Anticancer metallodrugs based on ruthenium and osmium are among the most investigated and advanced non-platinum metallodrugs. Inorganic drug discovery with these agents has undergone considerable advances over the past two decades and has currently two representatives in active clinical trials. As many ruthenium and osmium metallodrugs are prodrugs, a key question to be addressed is how the molecular reactivity of such metal-based therapeutics dictates the selectivity and the type of interaction with molecular targets. Within this frame, this review introduces the field by the examples of the most advanced ruthenium lead structures. Then, global structure–activity relationships are discussed for ruthenium and osmium metallodrugs with respect to in vitro antiproliferative/cytotoxic activity and in vivo tumor-inhibiting properties, as well as pharmacokinetics. Determining and validating global mechanisms of action and molecular targets are still major current challenges. Moreover, significant efforts must be invested in screening in vivo tumor models that mimic human pathophysiology to increase the predictability for successful preclinical and clinical development of ruthenium and osmium metallodrugs.

中文翻译：

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钌和抗癌药的结构-活性关系–走向临床发展

基于钌和的抗癌金属药物是研究最多的高级非铂金属药物之一。在过去的二十年中，使用这些药物的无机药物发现取得了长足的进步，目前有两名代表参与了积极的临床试验。由于许多钌和金属药物是前药，因此需要解决的关键问题是这种基于金属的疗法的分子反应性如何决定选择性和与分子靶标相互作用的类型。在此框架内，本文以最先进的钌铅结构为例介绍了该领域。然后，讨论了钌和金属药物在体外抗增殖/细胞毒性活性和体内的肿瘤抑制特性以及药代动力学。确定和验证整体作用机制和分子靶标仍然是当前的主要挑战。而且，必须投入大量的努力来筛选模仿人类病理生理学的体内肿瘤模型，以提高钌和金属药物的成功临床前和临床开发的可预测性。