The reaction of mono- and di-functional alkylating agents with nucleic acids

Abstract

The rate and extent of alkylation of ribonucleic acid and of deoxyribonucleic acid (DNA) in neutral aq. solns. at 37° by a variety of alkylating agents have been detd. (EtI, Et2SO4, MeSO3Me, MeSO3Et, 1,4-bis(methylsulfonyloxy). butane (I), HN2, nor-HN2, N,N-bis(2-chloroethyl)aniline, and 2-hydroxyethyl 2-chloroethyl sulfide (II)). Alkylation has been shown to occur at N-7 of guanine moieties, monofunctional agents yielding 7-alkylguanines and difunctional agents yielding in addn. di(guanin-7-yl) derivs. The extent of binding has been detd. of H3-labeled I, S35 labeled mustard gas (III) and of II-S35 to cellular constituents of the Ehrlich ascites tumor and of H3-labeled I to leukemic cells in the mouse. The only difference found in vivo or in vitro for reaction of III and II with nucleic acids is that III yields di(β-guanin-7-yl) sulfide. III is at least 30 times as effective as II as an inhibitor of the growth of an ascites tumor in the mouse. The mode of combination of monofunctional and of difunctional alkylating agents with nucleic acids is discussed in terms of the Crick-Watson model for the structure of DNA. The possible relation between the alkylation of DNA and the biol. properties of the alkylating agents is discussed. [on SciFinder(R)]