Metallodrugs are unique: opportunities and challenges of discovery and development.
Metallodrugs are unique: opportunities and challenges of discovery and development.
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DOI：
10.1039/d0sc04082g
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发表时间：
2020-11-12
期刊：
影响因子：
8.4
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Anthony EJ;Bolitho EM;Bridgewater HE;Carter OWL;Donnelly JM;Imberti C;Lant EC;Lermyte F;Needham RJ;Palau M;Sadler PJ;Shi H;Wang FX;Zhang WY;Zhang Z
金属在营养素和药物中起着至关重要的作用，并提供纯有机化合物无法获得的化学功能。至少有10种金属是人类生命所必需的，大约46种其他非必需金属（包括放射性核素）也用于药物治疗和诊断剂。这些药物包括铂类药物（50%的癌症化疗药物）、锂（双相情感障碍）、银（抗菌剂）和铋（广谱抗生素）。虽然对新型和更好药物的追求现在和以往一样紧迫，但为有机药物建立的药物发现和开发管道，以及基于目标识别和化合物库的高通量筛选，在应用于金属药物时效果不太好。金属药物通常是通过配体取代或氧化还原反应进行活化的前药，并且是多靶向的，在建立结构-活性关系时需要考虑所有这些。我们专注于早期阶段的体外药物发现，强调在培养细胞中评估抗癌，抗菌和抗病毒金属药效团的挑战，并确定其目标。我们强调了金属特异性技术的应用进展，这些技术可以帮助临床前开发，包括同步加速器X射线光谱（显微镜），发光和基于质谱的方法，结合蛋白质组学和基因组学（金属组学）方法。深入了解金属和金属药物在生物系统中的行为不仅是设计具有独特作用机制的新型药物的关键，也是对临床药物的新理解。金属在营养和药物中的重要作用是纯有机化合物所无法达到的。
Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure–activity relationships. We focus on early-stage in vitro drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs. The vital roles of metals in nutrients and medicines are not accessible to purely organic compounds.
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影响因子：
5.8
作者：
Bains, Simer J.;Abrahamsson, Hanna;Ree, Anne Hansen
通讯作者：
Ree, Anne Hansen
DOI：
10.1007/s00259-017-3643-2
发表时间：
2017-08-01
影响因子：
9.1
作者：
Aalbersberg, E. A.;de Wit-van der Veen, B. J.;Vogel, Wouter V.
通讯作者：
Vogel, Wouter V.
影响因子：
16.6
作者：
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通讯作者：
Sadler, Peter J.
影响因子：
3.2
作者：
Akshintala, Srivandana;Marcus, Leigh;Widemann, Brigitte C.
通讯作者：
Widemann, Brigitte C.
影响因子：
2
作者：
Alexander, J. Wesley
通讯作者：
Alexander, J. Wesley