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

有机金属化合物的分子建模：作为催化剂和抗癌药物的 RU-芳烃

基本信息

批准号：
EP/F042159/1
负责人：
Robert James Deeth
金额：
$ 39.47万
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2009
资助国家：
英国
起止时间：
2009 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FF042159%2F1
关键词：
MOLECULAR MODELLING ORGANOMETALLIC COMPOUNDS RU

项目摘要

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.

过渡金属系统在催化和生物学中发挥着许多重要作用。对于前者，含有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。对手性的控制至关重要，因为每种形式的分子可能具有显着不同的特性。一种形式可能是特别有效的药物，而另一种形式可能具有可怕的副作用。金属键合到苯或取代苯分子表面的钌化合物已被证明对于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，非常相似的钌芳烃化合物已显示出抗癌活性，并且正在积极研究作为现有金属药物（例如顺铂）的潜在替代品。在这两种情况下，从原子层面了解分子的功能非常重要。一方面，我们想知道氢如何通过 C=O 键添加的详细信息，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标 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有力的工具。然而，对含有过渡金属的系统进行计算机建模很困难。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，量子方法不可行。另一种经典方法是分子力学 (MM)，速度要快得多，但需要进行大量修改才能处理金属中心。因此，该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的实验组结合，将其应用于不对称氢转移反应和Ru-DNA结合。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A novel dual-functioning ruthenium(II)-arene complex of an anti-microbial ciprofloxacin derivative - Anti-proliferative and anti-microbial activity.

抗微生物环丙沙星衍生物的新型双功能钌 (II)-芳烃复合物 - 抗增殖和抗微生物活性。

DOI：
10.1016/j.jinorgbio.2016.02.018
发表时间：
2016
期刊：
Journal of inorganic biochemistry
影响因子：
3.9
作者：
Ude Z
通讯作者：
Ude Z

Comprehensive Vibrational Spectroscopic Investigation of trans,trans,trans-[Pt(N3)2(OH)2(py)2], a Pt(IV) Diazido Anticancer Prodrug Candidate.

DOI：
10.1021/acs.inorgchem.6b00476
发表时间：
2016-06-20
期刊：
Inorganic chemistry
影响因子：
4.6
作者：
Vernooij RR;Joshi T;Shaili E;Kubeil M;Appadoo DR;Izgorodina EI;Graham B;Sadler PJ;Wood BR;Spiccia L
通讯作者：
Spiccia L