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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
Author(s) -
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.
Publication year - 2011
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01193.x
Subject(s) - atropisomer , chemistry , prodrug , enantiomer , alkoxy group , conformational isomerism , stereochemistry , hydrazine (antidepressant) , molecule , organic chemistry , chromatography , biochemistry , alkyl
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 °C in aqueous solution by first‐order kinetics with t 1/2 values of ∼50 and ∼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.