Organometallic anticancer compounds.
Organometallic anticancer compounds.
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有机金属抗癌化合物。
DOI：
10.1021/jm100020w
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发表时间：
2011-01-13
影响因子：
7.3
通讯作者：
Metzler-Nolte N
中科院分区：
文献类型：
--
作者：
Gasser G;Ott I;Metzler-Nolte N
非常需要寻求众所周知的顺铂及其衍生物的替代药物，顺铂及其衍生物仍用于超过50%的癌症患者的治疗方案中。1，2尽管它们取得了巨大的成功，但这些铂化合物存在两个主要缺点：它们对铂耐药肿瘤无效，并且它们具有严重的副作用，如肾毒性。后一个缺点是这些药物的最终靶点是普遍存在的事实的结果：人们普遍认为铂抗癌药物靶向DNA，DNA存在于所有细胞中。此外，由于其特殊的化学结构，顺铂特别是提供合理改进以增加其肿瘤特异性并从而减少不希望的副作用的可能性很小。在这种情况下，有机金属化合物，其被定义为含有至少一个直接的，共价的金属-碳键的金属配合物，最近被发现是有前途的抗癌药物候选物。有机金属化合物具有很大的结构多样性（从线性到八面体甚至更大），具有比有机化合物更多样化的立体化学（对于具有六种不同配体的八面体络合物，存在30种立体异构体！），并通过合理的配体设计，提供对关键动力学性质（例如配体的水解速率）的控制。此外，它们是动力学稳定的，通常不带电荷，并且相对亲脂，并且它们的金属原子处于低氧化态。由于与“经典配位金属络合物”相比这些根本差异，有机金属化合物在设计新型药物化合物方面提供了充足的机会，可能具有新的金属特异性作用模式。有趣的是，所有典型类别的有机金属化合物，如双烯，半夹心，卡宾，CO或π-配体，已广泛用于催化或生物传感目的，现在也发现在药物化学中的应用（见图1这些典型类别的有机金属化合物的概述）。在这个角度来看，我们报告的最新进展，发现有机金属与证明抗增殖活性。我们强调那些已经通过生物化学或细胞生物学研究努力确定其分子靶点和作用模式的化合物。这一观点涵盖了更多的化合物类别，比Hartinger和Dyson最近的教程评论更详细。5此外，尽管最近的评论和书籍的贡献证明了生物有机金属化学的快速发展，6，7这一观点的重点是它们作为抗癌化疗药物的潜在应用。另一篇最近的综述文章根据作用模式对无机抗癌候选药物进行了分类。[8]应当指出，在一份简明的综述中，几乎不可能对目前研究的所有类型的化合物进行全面描述。例如，一类特别有前途的有机金属抗癌化合物，即放射性标记的有机金属化合物，由于篇幅限制而被省略。Alberto详细综述了这类化合物的最新进展。9
The quest for alternative drugs to the well-known cisplatin and its derivatives, which are still used in more than 50% of the treatment regimes for patients suffering from cancer, is highly needed. 1, 2 Despite their tremendous success, these platinum compounds suffer from two main disadvantages: they are inefficient against platinum-resistant tumors, and they have severe side effects such as nephrotoxicity. The latter drawback is the consequence of the fact that the ultimate target of these drugs is ubiquitous: It is generally accepted that Pt anticancer drugs target DNA, which is present in all cells. 3, 4 Furthermore, as a consequence of its particular chemical structure, cisplatin in particular offers little possibility for rational improvements to increase its tumor specificity and thereby reduce undesired side effects. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct, covalent metal-carbon bond, have recently been found to be promising anticancer drug candidates. Organometallics have a great structural variety (ranging from linear to octahedral and even beyond), have far more diverse stereochemistry than organic compounds (for an octahedral complex with six different ligands, 30 stereoisomers exist!), and by rational ligand design, provide control over key kinetic properties (such as hydrolysis rate of ligands). Furthermore, they are kinetically stable, usually uncharged, and relatively lipophilic and their metal atom is in a low oxidation state. Because of these fundamental differences compared to “classical coordination metal complexes”, organometallics offer ample opportunities in the design of novel classes of medicinal compounds, potentially with new metal-specific modes of action. Interestingly, all the typical classes of organometallics such as metallocenes, half-sandwich, carbene-, CO-, or π-ligands, which have been widely used for catalysis or biosensing purposes, have now also found application in medicinal chemistry (see Figure 1 for an overview of these typical classes of organometallics). In this Perspective, we report on the recent advances in the discovery of organometallics with proven antiproliferative activity. We are emphasizing those compounds where efforts have been made to identify their molecular target and mode of action by biochemical or cell biology studies. This Perspective covers more classes of compounds and in more detail than a recent tutorial review by Hartinger and Dyson. 5 Furthermore, whereas recent reviews and book contributions attest to the rapid development of bioorganometallic chemistry in general, 6, 7 this Perspective focuses on their potential application as anticancer chemotherapeutics. Another very recent review article categorizes inorganic anticancer drug candidates by their modes of action. 8 It should be mentioned that a full description of all currently investigated types of compounds is hardly possible anymore in a concise review. For example, a particularly promising class of organometallic anticancer compounds, namely, radiolabeled organometallics, has been omitted for space limitations. Recent developments of such compounds have been reviewed in detail by Alberto. 9
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影响因子：
4
作者：
Alberto, Roger;Motterlini, Roberto
通讯作者：
Motterlini, Roberto
影响因子：
4.9
作者：
Biot, Christophe;Taramelli, Donatella;Egan, Timothy J.
通讯作者：
Egan, Timothy J.
影响因子：
2.8
作者：
Arezki, Anusch;Brule, Emilie;Jaouen, Gerard
通讯作者：
Jaouen, Gerard
影响因子：
8.8
作者：
Aird, R E;Cummings, J;Ritchie, A A;Muir, M;Morris, R E;Chen, H;Sadler, P J;Jodrell, D I
通讯作者：
Jodrell, D I
影响因子：
4.3
作者：
Buriez, Olivier;Heldt, Jan Martin;Amatore, Christian
通讯作者：
Amatore, Christian