CO Releasing Organic Polymers for Biomedical Applications

项目摘要/摘要 在过去的几十年里，一氧化碳(CO)气体显然是一种重要的 对人类健康有很大影响的分子。事实上，一氧化碳是在小浓度下内生产生的， 已被证明是人类神经系统中必不可少的信号分子。此外，一氧化碳气体具有 已被证明是一种有价值的治疗方法，具体地说，它可以缓解急性和慢性炎症，可以 减少器官移植的排斥反应，并可治疗心血管疾病。然而，直接学习或使用 生物系统中的CO本身就很复杂，因为它是一种气体，在水中的溶解度有限，而且是有毒的 在高浓度下。因此，一氧化碳在人体内运行的许多机制和途径 身体仍然难以捉摸。作为对这些并发症的回应，CO释放分子(COMMS)出现了 一类能在外界刺激下释放一氧化碳的物质。因为过渡金属很容易配位 在各种条件下释放和释放CO，这些材料是第一类球茎发育并保留下来的 到目前为止最受欢迎和使用最频繁的。不幸的是，基于过渡金属羰基的球茎 络合物具有细胞毒性，在CO释放后形成定义不明确的产物，不能直接 聚合形成大分子靶向治疗药物。Worrell实验室的研究灵感来自于 当前CORM技术的不足，我们正在积极致力于创建稳定、模块化和高效的 有机CO释放分子。我们的工作主要集中在二苯基环丙烯的类似物上。 (DPCP)，一种独特的稳定的生物正交分子，具有高度应变的三元环。上一首 在小分子环境中的研究表明，DPCP在清洁和高效生产方面是无与伦比的 一氧化碳气体。概念验证演示表明，可以有效地合成DPCP的类似物，可以 可以直接聚合，并且可以通过光解释放CO气体，然而，对于球茎的应用，这必须 在生物系统中被证明。在该计划的五年期间，未来的工作将集中在 DPCP可控聚合方法的研究进展 可溶的、靶向的、无毒的和生物兼容的材料。我们将进一步集中精力改善 通过利用DPCP的独特光物理原理在创建明确定义的同时释放CO的速率和效率 摄影产品。归根结底，这项工作最有影响力的延伸将是它在研究方面的发展 和治疗胃肠道炎症，作为与Colgan/Onyi小组长期合作的一部分， 科罗拉多大学医学院。尽管存在与此相关的重大挑战 该计划的科学影响将是深远的。如果成功，有机球茎将取代基于 过渡金属络合物，刺激基于生产的新靶向治疗药物的发展 一氧化碳气体。

PROJECT SUMMARY/ABSTRACT Over the last several decades it has become apparent that carbon monoxide (CO) gas is an important small molecule that greatly impacts human health. Indeed, CO is created endogenously in small concentrations and has been shown to be an essential signaling molecule in the human neuronal system. Moreover, CO gas has been revealed to be a valuable therapeutic, specifically, it can ameliorate acute and chronic inflammation, can reduce rejection of organ transplants, and can treat cardiovascular diseases. However, the direct study or use of CO in biological systems is inherently complex because it is a gas, has limited solubility in water, and is toxic at high concentrations. As such, many of the mechanisms and pathways by which CO operates in the human body remain elusive. In response to these complications, CO Releasing Molecules (CORMs) have emerged as a class of materials that can release CO in response to an external stimulus. As transition metals readily ligate to and release CO under various conditions, these materials were the first class of CORMs developed and remain the most popular and frequently utilized to date. Unfortunately, CORMs based on transition metal carbonyl complexes are cytotoxic, form poorly defined products following release of CO, and cannot be directly polymerized to form macromolecular targeted therapeutics. Research in the Worrell laboratory is inspired by the shortcomings in current CORM technology, and we are actively engaged in creating stable, modular, and efficient organic CO releasing molecules. Our work has been concentrated on analogs of diphenylcyclopropenone (DPCP), a uniquely stable and bio-orthogonal molecule that features a highly strained 3 membered ring. Previous work in a small molecule setting has shown that DPCP is unrivaled in its ability to cleanly and efficiently produce CO gas. Proof-of-concept demonstrations have shown that analogs of DPCP can be effectively synthesized, can be directly polymerized, and can release CO gas by photolysis, however, for application as a CORM, this must be demonstrated in a biological system. Future work over the five-year course of this program will concentrate on the development of methods for the controlled polymerization of DPCP to create tailored macromolecular materials that are soluble, targeted, non-toxic, and biocompatible. We will further concentrate on improving the rate and efficacy of CO release by leveraging the unique photophysics of DPCPs while creating well-defined photoproducts. Ultimately, the most impactful extension of this work will be related to its development in studying and treating gastrointestinal inflammation as part of a long-term collaboration with the Colgan/Onyiah group at the University of Colorado Medical School. Although there are significant challenges associated with this program, its scientific impacts will be far-reaching. If successful, organic CORMs will supersede those based on transition metal complexes, stimulating the development of new targeted therapeutics based on the production of CO gas.