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

过渡金属体系在催化和生物学中起着重要的作用。对于前者，含有金属中心的催化剂被广泛用于不对称有机合成。在这里，制备具有特定手性的分子。对手性的控制是至关重要的，因为每种形式的分子可能具有显著不同的性质。一种形式可能是特别有效的药物，而另一种可能具有可怕的副作用。钌化合物（其中金属结合到苯或取代的苯分子的表面）已被证明特别适用于将氢转移到羰基的两端以产生相应的手性醇。有趣的是，非常相似的Ru-芳烃化合物已显示出抗癌活性，并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级的理解分子如何运作。一方面，我们想知道氢如何在C=O键上加成的细节，以及我们如何设计更好的催化剂，而另一方面，我们想知道Ru药物如何与其生物靶DNA相互作用，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强有力的工具。然而，含有过渡金属的系统的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，数量太多，量子力学（相对）太慢，量子方法是可行的。另一种经典的方法，分子力学（MM），要快得多，但需要广泛的修改，以便能够处理金属中心。因此，该提案描述了一个计划，用于扩展MM，以方便建模Ru-芳烃系统，并结合威尔斯和萨德勒的实验组，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.