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The synthesis and biologic evaluation of exhaustively stereodiversified libraries of acyclic 1,5-enediols.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The synthesis and biologic evaluation of exhaustively stereodiversified libraries of acyclic 1,5-enediols.
Author:	Harrison, Bryce Alden.
Description:	174 p.
Notes:	Adviser: Gregory L. Verdine.
Notes:	Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0213.
Contained By:	Dissertation Abstracts International64-01B.
Subject:	Chemistry, Organic.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3076891
ISBN:	0493973532

The synthesis and biologic evaluation of exhaustively stereodiversified libraries of acyclic 1,5-enediols.
Harrison, Bryce Alden.

The synthesis and biologic evaluation of exhaustively stereodiversified libraries of acyclic 1,5-enediols. [electronic resource] - 174 p.

Adviser: Gregory L. Verdine.

Thesis (Ph.D.)--Harvard University, 2003.

The discovery of biologically active small molecules often is achieved by preparing libraries of chemically diverse molecules and screening these libraries for compounds with the desired biologic properties. Due to synthetic considerations, many libraries achieve diversity by attaching varied functional groups to a fixed cyclic scaffold. Although these libraries achieve a high level of structural diversity, the functional groups in all library members have the same geometric orientation, perhaps limiting the functional diversity of the library. Consequently, we wanted to investigate a complementary approach to library design in which stereochemical diversity of densely branched, acyclic molecules was used to generate libraries with high geometric diversity.

ISBN: 0493973532Subjects--Topical Terms:

193634
Chemistry, Organic.

The synthesis and biologic evaluation of exhaustively stereodiversified libraries of acyclic 1,5-enediols.
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100 $a Harrison, Bryce Alden. $3 226915
245 1 4 $a The synthesis and biologic evaluation of exhaustively stereodiversified libraries of acyclic 1,5-enediols. $h [electronic resource]
300 $a 174 p.
500 $a Adviser: Gregory L. Verdine.
500 $a Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0213.
502 $a Thesis (Ph.D.)--Harvard University, 2003.
520 $a The discovery of biologically active small molecules often is achieved by preparing libraries of chemically diverse molecules and screening these libraries for compounds with the desired biologic properties. Due to synthetic considerations, many libraries achieve diversity by attaching varied functional groups to a fixed cyclic scaffold. Although these libraries achieve a high level of structural diversity, the functional groups in all library members have the same geometric orientation, perhaps limiting the functional diversity of the library. Consequently, we wanted to investigate a complementary approach to library design in which stereochemical diversity of densely branched, acyclic molecules was used to generate libraries with high geometric diversity.
520 $a Therefore, we prepared exhaustively stereodiversified libraries of acyclic 1,5-enediols. N-terminal monomers were synthesized by asymmetric allylation of alpha-amino aldehydes, and C-terminal monomers were synthesized through chiral auxiliary directed asymmetric aldol reactions. The monomers were coupled by either silyl-tethered olefin ring closing metathesis to give cis -olefin libraries or olefin cross metathesis to give trans -olefin libraries. These procedures were investigated as both solution-phase and solid-phase methodologies. Additionally, the 1,5-enediols could be hydrogenated on the solid-phase to give reduced 1,5-diols.
520 $a To evaluate the properties of these exhaustively stereodiversified libraries of 1,5-enediols, we screened the libraries for inhibition of the aspartyl protease renin and for activity at the mu opioid receptor (MOR). In the renin screens, we discovered a new class of nanomolar renin inhibitors based on the structure of the renin peptide substrate but with reduced peptide content. In the MOR screens, we discovered a new class of trans-1,5-enediol MOR ligands based on the structure of the endogenous peptide ligand endomorphin-2. Structure activity relationship studies revealed that the trans-olefin was essential for high activity, but that amide bonds were not, allowing us to develop completely non-peptidic subnanomolar MOR ligands with good selectivity and efficacy. In both of these cases, stereochemical diversity generated high levels of functional diversity, indicating that stereochemical diversity may be useful for a broad range of applications in the discovery of bioactive small molecules.
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650 $a Chemistry, Organic. $3 193634
650 $a Chemistry, Biochemistry. $3 226900
710 $a Harvard University. $3 212445
773 0 $g 64-01B. $t Dissertation Abstracts International
790 $a 0084
790 1 0 $a Verdine, Gregory L., $e advisor
791 $a Ph.D.
792 $a 2003
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