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

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Discovery of small molecule probes for chemical genetics using biased and unbiased diversity-oriented organic synthesis.
作者:	Wong, Jason Christopher.
面頁冊數:	219 p.
附註:	Adviser: Stuart L. Schreiber.
附註:	Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2427.
Contained By:	Dissertation Abstracts International65-05B.
標題:	Chemistry, Organic.
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3132029
ISBN:	0496792695

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

Discovery of small molecule probes for chemical genetics using biased and unbiased diversity-oriented organic synthesis.[electronic resource] - 219 p.

Adviser: Stuart L. Schreiber.

Thesis (Ph.D.)--Harvard University, 2004.

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.

ISBN: 0496792695Subjects--Topical Terms:

193634
Chemistry, Organic.

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