文章：

发现和发展癌症治疗的化学方法

Chemical approaches to the discovery and development of cancer therapies

原文发布日期：2005-04-01

DOI: 10.1038/nrc1587

类型: Review Article

开放获取: 否

要点：

1. The diverse roles of chemistry in the discovery of anticancer drugs include not only chemical synthesis, but an understanding of drug–target interactions and of the features of drug molecules that govern uptake and metabolism.
2. The role of chemistry in the development of anticancer drugs began with the mechanism-driven modification and synthesis of the nitrogen mustards.
3. Since the 1950s, several important drugs have been discovered by screening novel organic compounds and natural products using in vitro cell lines.
4. Structural biology and chemistry represent new approaches for discovering anticancer drugs, and are being used to determine the molecular aspects of kinase and protein–protein inhibition.
5. In silico screening can be used to screen large virtual libraries of compounds against the known structure of a target.
6. Molecules are being developed that selectively target a unique DNA sequence to inhibit transcription.
7. Synthetic medicinal chemistry has made important contributions to the development of targeted therapies and prodrugs — otherwise inactive compounds that are converted in tumour cells to active species.
8. Chemistry is essential for transforming 'lead molecules' into drugs. This requires optimizing the distribution, metabolism and excretion properties of a molecule as early as possible in the drug-discovery cycle.

要点翻译：

1. 化学在抗癌药物研发中的多元化作用不仅体现在化学合成领域，更涵盖了对药物-靶点相互作用的理解，以及对调控药物吸收与代谢的分子特性的认知。
2. 化学在抗癌药物发展中的角色始于对氮芥类药物的机制驱动型修饰与合成。
3. 自20世纪50年代以来，通过利用体外细胞系筛选新型有机化合物和天然产物，多个重要药物得以发现。
4. 结构生物学与化学代表了抗癌药物研发的新途径，正被用于揭示激酶抑制和蛋白质-蛋白质相互作用抑制的分子机制。
5. 计算机虚拟筛选技术可针对已知结构的靶点，对大型虚拟化合物库进行筛选。
6. 目前正在开发能够特异性靶向独特DNA序列以抑制转录的分子。
7. 合成药物化学为靶向治疗和前体药物（即在肿瘤细胞内转化为活性物质的原惰性化合物）的发展做出了重要贡献。
8. 化学在将"先导分子"转化为药物的过程中至关重要。这需要在药物发现周期中尽早优化分子的分布、代谢和排泄特性。

英文摘要：

The chemical sciences are essential for the process of anticancer-drug discovery, and a range of chemical research techniques is needed to develop clinically effective drugs. Improved understanding of the cellular, molecular and genetic basis of cancer has increased the number of drug targets available. What chemical approaches are used to develop agents that target specific features of cancer cells and make these therapeutics more effective? We outline the roles that chemical synthesis and understanding of drug uptake have had in drug discovery over the past 100 years, as well as the chemical insights derived from knowledge of the three-dimensional structure of targets.

摘要翻译： 

化学科学在抗癌药物发现过程中至关重要，开发临床有效药物需要一系列化学研究技术。对癌症细胞、分子和遗传基础的深入理解，增加了可供靶向的药物靶点数量。为了开发能够靶向癌细胞特定特征并提高治疗效果的药物，采用了哪些化学方法？我们概述了在过去100年中，化学合成和对药物摄取机制的理解在药物发现中的作用，以及从靶点三维结构知识中获得的化学洞见。

原文链接：

Chemical approaches to the discovery and development of cancer therapies