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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

Penketh, Philip G.
; 
Baumann, Raymond P.
; 
Shyam, Krishnamurthy
; 
Williamson, Hugh S.
; 
Ishiguro, Kimiko
; 
Zhu, Rui
; 
Eriksson, Emma S. E.
; 
Eriksson, Leif A.
; 
Sartorelli, Alan C.
Identifiers
http://hdl.handle.net/10379/13442
 https://doi.org/10.13025/28259
Publication Date
2011-09-06
Keywords
atropisomers, chemotherapy, conformers, cytotoxicity, hypoxia, ks119, prodrug, targeting, tumor hypoxia, cancer-therapy, cells, atropisomerism, enantiomers, energies, model
Type
Article
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Citation
Penketh, 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
Abstract
The 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.
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Publisher
Wiley-Blackwell
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Attribution-NonCommercial-NoDerivs 3.0 Ireland
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Externally hosted open access publications with University of Galway authors (2)