MOLECULAR MODELLING FOR ORGANOMETALLIC COMPOUNDS: RU-ARENES AS CATALYSTS AND ANTI-CANCER DRUGS

过渡金属系统在催化和生物学中起着重要的作用。对于前者，含金属中心的催化剂广泛用于不对称有机合成。在这里，制备了具有特定手性的分子。控制手性是至关重要的，因为每种形式的分子可能具有截然不同的性质。一种形式可能是特别有效的药物，而另一种形式可能有可怕的副作用。钌化合物的金属与苯或取代苯分子的表面结合，已被证明对将氢转移到羰基的两端以生成相应的手性醇特别有用。有趣的是，非常相似的ru -芳烃化合物已经显示出抗癌活性，并且正在积极研究作为现有金属药物（如顺铂）的潜在替代品。在这两种情况下，重要的是要有一个原子水平的理解如何分子的功能。一方面，我们想知道氢是如何通过C=O键加入的，以及我们如何设计更好的催化剂，另一方面，我们想知道Ru药物是如何与其生物靶DNA相互作用的，以及我们如何设计更好的药物。理论可以为解决这些问题提供有力的工具。然而，对含有过渡金属的系统进行计算机建模是困难的。金属中心往往具有复杂的电子结构，这似乎需要同样复杂的理论方法/特别是量子力学（QM）。这里的问题是，我们感兴趣的分子系统太大、太多，而量子力学（相对）太慢，量子方法无法实现。另一种经典方法，分子力学（MM），要快得多，但需要大量的修改，以便能够处理金属中心。因此，本提案描述了一种扩展MM以促进ru -芳烃系统建模的方案，并与Wills和Sadler的实验组一起，将其应用于不对称氢转移反应和Ru-DNA结合。

Transition metal systems play many vital roles in catalysis and biology. For the former, catalysts containing metal centres are used extensively for asymmetric organic synthesis. Here, molecules with specific chirality are prepared. Control over the chirality is critical as each form of the molecule may have dramatically different properties. One form may be a particularly efficacious pharmaceutical while the other may have dire side effects. Ruthenium compounds where the metal is bound to the face of a benzene or substituted benzene molecule have proved particularly useful for transferring hydrogen to both ends of a carbonyl group to generate the corresponding chiral alcohol. Interestingly, very similar Ru-arene compounds have shown anti-cancer activity and are being actively studied as potential replacements for existing metallodrugs such as cisplatin. In both cases, it is important to have a atomic-level understanding of how the molecules function. On the one hand, we want to know the intimate details of how hydrogen adds across the C=O bond and how we might design even better cataylsts while, on the other, we want to know how the Ru drug interacts with its biological target DNA and how we might design better drugs. Theory can provide a powerful tool for addressing these issues. However, computer modelling of systems containing transition metals is difficult. Metal centres tend to have complicated electronic structures which appear to demand an equally complicated theoretical method / specifically quantum mechanics (QM). The problem here is that the molecular systems we are interested in are too large and too numerous and QM is (relatively) too slow for a quantum approach to be viable. The alternative classical approach, molecular mechanics (MM), is much faster but requires extensive modification in order to be able to deal with metal centres. Hence, this proposal describes a scheme for extending MM to facilitate modelling Ru-arene systems and, in conjunction with the experimental groups of Wills and Sadler, its application to asymmetric hydrogen transfer reactions and Ru-DNA binding.