Staff View
Design, synthesis and evaluation of potential MTA prodrugs for the treatment of MTAP-deficient tumors in combination with 5-FU/6-TG/antifolates

Descriptive

TitleInfo
Title
Design, synthesis and evaluation of potential MTA prodrugs for the treatment of MTAP-deficient tumors in combination with 5-FU/6-TG/antifolates
Name (type = personal)
NamePart (type = family)
Ranade
NamePart (type = given)
Ashwini
NamePart (type = date)
1993-
DisplayForm
Ashwini Ranade
Role
RoleTerm (authority = RULIB)
author
Name (type = personal)
NamePart (type = family)
Hu
NamePart (type = given)
Longqin
DisplayForm
Longqin Hu
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
chair
Name (type = personal)
NamePart (type = family)
Lavoie
NamePart (type = given)
Edmond
DisplayForm
Edmond Lavoie
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = personal)
NamePart (type = family)
Augeri
NamePart (type = given)
David
DisplayForm
David Augeri
Affiliation
Advisory Committee
Role
RoleTerm (authority = RULIB)
internal member
Name (type = corporate)
NamePart
Rutgers University
Role
RoleTerm (authority = RULIB)
degree grantor
Name (type = corporate)
NamePart
School of Graduate Studies
Role
RoleTerm (authority = RULIB)
school
TypeOfResource
Text
Genre (authority = marcgt)
theses
OriginInfo
DateCreated (qualifier = exact)
2018
DateOther (qualifier = exact); (type = degree)
2018-10
CopyrightDate (encoding = w3cdtf)
2018
Place
PlaceTerm (type = code)
xx
Language
LanguageTerm (authority = ISO639-2b); (type = code)
eng
Abstract (type = abstract)
Many solid tumors and hematologic malignancies are characterized by a deficiency of the enzyme methylthioadenosine phosphorylase (MTAP). MTAP cleaves its natural substrate MTA which is generated during polyamine biosynthesis to adenine via a salvage pathway for AMP production. MTAP deficient cells are unable to salvage adenine from MTA. The difference in the lack of expression of MTAP in tumor cells compared to normal healthy cells has been explored in a therapeutic strategy for selectively killing tumor cells. Antimetabolites such as 5-FU, 6-TG or antifolates disrupt DNA replication and inhibit de-novo purine synthesis through the release of cytotoxic nucleotides generated via phosphorylation using phosphoribosyl-1-pyrophosphate (PRPP). Unfortunately, one major drawback of these cytotoxic nucleotides is that they produce harmful effects on the growth and proliferation of normal cells. To eliminate or reduce the cytotoxicity of these chemotherapeutic drugs and thus increase their therapeutic index, administration of MTA or MTA analogs in conjugation with antimetabolites could prevent damage to healthy MTAP competent cells. This is because adenine generated in this process by MTAP in healthy cells will block the conversion of 5-FU/6-TG to their cytotoxic nucleotides by competing for the rate-limiting pools of PRPP. Since no adenine is produced in tumor cells due to lack of MTAP, PRPP is present in sufficient levels and the co-administered drug can be readily converted to its toxic metabolite. Thus, a high degree of selectivity can be achieved. There are several MTA prodrugs discussed in the literature for delivering MTA to protect MTAP competent cells and proof of concept exists through in vitro studies emphasizing the protective effects of MTA in the presence of antimetabolites. However, there is still no successful clinical trial reported to have co-administered MTA or its analog with an antimetabolite. Also, the optimum dose of MTA that can rescue normal MTAP competent cells without compromising the ability of antimetabolites to selectively kill MTAP deficient tumor cells remains to be identified. In this thesis work, prodrugs of MTA were designed to be activated by the carboxylesterases to release MTA. We explored two types of prodrugs, namely the N-(alkyloxy)carbonyl-MTA derivatives and N-[(acyloxy)alkyloxy]carbonyl-MTA derivatives. The N-(alkyloxy)carbonyl-MTA prodrugs were stable at physiological pH and showed longer activation half-lives when tested in mouse liver microsomes but failed to be activated in human liver microsomes. Conversely, the N-[(acyloxy)alkyloxy]carbonyl-MTA prodrugs showed shorter half-lives ranging from a few minutes to a few hours in the presence of mouse and human liver microsomes but suffered from an inherent instability at physiological pH. As expected, the hydrolytic susceptibility of the ester group in N-[(acyloxy)alkyloxy]carbonyl-MTA prodrugs decreased with increasing steric hindrance around the ester bond by replacement with bulkier alkyl groups. Therefore, the N-[(acyloxy)alkyloxy]carbonyl-MTA prodrugs show promise and further modifications can be made to increase stability at physiological pH.
Subject (authority = RUETD)
Topic
Medicinal Chemistry
Subject (authority = ETD-LCSH)
Topic
Tumors
Subject (authority = ETD-LCSH)
Topic
Prodrugs
RelatedItem (type = host)
TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier (type = RULIB)
ETD
Identifier
ETD_9055
PhysicalDescription
Form (authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
1 online resource (72 pages : illustrations)
Note (type = degree)
M.S.
Note (type = bibliography)
Includes bibliographical references
Note (type = statement of responsibility)
by Ashwini Ranade
RelatedItem (type = host)
TitleInfo
Title
School of Graduate Studies Electronic Theses and Dissertations
Identifier (type = local)
rucore10001600001
Location
PhysicalLocation (authority = marcorg); (displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier (type = doi)
doi:10.7282/t3-9qp4-gz07
Genre (authority = ExL-Esploro)
ETD graduate
Back to the top

Rights

RightsDeclaration (ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder (type = personal)
Name
FamilyName
Ranade
GivenName
Ashwini
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-06-02 03:19:27
AssociatedEntity
Name
Ashwini Ranade
Role
Copyright holder
Affiliation
Rutgers University. School of Graduate Studies
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
Type
Embargo
DateTime (encoding = w3cdtf); (qualifier = exact); (point = start)
2018-10-31
DateTime (encoding = w3cdtf); (qualifier = exact); (point = end)
2020-10-30
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after October 30th, 2020.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
Back to the top

Technical

RULTechMD (ID = TECHNICAL1)
ContentModel
ETD
OperatingSystem (VERSION = 5.1)
windows xp
CreatingApplication
Version
1.7
ApplicationName
Microsoft® Word 2016
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2018-06-01T20:07:50
DateCreated (point = end); (encoding = w3cdtf); (qualifier = exact)
2018-06-01T20:07:50
Back to the top
Version 8.5.3
Rutgers University Libraries - Copyright ©2024