Synthesis of Specifically Deuterium Labeled Sulfur and Oxygen Ether Side-Chain-Extended Antileukemic (2-Chloroethyl)nitrosoureas and Study of Their Products and Pathways of Decomposition under Physiological Conditions

Article abstract of DOI:10.1021/jo00132a010

The synthesis of certain specifically deuterium labeled ether and thioether side-chain-extended (2-chloroethyl)nitrosoureas is described.Controlled aqueous decomposition of α-d2-S-CENU and β-d2-S-CENU under physiological conditions affords six products including 2-chloroethyl vinyl ether, bis(2-chloroethyl)thioether, and 1,2-dihydrothiophenes.The reactions, which are dominated by elimination under these conditions, the products, and the distribution of isotopic labels are consistent with the formation of thiiranium intermediates which are then subject to ring opening and ring expansion.Similar decomposition of α-d2-O-CENU and β-d2-O-CENU affords seven products including the 2-chloroethyl vinyl ether, acetalaldehyde, vinyl chloride, and bis(2-chloroethyl) ether but no dihydrofuran.The products and isotope distributions in these cases are consistent with an oxiranium species formed at the demand of the incipient cationic center but not formed at the ω-position.The rates of aqueous decomposition of α-d2-S-CENU, and α-d2-O-CENU show no isotope effects in accord with the suggested rate-determining step.In contrast, the 2-chloroethyl vinyl ether (or thioether) product distributions, corresponding to elimination of a proton or deuteron, of 4:1 for α-d2-S-CENU and 15:1 for α-d2-O-CENU are in accord with large primary isotope effects at the stage of the intermediate thiiranium or oxiranium ions.The overall results are in accord with the observed property of S-CENU to cross-link DNA readily due to sulfur participation at two sites unlike O-CENU which only alkylates and does not cross-link DNA.These results may relate to the superior antileukemic activity of S-CENU.