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

可调节的有机金属和有机一氧化碳 (CO) 释放分子：控制 CO 释放的速率和程度

基本信息

批准号：
EP/E005152/1
负责人：
Ian Fairlamb
金额：
$ 12.35万
依托单位：
University of York
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2006
资助国家：
英国
起止时间：
2006 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FE005152%2F1
关键词：
Tuneable organometallic organic carbon monoxide

项目摘要

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.

现在有令人信服的证据表明，一氧化碳（CO），汽车尾气产生的有毒气体的鸡尾酒之一，促进显着的生物效应时，在低浓度管理。这些令人惊讶的效果得到了研究结果的支持，即CO是由体内的一些细胞产生的，它似乎在体内发挥着奇怪但明确的有益作用。我们呼吸中产生的CO气体是我们健康程度的指标，而CO浓度越高，表明人体处于压力之下。从本质上讲，人们认为CO被体内的关键过程用于预防疾病。这一点得到了CO具有一些显著性质的事实的支持。例如，一氧化碳已被证明可以抑制移植心脏的排斥反应，它具有有效的抗炎作用，并在心脏移植过程中促进对组织损伤的保护。在涉及大鼠心脏移植的研究中，那些暴露于低浓度CO气体的动物的寿命增加了8倍，相对于没有施用CO的相同实验，这一有希望的发现本身就说明了需要在更大的范围内研究人类已知的最简单的治疗剂。虽然CO的临床效果因此具有明显的益处，但以其裸露形式（作为气体）吸入CO代表着显著的风险。为了帮助以更安全的方式管理CO，已经进行了涉及含有CO的分子的研究，这些分子随后将低浓度的气体释放到体内。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CORM将显著有助于理解CO效应的起源。第一代CORM仅仅涉及CO和金属（通常是铁或锰），我们通过对一些含有铁，一氧化碳和一个称为2-吡喃酮的新分子的不良溶液稳定性的关键观察而参与了这个迷人的领域。这一特性导致了这些物种的CO释放能力的检查，这被证明是非常有前途的。以及释放控制量的CO在低浓度下，它出现的2-吡喃酮的结构的小的变化调制的CO释放的速率和程度。这使我们设计出一个概念，即CORM结构内的这些细微变化可以用于调谐CORM的CO释放特性，以便能够识别CO的“快”和“慢”释放者。可以想象在无线电接收器上移动调谐拨盘/使用不同的频率给出不同的频道。从本质上讲，我们希望创建一个可调的CORM库，以探测用快速和慢速CO释放剂观察到的差异生物效应。我们将使用生物和化学技术相结合，以评估CO释放的速度和程度。重要的是，建立的物理参数将预测的CO释放能力的新类别的CORM，使用的方法被称为一个预测导向的发现策略或PODS。我们还计划探索使用过渡金属自由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，但也已知各种有机结构含有可以在某些条件下通过所谓的脱羰基反应挤出（释放）的CO。因此，我们计划准备有机CORM，以评估其CO释放能力，并比较其效果（有益的和毒理学）与过渡金属为基础的CORM。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Group 6 carbon monoxide-releasing metal complexes with biologically-compatible leaving groups.

DOI：
10.1021/ic101230j
发表时间：
2010-10
期刊：
Inorganic chemistry
影响因子：
4.6
作者：
Wei-Qiang Zhang;A. Whitwood;I. Fairlamb;Jason M. Lynam
通讯作者：
Wei-Qiang Zhang;A. Whitwood;I. Fairlamb;Jason M. Lynam

Diversity and design of metal-based carbon monoxide-releasing molecules (CO-RMs) in aqueous systems: revealing the essential trends.

DOI：
10.1039/b822157j
发表时间：
2009-05
期刊：
Dalton transactions
影响因子：
4
作者：
Wei-Qiang Zhang;Anthony J. Atkin;R. Thatcher;A. Whitwood;I. Fairlamb;Jason M. Lynam
通讯作者：
Wei-Qiang Zhang;Anthony J. Atkin;R. Thatcher;A. Whitwood;I. Fairlamb;Jason M. Lynam

Synthesis and Reactivity of Molybdenum Complexes Containing Functionalized Alkynyl Ligands: A Photochemically Activated CO-Releasing Molecule (PhotoCO-RM)