title: Isolation and characterization of electrophiles from 2-haloethylnitrosoureas forming cytotoxic DNA cross-links and cyclic nucleotide adducts and the analysis of base site-selectivity by ab initio calculations.
abstract: E- and Z-2-haloethyldiazotates--electrophilic species hitherto suggested as intermediates in the reactions of 2-haloethylnitrosoureas (HENUs) under physiological conditions--were synthesized and characterized by 1H-, 15N- and 13C-NMR (nuclear magnetic resonance). They were stabilized and solubilized in organic solvents as their 18-crown-6 ether complexes. Characterization of the Z-2-fluoroethyldiazotate by 19F- and 13C-NMR, and comparison with the Z-2-chloroethyl compound, confirmed facile cyclization to the 1,2,3-oxadiazoline and subsequent decomposition to nitrogen and ethylene oxide. The E-2-haloethyldiazotates form DNA interstrand cross-links at a rate, and to an extent, and with a DNA base dependence, which parallels the behaviour of the parent HENUs, while the Z isomers alkylate DNA but show minimal cross-linking. Both E-and Z-(2'-chloroethyl)thioethyldiazotates, neither of which can undergo cyclization, cross-link DNA efficiently. Self-consistent-field (SCF) ab initio calculations provided optimized geometries, atomic charges and LUMO (Lowest Unoccupied Molecular Orbital) atom contributions for the E- and Z-2-haloethyldiazohydroxides. The HSAB (Hard and Soft Acids and Bases) theory, in conjunction with HOMO (Highest Occupied Molecular Orbital) values on key DNA base sites, accounted for the observed site-selectivity in the formation of identified cross-links produced by 1,3-bis-(2-chloroethyl)-1-nitrosourea. Independent chemical studies on cytosine derivatives corroborated the predicted site selectivity of attack by electrophiles and the formation of ethanocytidine cyclic adducts.
mesh_terms: D000478:Alkylation; D002330:Carmustine / Q000031:analogs & derivatives* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D003432:Cross-Linking Reagents; D003562:Cytidine; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D006151:Guanosine
chemical_list: D003432:Cross-Linking Reagents; D006151:Guanosine; D003562:Cytidine; D004247:DNA; D005038:Ethylnitrosourea; D002330:Carmustine