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

Abstract

The rates and extents of alkylation of RNA and DNA in neutral aqueous solution at 37[degree] by a variety of alkylating agents have been determined. Alkylation has been shown to occur at N-7 of guanine moieties, mono-functional agents yielding 7-alkylguanines, and difunctional agents yielding in addition di(guanin-7-yl) derivatives. Alkylated ribonucleic acid is stable in neutral aqueous solution but alkylated deoxyribonucleic acid decomposes with loss of the alkylated guanine products. The extent of binding has been determined of H3-labelled myleran, S35-labelled mustard gas and of 2-hydroxyethyl 2-chloroethyl [S35]sulphide to cellular constituents of the Ehrlich-ascites tumor and of H3-labelled myleran to leukemic cells in the mouse. The only difference found in vivo or in vitro for reaction of mustard gas and 2-hydroxyethyl 2-chloroethyl sulphide with nucleic acids is that mustard gas yields di-([beta]-guanin-7-yl) sulphide. Mustard gas is at least 30 times as effective as 2-hydroxyethyl 2-chloroethyl sulphide as an inhibitor of the growth of an ascites tumor in the mouse. The mode of combination of monofunqtional and of difunctional alkylating agents with nucleic acids is discussed in terms of the Crick-Watson model for the structure of DNA. The possible relationship between the alkylation of DNA and the bio-logicalproperties of the alkylating agents is discussed.