Tuneable organometallic and organic carbon monoxide (CO) releasing molecules: controlling the rate and extent of CO release

现在有令人信服的证据表明，一氧化碳（CO），一种由汽车尾气产生的有毒气体混合物，在低浓度下可以促进显著的生物效应。这些令人惊讶的效果得到了一些发现的支持，即CO是由体内的一些细胞产生的，在这些细胞中，CO似乎发挥了一种奇怪但明确的有益作用。我们呼吸中CO气体的产生是我们健康状况的一个指标，高浓度的CO表明人体处于压力之下。从本质上讲，人们认为一氧化碳在体内的关键过程中被用来预防疾病。一氧化碳具有一些显著的性质，这一事实支持了这一观点。例如，一氧化碳已被证明可以抑制移植心脏的排斥反应，它具有强大的抗炎作用，并在心脏移植过程中促进对组织损伤的保护。在对老鼠进行心脏移植的研究中，那些暴露在低浓度一氧化碳气体中的动物的寿命比没有施用一氧化碳的相同实验增加了8倍。这一有希望的发现本身就说明了研究人类已知的最简单的治疗剂的必要性。因此，尽管一氧化碳的临床效果有明显的好处，但吸入其裸露形式的一氧化碳（作为气体）代表着重大的风险。为了帮助以更安全的方式管理一氧化碳，已经进行了涉及含有一氧化碳的分子的研究，这些分子随后会向体内释放低浓度的气体。这些CO载体分子被称为CO释放分子或corm。为了充分探索CO的生物学功能及其作为治疗剂的可能性，目前认为CORMs将有助于了解CO效应的起源。第一代corm仅涉及CO和金属（通常是铁或锰），我们通过对一些含有铁，一氧化碳和2-吡酮的新分子的溶液稳定性差的关键观察而参与到这个迷人的领域。这一特性导致了对这些物种CO释放能力的研究，结果表明这是非常有希望的。除了在低浓度下释放可控数量的CO外，2-吡啶酮结构的微小变化似乎还调节了CO释放的速度和程度。这导致我们设计了一个概念，即CORM结构中的这些细微变化可用于调整CORM的CO释放特性，以便能够识别CO的“快速”和“慢速”释放。可以想象移动无线电接收器上的调谐盘/具有不同频率的不同频道。从本质上讲，我们希望创建一个可调的corm库，以探索快速和慢速CO释放剂所观察到的差异生物学效应。我们将结合使用生物和化学技术来评估二氧化碳释放的速度和程度。重要的是，已建立的物理参数将使用一种称为面向预测的发现策略（pod）的方法来预测新型corm的CO释放能力。我们还计划探索使用过渡金属无CO释放分子。虽然含金属的CO源可以说是目前携带和运输CO的最佳方式，但已知各种有机结构也含有CO，这些CO可能在特定条件下通过所谓的脱碳反应被挤出（释放）。因此，我们计划制备有机corm，以评估其CO释放能力，并将其与过渡金属基corm的效果（有益和毒理学）进行比较。

There is now convincing evidence that carbon monoxide (CO), one of the cocktail of toxic gases produced by car exhausts, promotes remarkable biological effects when administered at low concentration. These surprising effects are supported by findings that CO is made by some cells in the body, where it appears to play a curious but clear beneficial role. The production of CO gas in our breath is an indicator for how healthy we are and higher concentrations of CO shows that the human body is under stress. Essentially, it is believed that CO is used by key processes within the body to protect against disease. This is supported by the fact that CO possesses some remarkable properties. For example, CO has been shown to suppress the rejection of transplanted hearts, it has potent anti-inflammatory effect, and promotes protection against tissue injury during heart transplant. In studies involving heart transplants in rats, those animals that had been exposed to low concentrations of CO gas had an eight-fold increase in their lifetime, relative to the same experiment without administered CO. This promising finding alone illustrates the need to study in much greater arguably the simplest therapeutic agent known to mankind. Although the clinical effects of CO are therefore of a clear benefit, breathing in CO in its naked form (as a gas) represents a significant risk. To help administer CO in a safer way, studies involving molecules containing CO that subsequently release low concentrations of the gas into the body have been performed. These CO carrier molecules have been termed CO releasing molecules or CORMs. To fully explore the biological function of CO, and its possibilities as a therapeutic agent, it is currently believed that CORMs will significantly help to understand the origin(s) of CO effects. The first generation of CORMs simply involve CO and a metal (typically either iron or manganese), we became involved in this fascinating area through key observations about the poor solution stability of some novel molecules containing the iron, carbon monoxide and a group called 2-pyrone. This property led to an examination of the CO releasing ability of these species, which turned out to be very promising. As well as releasing controlled quantities of CO at low concentration, it appears that small variations in structure of the 2-pyrone modulated the rate and extent of CO release. This led us to devise a concept that these subtle variations within the structure of CORMs could be used for tuning the CO-release properties of the CORM with a view to been able to identifying 'fast' and 'slow' releasers of CO. One can imagine shifting the tuning dial on a radio receiver / with different frequencies giving different channels. In essence, we wish to create a tuneable library of CORMs, to probe the differential biological effects observed with fast and slow CO releasers. We will use a combination of biological and chemical techniques to assess the rate and extent of CO release. Importantly, established physical parameters will predict the CO releasing ability of the new classes of CORMs, using an approach referred to as a predictive-orientated-discovery-strategy or PODS.We also plan to explore the use of transition metal-free CO releasing molecules. Although metal-continaing CO sources are arguably the best way to carry and transport CO at the present time, various organic structures are also known to contain CO that may be extruded (released) under certain conditions via what is known as a decarbonylation reaction. Thus, we plan to prepare organic CORMs with a view to assessing their CO releasing capacity and to comparing their effects (beneficial and toxicological) with those of transition metal-based CORMs.