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Discovery of small molecule probes for chemical genetics using biased and unbiased diversity-oriented organic synthesis.

机译：使用有偏和无偏的面向多样性的有机合成发现用于化学遗传学的小分子探针。

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摘要

While natural products are enormously diverse, often complex, and frequently useful as probes of biological systems, nonnatural molecules attainable through modern synthetic methodology have the potential to complement, and even improve upon, the diversity and utility of natural products. In order to access this nonnatural chemical diversity efficiently and comprehensively, a new approach to organic synthesis, known as diversity-oriented synthesis (DOS) has been undertaken in recent years. In contrast to target-oriented synthesis (TOS), where pathway development is guided by retrosynthetic analysis of a specific molecular target, pathway development in DOS is guided primarily by the ideal of generating, in an efficient manner, collections of complex molecules that are maximally different from one another. Toward this ideal, herein is described the modular, split-pool synthesis of over 34,000 enantio-enriched 1,3-dioxanes having a diverse set of stereochemically distinct skeletons. The majority of these molecules were constructed in a purely unbiased manner, that is, no particular realm of biology or preexisting natural products guided their design. Evaluation of these unbiased molecules in both protein-binding and phenotypic assays led to the discovery of a calmodulin binding element and a potent, reversible inhibitor of cardiomyocyte function, respectively. In comparison, a portion of these molecules was designed to have in-cell inhibitory activity toward the histone deacetylases (HDACs), a family of zinc-dependent hydrolases which have emerged as multifunctional members of multiprotein complexes involved in an array of biological processes. In particular, dioxane structural diversity was targeted toward the region of greatest genetic diversity among the HDAC active sites, in order to overcome a current limitation of all known natural and synthetic HDAC inhibitors, which is that they cannot discriminate among individual HDAC family members. Phenotypic screening of these molecules led to the discovery of the first HDAC inhibitor with unprecedented selectivity for an individual HDAC family member, demonstrating the power of DOS to complement, and improve upon, small molecules available in nature. Detailed biological characterization and molecular imaging of this molecule provided insights into the structural basis for its selectivity as well as facilitated the functional dissection of its multifunctional intracellular target, HDAC6.
机译：尽管天然产物种类繁多，通常很复杂并且经常用作生物系统的探针，但通过现代合成方法可获得的非天然分子有潜力补充甚至改善天然产物的多样性和实用性。为了有效和全面地利用这种非天然化学多样性，近年来已经采取了一种新的有机合成方法，即面向多样性的合成（DOS）。与目标导向的合成（TOS）相比，通过特定分子目标的逆向合成分析来指导途径发展，而DOS中的途径发展主要是以有效地生成最大程度地收集复杂分子集合的理想为指导。彼此不同。为了达到这一理想，本文描述了超过34,000种对映体富集的1,3-二恶烷的模块化，分池合成，这些化合物具有多种立体化学不同的骨架。这些分子中的大多数都是以纯无偏的方式构建的，也就是说，没有特定的生物学领域或预先存在的天然产物指导它们的设计。在蛋白质结合和表型分析中对这些无偏分子的评估分别导致钙调蛋白结合元件和强力，可逆的心肌细胞功能抑制剂的发现。相比之下，这些分子的一部分被设计为对组蛋白脱乙酰基酶（HDACs）具有细胞内抑制活性，组蛋白脱乙酰基酶是一系列依赖锌的水解酶，已成为涉及一系列生物过程的多蛋白复合物的多功能成员。尤其是，二恶烷结构多样性的目标是HDAC活性位点之间最大的遗传多样性区域，以克服目前所有已知的天然和合成HDAC抑制剂的局限性，即它们无法区分各个HDAC家族成员。通过对这些分子的表型筛选，发现了第一个对单个HDAC家族成员具有空前选择性的HDAC抑制剂，这证明了DOS可以补充并改善自然界中可用的小分子。该分子的详细生物学特性和分子成像为深入了解其选择性提供了结构基础，并促进了其多功能细胞内靶标HDAC6的功能分离。

著录项

  • 作者

    Wong, Jason Christopher.;

  • 作者单位

    Harvard University.;

  • 授予单位 Harvard University.;
  • 学科 Chemistry Organic.; Chemistry Biochemistry.; Biology Cell.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 219 p.
  • 总页数 219
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 有机化学;生物化学;细胞生物学;
  • 关键词

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