure of the sulfonium-activated functional groups to maximize the efficiency of both "Click ON" and "Click OFF" reactions. One interesting aspect of the proposed chemistry is that the "Click OFF" reaction can, in principle, be initiated by a biologically relevant stimulus contained specifically within certain cell populations. More specifically, it is strongly associated with chronic inflammation, neurodegenerative diseases, and cancer. Our program will therefore seek to validate that "Click OFF" can be initiated by such diseased cells, and exploit this knowledge for the development of new lines of responsive drug delivery systems. Overall, this is a multi-disciplinary program that is ideally suited for training numerous graduate students using an innovative chemical platform. Several applications of this work are foreseen in the biotechnological and pharmaceutical sectors, which we plan to translate to local industry for maximal impact on the life and well-being of Canadians.***