BASE SEQUENCE SELECTIVITY IN THE ALKYLATION OF DNA BY 1,3-DIALKYL-3-ACYLTRIAZENES

The base sequence selectivity of DNA alkylation for a series of struct urally related 1,3-dialkyl-3-acyltriazenes was examined with calf thym us DNA or polymers containing the sequences GGG, CGC, TGT, and AGA. Th e reaction products at the N7 and the O-6 positions of guanine were id entified, quantitated, and then correlated with the decomposition rate s of the triazenes, 1-(2-chloroethyl)-3-methyl-3-carbethoxy-(CMC), 1-( 2-chloroethyl)-3-methyl-3-acetyl-(CMA), 1-(2-hydroxyethyl)-3-methyl-3- carbethoxy-(HMC), 1-(2-hydroxyethyl)-3-methyl-3-acetyl-(HMA), and 1,3- dimethyl-3-acetyl- (DMA). The results of these studies revealed that D NA sequences with runs of purines were more reactive toward alkylation by all of the triazenes tested, irrespective of whether the alkylatio n was measured by N7, O-6, or total guanine adducts. Within this gener alization, the (hydroxyethyl)triazenes showed a preference for the AGA sequence, while the (chloroethyl)triazenes favored the GGG sequence. The structure of the 3-acyl group of the triazene also played a role i n the extent of alkylation of a particular sequence of DNA. Both the ( chloroethyl)- and the (hydroxyethyl)triazenes produced higher alkylati on product yields for the 3-carbethoxytriazenes as compared with the 3 -acetyl derivatives for most of the sequences examined. These overall patterns correlated well with the order of decomposition of the triaze nes at 37 degrees C: HMC > DMA > HMA > CMC > CMA. This study has demon strated how varying the structure of 1,3-dialkyl-3-acyltriazenes can m odulate DNA alkylation, a finding which may be important in the design of new triazene antitumor agents.