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dc.contributor.authorNiculescu-Duvaz, I
dc.contributor.authorScanlon, I
dc.contributor.authorNiculescu-Duvaz, D
dc.contributor.authorFriedlos, F
dc.contributor.authorMartin, J
dc.contributor.authorMarais, R
dc.contributor.authorSpringer, CJ
dc.date.accessioned2018-06-25T15:21:23Z
dc.date.issued2004-05
dc.identifier.citationJournal of medicinal chemistry, 2004, 47 (10), pp. 2651 - 2658
dc.identifier.issn0022-2623
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1917
dc.identifier.eissn1520-4804en_US
dc.identifier.doi10.1021/jm030966wen_US
dc.description.abstractNine new nitrogen mustard compounds derived from 2,6-difluoro-4-hydroxy- (3a-e) and 2,6-difluoro-4-amino- (4a-d) aniline were synthesized as potential prodrugs. They were designed to be activated to their corresponding 3,5-difluorophenol and -aniline (4)-nitrogen mustards by the enzyme carboxypeptidase G2 (CPG2) in gene-directed enzyme prodrug therapy (GDEPT) models. The compounds were tested for cytotoxicity in the MDA MB-361 breast adenocarcinoma. The cell line was engineered to express stably either CPG2 tethered to the cell surface stCPG2-(Q)3 or beta-galactosidase (beta-Gal) as control. The cytotoxicity differentials were calculated between CPG 2-expressing and -nonexpressing cells and yielded different results for the two series of prodrugs despite their structural similarities. While the phenol compounds are ineffective as prodrugs, their aniline counterparts exhibit outstanding activity in the tumor cell lines expressing CPG2. [3,5-Difluoro-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl-l-glutamic acid gave a differential of >227 in MDA MB361 cells as compared with 19 exhibited by 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]benzoyl-l-glutamic acid, 1a, which has been in clinical trials.
dc.formatPrint
dc.format.extent2651 - 2658
dc.languageeng
dc.language.isoeng
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectBenzene Derivatives
dc.subjectNitrogen Mustard Compounds
dc.subjectAniline Mustard
dc.subjectgamma-Glutamyl Hydrolase
dc.subjectGlutamic Acid
dc.subjectAntineoplastic Agents
dc.subjectProdrugs
dc.subjectTransplantation, Heterologous
dc.subjectDrug Screening Assays, Antitumor
dc.subjectNeoplasm Transplantation
dc.subjectStructure-Activity Relationship
dc.subjectHalf-Life
dc.subjectFemale
dc.subjectGenetic Therapy
dc.titleSignificant differences in biological parameters between prodrugs cleavable by carboxypeptidase G2 that generate 3,5-difluoro-phenol and -aniline nitrogen mustards in gene-directed enzyme prodrug therapy systems.
dc.typeJournal Article
rioxxterms.versionofrecord10.1021/jm030966w
rioxxterms.licenseref.startdate2004-05en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfJournal of medicinal chemistry
pubs.issue10
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Gene & Oncogene Targeting
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Signal Transduction
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Gene & Oncogene Targeting
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Signal Transduction
pubs.publication-statusPublished
pubs.volume47en_US
pubs.embargo.termsNot known
icr.researchteamGene & Oncogene Targetingen_US
icr.researchteamSignal Transductionen_US
dc.contributor.icrauthorMarais, Richard Malcolmen
dc.contributor.icrauthorSpringer, Carolineen
dc.contributor.icrauthorNiculescu-Duvaz, Danen


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