SYNTHESIS AND DNA-SEQUENCE SELECTIVITY OF A SERIES OF MONOFUNCTIONAL AND DIFUNCTIONAL 9-AMINOACRIDINE NITROGEN MUSTARDS

The aim of this work was to identify nitrogen mustards that would reac t selectively with DNA, particularly in G-rich regions. A sei ies of m ono- and difunctional nitrogen mustards was synthesized in which the ( 2-chloroethyl)amino functions were connected to the N-9 of 9-aminoacri dine by way of a spacer chain consisting of two to six methylene units . The length of the spacer chain connecting the alkylating and putativ e DNA-intercalating groups was found to affect the preference for the alkylation of different guanine-N-7 positions in a DNA sequence. All o f the compounds reacted preferentially at G's that are followed by G a s do most other types of nitrogen mustards, but the degree of selectiv ity was greater. The compounds reacted at much lower concentrations th an were required for comparable reaction by mechlorethamine (HN2), con sistent with initial noncovalent binding to DNA prior to guanine-N-7 a lkylation. The degree of DNA-sequence selectivity increased as the spa cer-chain length decreased below four methylene units. Most strikingly , long spacer compounds reacted strongly at 5'-GT-3' sequences, Wherea s this reaction was almost completely suppressed when-the spacer lengt h was reduced to two or three methylenes. Mono- and difunctional compo unds of a given spacer length showed no consistent difference in DNA-s equence preference.