Abstract/Details

Diversity-oriented synthesis of biaryl -containing medium rings for chemical genetic studies


2004 2004

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Abstract (summary)

The chemical genetic approach employs small molecules to modulate the functions of proteins in order to elucidate their roles in biological processes. The use of small molecules contrasts with a genetic approach that relies on mutations in the gene encoding the protein of interest. Protein binding small molecules can rapidly and conditionally activate or deactivate their target proteins or disrupt protein-protein interactions. The discovery of small molecules that bind to their protein targets with high affinity and specificity is central to the chemical genetic approach. Diversity-oriented synthesis allows the synthesis of large numbers of structurally complex and diverse small molecules, which can then be screened in forward or reverse chemical genetic assays to discover small molecules that modulate protein function.

This thesis describes the development of synthetic methods in solution as well as on solid support towards the efficient, stereoselective synthesis of biaryl-containing medium rings. The synthesis of an unbiased 1,412 member library was carried out by split-pool synthesis on solid phase using a one bead/one stock solution technology platform. Evaluation of the molecules synthesized in phenotypic assays led to the discovery of potent small molecule modulators of zebrafish embryonic development. Plant development assays in Arabidopsis led to the discovery of a small molecule modulator of plant development. Chemical genetic modifier screens in yeast led to the discovery of small molecules that allow yeast to grow in the presence of anti-mitotics that disrupt the actin cytoskeleton and depolymerize microtubules. In many cases the biological activity of the biaryl-containing medium rings was found to be strongly dependent on the stereochemistry about the dissymmetric biaryl axis.

This thesis also describes the diversity-oriented synthesis of a library of stereochemically diverse nine membered biaryl-containing medium rings. This synthesis was carried out in parallel on solid phase and revealed new facets of the atropisomerism exhibited by these molecules. Approaches to dimeric molecules were explored and a novel synthetic route to bis-macrocycles via a double-cyclization was demonstrated in solution.

Indexing (details)


Subject
Organic chemistry
Classification
0490: Organic chemistry
Identifier / keyword
Pure sciences; Atropisomerism; Biaryl; Medium rings
Title
Diversity-oriented synthesis of biaryl -containing medium rings for chemical genetic studies
Author
Krishnan, Shyam
Number of pages
294
Publication year
2004
Degree date
2004
School code
0084
Source
DAI-B 65/10, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780496094226, 049609422X
Advisor
Schreiber, Stuart L.
University/institution
Harvard University
University location
United States -- Massachusetts
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3149563
ProQuest document ID
305190540
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/305190540
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