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Structure-activity studies of novel noncamptothecin topoisomerase I-targeting agents

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TypeOfResource
Text
TitleInfo (ID = T-1)
Title
Structure-activity studies of novel noncamptothecin topoisomerase I-targeting agents
Identifier
ETD_825
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051088
Language
LanguageTerm (authority = ISO639-2); (type = code)
eng
Genre (authority = marcgt)
theses
Subject (ID = SBJ-1); (authority = RUETD)
Topic
Medicinal Chemistry
Subject (ID = SBJ-1); (authority = ETD-LCSH)
Topic
DNA topoisomerase I
Abstract
Topoisomerases are ubiquitous enzymes that participate in processes such as DNA replication, transcription and repair. Two camptothecin derivatives, topotecan (Hycamtin®) and irinotican (CPT-11/ Camptosar®), are currently used in the clinic as topoisomerse I targeting anticancer agents. Camptothecins can stabilize the enzyme-DNA cleavage complex, leading to DNA damage and ultimately cell death. Despite their unique tumor suppression mechanism, topotecan and irinotican can undergo hydrolysis and inactivation in vivo due to an unstable lactone moiety. In addition, both topotecan and irinotican are substrates for efflux transporters, BCRP and MDR1, which are associated with drug resistance. 8,9-Dimethoxy-5-(2-dimethylaminoethyl)-2,3-methylenedioxy- 5H-dibenzo[c,h][1,6]naphthyridine-6- one (ARC-111) has been identified as exceptionally active TOP1-targeting agent with potent antitumor activity both in vitro and in vivo. Unlike camptothecins, ARC-111 is not a substrate for major efflux transporters, and does not bind to human serum albumin. ARC-111 structurally related analogs, 12-carboxamides of benzo[i]phenathridine and the "reversed lactams" have also exhibited excellent cytotoxicity and potent TOP1 targeting activity. In this dissertation, further insights into structure-activity relationship of ARC-111 and related compounds have been carefully examined. Alteration of both D-ring and side chain of ARC-111 have afforded potent TOP1-targeting agents. Inspired by the success of ARC-111, the design, synthesis and biological activities of other B-ring modified benzo[i]phenathridines have been systematically investigated. In review of possible metabolites of ARC-111, together with the known structure-activity relationships associated with the "reversed lactams", 11-carboxamides and 12-carboxamides of benzo[i]phenathridine, have prompted the examination of α,α-dimethyl substitution on the amino side chain on pharmacologic activity. Efficient synthetic methods associated with these novel non-camptothecin anticancer agents have also been developed. Several agents identified in this study have demonstrated excellent cancer cell cytotoxicity, TOP1 targeting specificity, as well as in vivo antitumor efficacy, comparable as the lead compound, ARC-111.
PhysicalDescription
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electronic resource
Extent
xiv, 219 p. : ill.
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application/pdf
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text/xml
Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references (p. 198-218)
Note (type = statement of responsibility)
by Wei Feng
Name (ID = NAME-1); (type = personal)
NamePart (type = family)
Feng
NamePart (type = given)
Wei
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author
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Wei Feng
Name (ID = NAME-2); (type = personal)
NamePart (type = family)
LaVoie
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Edmond
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chair
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Advisory Committee
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Edmond J. LaVoie
Name (ID = NAME-3); (type = personal)
NamePart (type = family)
Rice
NamePart (type = given)
Joseph
Role
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internal member
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Advisory Committee
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Joseph E. Rice
Name (ID = NAME-4); (type = personal)
NamePart (type = family)
Kimball
NamePart (type = given)
S. David
Role
RoleTerm (authority = RULIB); (type = )
internal member
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Advisory Committee
DisplayForm
S. David Kimball
Name (ID = NAME-5); (type = personal)
NamePart (type = family)
Jones
NamePart (type = given)
Roger
Role
RoleTerm (authority = RULIB); (type = )
outside member
Affiliation
Advisory Committee
DisplayForm
Roger A. Jones
Name (ID = NAME-1); (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB); (type = )
degree grantor
Name (ID = NAME-2); (type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm (authority = RULIB); (type = )
school
OriginInfo
DateCreated (point = ); (qualifier = exact)
2008
DateOther (qualifier = exact); (type = degree)
2008-05
Place
PlaceTerm (type = code)
xx
Location
PhysicalLocation (authority = marcorg)
NjNbRU
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
RelatedItem (type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Identifier (type = doi)
doi:10.7282/T3WD40TK
Genre (authority = ExL-Esploro)
ETD doctoral
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The author owns the copyright to this work.
Copyright
Status
Copyright protected
Availability
Status
Open
RightsEvent (AUTHORITY = rulib); (ID = 1)
Type
Permission or license
Detail
Non-exclusive ETD license
AssociatedObject (AUTHORITY = rulib); (ID = 1)
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.
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ETD
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application/pdf
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application/x-tar
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3952640
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