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Design and synthesis of novel small molecule modulators of KEAP1-NRF2-ARE pathway
Descriptive
TitleInfo
Title
Design and synthesis of novel small molecule modulators of KEAP1-NRF2-ARE pathway
Name
(type = personal)
NamePart
(type = family)
Chen
NamePart
(type = given)
Lin
NamePart
(type = date)
1981-
DisplayForm
LIN CHEN
Role
RoleTerm
(authority = RULIB)
author
Name
(type = personal)
NamePart
(type = family)
Hu
NamePart
(type = given)
Longqin
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Longqin Hu
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
chair
Name
(type = personal)
NamePart
(type = family)
LaVoie
NamePart
(type = given)
Edmond J
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Edmond J LaVoie
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Rice
NamePart
(type = given)
Joseph E
DisplayForm
Joseph E Rice
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Knapp
NamePart
(type = given)
Spencer
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Spencer Knapp
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
(type = corporate)
NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
(type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm
(authority = RULIB)
school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2014
DateOther
(qualifier = exact);
(type = degree)
2014-01
Place
PlaceTerm
(type = code)
xx
Language
LanguageTerm
(authority = ISO639-2b);
(type = code)
eng
Abstract
(type = abstract)
Keap1-Nrf2-ARE system represents a key signaling pathway in the regulation of cellular defense mechanisms against oxidative stress and inflammation. Activation of Keap1-Nrf2-ARE system can induce the expression of a number of antioxidant defense enzymes and proteins critical for preventing oxidative damage, inflammation and tumorigenesis. Curcumin exhibits antioxidant, anti-inflammatory and anti-carcinogenic properties and is demonstrated as an indirect inhibitor of Keap1-Nrf2 protein-protein interaction. Novel classes of iminothiazinylbutadienols and divinylpyrimidinethiones were designed and synthesized as analogs of curcumin with its β-diketone moiety masked as a heterocyclic adduct with thiourea. The chemical stability of these novel heterocyclic compounds was improved as compared to curcumin. The biological activity evaluations revealed that some of these new curcumin analogs are more effective ARE activators than curcumin and isothiocyanates. Most available modulators of Keap1-Nrf2-ARE pathway modify the cysteine sulfhydryl groups of Keap1 for ARE activation. There are safety concerns about these thiol-reactive compounds. A high-throughput screen (HTS) of the MLPCN library identified the first-in-class inhibitor specifically for the direct inhibition of the Keap1-Nrf2 protein-protein interaction. The HTS hit has three chiral centers and the active stereoisomer was designated as LH601A and its stereochemistry was confirmed by X-ray crystallography and stereospecific synthesis. Various analogs of LH601A were designed and synthesized to improve the binding affinity. The obtained structure activity relationships (SAR) provided guidance for further structural optimization. Several analogs showed to be more potent than LH601A. These direct Keap1-Nrf2 inhibitors can mimic the actions of electrophiles in the induction of cytoprotective enzymes but are more selective and specific. Therefore, these direct inhibitors of Keap1-Nrf2 protein-protein interaction have great potential to be developed into innovative therapeutic agents for many diseases and conditions involving oxidative stress.
Subject
(authority = RUETD)
Topic
Medicinal Chemistry
RelatedItem
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TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
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ETD
Identifier
ETD_5312
PhysicalDescription
Form
(authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
xix, 190 p. : ill.
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = statement of responsibility)
by Lin Chen
Subject
(authority = ETD-LCSH)
Topic
Cytology--Research
Subject
(authority = ETD-LCSH)
Topic
Cells--Preservation
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
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rucore19991600001
Location
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(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T3RJ4GJX
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
RightsDeclaration
(ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder
(type = personal)
Name
FamilyName
CHEN
GivenName
LIN
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = start)
2014-01-08 20:58:05
AssociatedEntity
Name
LIN CHEN
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime
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(qualifier = exact);
(point = start)
2014-01-31
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = end)
2016-01-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after January 31st, 2016.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical
RULTechMD
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ContentModel
ETD
OperatingSystem
(VERSION = 5.1)
windows xp
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