Wender Paul A, Verma Vishal A, Paxton Thomas J, Pillow Thomas H
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA.
Acc Chem Res. 2008 Jan;41(1):40-9. doi: 10.1021/ar700155p. Epub 2007 Dec 27.
This Account provides an overview and examples of function-oriented synthesis (FOS) and its increasingly important role in producing therapeutic leads that can be made in a step-economical fashion. Biologically active natural product leads often suffer from several deficiencies. Many are scarce or difficult to obtain from natural sources. Often, they are highly complex molecules and thus not amenable to a practical synthesis that would impact supply. Most are not optimally suitable for human therapeutic use. The central principle of FOS is that the function of a biologically active lead structure can be recapitulated, tuned, or greatly enhanced with simpler scaffolds designed for ease of synthesis and also synthetic innovation. This approach can provide practical access to new (designed) structures with novel activities while at the same time allowing for synthetic innovation by target design. This FOS approach has been applied to a number of therapeutically important natural product leads. For example, bryostatin is a unique natural product anticancer lead that restores apoptosis in cancer cells, reverses multidrug resistance, and bolsters the immune system. Remarkably, it also improves cognition and memory in animals. We have designed and synthesized simplified analogs of bryostatin that can be made in a practical fashion (pilot scale) and are superior to bryostatin in numerous assays including growth inhibition in a variety of human cancer cell lines and in animal models. Laulimalide is another exciting anticancer lead that stabilizes microtubules, like paclitaxel, but unlike paclitaxel, it is effective against multidrug-resistant cell lines. Laulimalide suffers from availability and stability problems, issues that have been addressed using FOS through the design and synthesis of stable and efficacious laulimalide analogs. Another FOS program has been directed at the design and synthesis of drug delivery systems for enabling or enhancing the uptake of drugs or drug candidates into cells and tissue. We have generated improved transporters that can deliver agents in a superior fashion compared with naturally occurring cell-penetrating peptides and that can be synthesized in a practical and step-economical fashion. The use of FOS has allowed for the translation of exciting, biologically active natural product leads into simplified analogs with superior function. This approach enables the development of synthetically innovative strategies while targeting therapeutically novel structures.
本综述介绍了面向功能的合成（FOS）及其在以逐步经济的方式生产治疗先导物方面日益重要的作用，并给出了相关示例。具有生物活性的天然产物先导物往往存在若干缺陷。许多天然产物稀缺或难以从天然来源获得。它们通常是高度复杂的分子，因此难以进行能够影响其供应的实际合成。大多数天然产物并非最适合用于人类治疗。FOS的核心原则是，具有生物活性的先导结构的功能可以通过设计用于易于合成和合成创新的更简单支架来重现、调整或大大增强。这种方法可以提供获得具有新活性的新（设计）结构的实际途径，同时通过目标设计实现合成创新。这种FOS方法已应用于许多具有治疗重要性的天然产物先导物。例如，苔藓抑素是一种独特的天然产物抗癌先导物，可恢复癌细胞中的细胞凋亡、逆转多药耐药性并增强免疫系统。值得注意的是，它还能改善动物的认知和记忆。我们已经设计并合成了苔藓抑素的简化类似物，这些类似物可以以实际方式（中试规模）制备，并且在包括多种人类癌细胞系生长抑制和动物模型在内的众多测定中优于苔藓抑素。劳利马肽是另一种令人兴奋的抗癌先导物，它像紫杉醇一样能稳定微管，但与紫杉醇不同的是，它对多药耐药细胞系有效。劳利马肽存在可得性和稳定性问题，通过FOS设计和合成稳定且有效的劳利马肽类似物解决了这些问题。另一个FOS项目致力于设计和合成药物递送系统，以促进或增强药物或候选药物进入细胞和组织的摄取。我们已经生成了改进的转运体，与天然存在的细胞穿透肽相比，它们能够以更优的方式递送药物，并且可以以实际且逐步经济的方式合成。FOS的使用使得令人兴奋的、具有生物活性的天然产物先导物转化为具有更优功能的简化类似物成为可能。这种方法能够在靶向治疗新结构的同时开发合成创新策略。
