title: 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.
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 °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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA. philip.penketh@gmail.com
authors.forename: Philip G
authors.initials: PG
authors.lastname: Penketh
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Baumann
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Shyam
authors.forename: Hugh S
authors.initials: HS
authors.lastname: Williamson
authors.forename: Kimiko
authors.initials: K
authors.lastname: Ishiguro
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.forename: Emma S E
authors.initials: ES
authors.lastname: Eriksson
authors.forename: Leif A
authors.initials: LA
authors.lastname: Eriksson
authors.forename: Alan C
authors.initials: AC
authors.lastname: Sartorelli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006834:Hydrazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007536:Isomerism; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C118156:1,2-bis(methylsulfonyl)-1--(2-chloroethyl)-2-((1-(4-nitrophenyl)ethoxy)carbonyl)hydrazine; D000970:Antineoplastic Agents; D006834:Hydrazines; D011355:Prodrugs