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dc.contributor.authorPenketh, Philip G.
dc.contributor.authorBaumann, Raymond P.
dc.contributor.authorShyam, Krishnamurthy
dc.contributor.authorWilliamson, Hugh S.
dc.contributor.authorIshiguro, Kimiko
dc.contributor.authorZhu, Rui
dc.contributor.authorEriksson, Emma S. E.
dc.contributor.authorEriksson, Leif A.
dc.contributor.authorSartorelli, Alan C.
dc.date.accessioned2018-09-20T16:21:23Z
dc.date.available2018-09-20T16:21:23Z
dc.date.issued2011-09-06
dc.identifier.citationPenketh, Philip G. Baumann, Raymond P.; Shyam, Krishnamurthy; Williamson, Hugh S.; Ishiguro, Kimiko; Zhu, Rui; Eriksson, Emma S. E.; Eriksson, Leif A.; Sartorelli, Alan C. (2011). 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (ks119): a cytotoxic prodrug with two stable conformations differing in biological and physical properties. Chemical Biology & Drug Design 78 (4), 513-526
dc.identifier.issn1747-0277
dc.identifier.urihttp://hdl.handle.net/10379/13442
dc.description.abstractThe anticancer prodrug 1,2-bis(methylsulfonyl)-1-( 2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) selectively releases a short-lived cytotoxin following enzymatic reduction in hypoxic environments found in solid tumors. KS119, in addition to two enantiomers, has two stable atropisomers (conformers differing in structure owing to hindered bond rotation) that interconvert at 37 degrees C in aqueous solution by first-order kinetics with t(1/2) values of similar to 50 and similar to 64 h. The atropisomers differ in physical properties such as partition coefficients that allow their chromatographic separation on non-chiral columns. A striking difference in the rate of metabolism of the two atropisomers occurs in intact EMT6 murine mammary carcinoma cells under oxygen-deficient conditions. A structurally related molecule, 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(3-hydroxy- 4-nitrophenyl) ethoxy]carbonyl]hydrazine (KS119WOH), was also found to exist in similar stable atropisomers. The ratio of the atropisomers of KS119 and structurally related agents has the potential to impact the bioavailability, activation, and therapeutic activity. Thus, thermally stable atropisomers/conformers in small molecules can result in chemically and enantiomerically pure compounds having differences in biological activities.
dc.publisherWiley-Blackwell
dc.relation.ispartofChemical Biology & Drug Design
dc.subjectatropisomers
dc.subjectchemotherapy
dc.subjectconformers
dc.subjectcytotoxicity
dc.subjecthypoxia
dc.subjectks119
dc.subjectprodrug
dc.subjecttargeting
dc.subjecttumor hypoxia
dc.subjectcancer-therapy
dc.subjectcells
dc.subjectatropisomerism
dc.subjectenantiomers
dc.subjectenergies
dc.subjectmodel
dc.title1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (ks119): a cytotoxic prodrug with two stable conformations differing in biological and physical properties
dc.typeArticle
dc.identifier.doi10.1111/j.1747-0285.2011.01193.x
dc.local.publishedsourcehttp://europepmc.org/articles/pmc3171514?pdf=render
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