Mechanism of interstrand cross-linking of DNA by anticancer 2-haloethylnitrosoureas.
E and Z-2-haloethyldiazotates, which have been postulated as the ultimate electrophiles responsible for the biological activity of 2-haloethylnitrosoureas (HENUs), have been synthesized and characterized by 15N-nmr. Their stability and solubility in organic solvents are increased by forming crown ether complexes. While E and Z forms are configurationally stable in solution the Z form cyclizes at greater than or equal to -20 degrees C to a 1,2,3-oxadiazoline. The E isomers cross-link DNA, in contrast to the Z isomers. However, both E and Z (2'chloroethyl)thioethyldiazotates (neither of which may cyclize) cross-link DNA extremely efficiently. The cross-linking by these agents is a two-step process and increases with the (G + C) content of the DNA. E-2-chloroethyldiazotate exhibits activity against P388 leukaemia in vivo, lending credence to the suggestion that it is the ultimate electrophile from HENUs. Ab initio calculations predicted the optimized geometry, LUMO energies and atom contributions and the net atomic charges for the diazohydroxides and the HOMO energies and atom contributions for the alternative DNA base sites. An analysis based on Frontier Orbital methods invoking the Hard and Soft Acids and Bases theory permitted an interpretation of the formation of a cross-link site and several modified bases isolated from the reaction of HENUs with DNA.
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004996:Ethidium / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy; D008958:Models, Molecular; D009607:Nitrosourea Compounds / Q000378:metabolism*; D009690:Nucleic Acid Conformation / Q000187:drug effects; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D004247:DNA; D004996:Ethidium