Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates.
Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates.
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DOI：
10.1002/med.21377
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发表时间：
2016-01
影响因子：
13.3
通讯作者：
Lee KH
中科院分区：
文献类型：
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作者：
Xiao Z;Morris-Natschke SL;Lee KH
在过去的几十年里，天然产物对癌症化疗做出了重大贡献，并且仍然是抗癌药物发现的分子和机制多样性的不可或缺的来源。通常情况下，天然产物可以作为进一步药物开发的先导，而不是作为有效的抗癌药物本身。通常，将天然先导化合物优化为抗癌药物或候选药物不仅应解决药物功效，而且还应改善与天然先导化合物相关的ADMET特征和化学可及性。优化策略包括功能基团的直接化学操作、构效关系导向的优化和基于天然模板的药效团导向的分子设计。两种基本的药物化学原理（例如，生物电子等排）和现有技术的计算机辅助药物设计技术（例如，基于结构的设计）可以被应用以促进优化工作。在这篇综述中，策略，以优化天然导致抗癌药物或药物候选人举例说明，并根据其目的进行描述。此外，成功的案例研究铅优化的生物活性化合物进行的天然产品研究实验室在ESTA强调。
Natural products have made significant contribution to cancer chemotherapy over the past decades and remain an indispensable source of molecular and mechanistic diversity for anticancer drug discovery. More often than not, natural products may serve as leads for further drug development rather than as effective anticancer drugs by themselves. Generally, optimization of natural leads into anticancer drugs or drug candidates should not only address drug efficacy, but also improve ADMET profiles and chemical accessibility associated with the natural leads. Optimization strategies involve direct chemical manipulation of functional groups, structure-activity relationship-directed optimization and pharmacophore-oriented molecular design based on the natural templates. Both fundamental medicinal chemistry principles (e.g., bio-isosterism) and state-of-the-art computer-aided drug design techniques (e.g., structure-based design) can be applied to facilitate optimization efforts. In this review, the strategies to optimize natural leads to anticancer drugs or drug candidates are illustrated with examples and described according to their purposes. Furthermore, successful case studies on lead optimization of bioactive compounds performed in the Natural Products Research Laboratories at UNC are highlighted.