DNA sequence specificity of guanine N⁷-alkylations for a series of structurally related triazenes

Abstract

The base sequence selectivity for reaction at the guanine-N7 position was examined for a series of structurally related triazenes by a modification of a standard DNA sequencing method. The monomethyl and monochloroethyl triazenes alkylate guanines extensively at the N7 position with a general preference for runs of contiguous guanines, similar to, but not as striking as that observed previously for the chloroethylnitrosoureas. In contrast to the nitrosoureas, the triazenes had patterns of base sequence selectivity that differed somewhat from agent to agent, with the monochloro-ethylphenyltriazene having the pattern most different from the others in the series. Thus, the nature of the nonalkylating portion of the molecule can influence the ultimate alkylation preference. The monoethylating analogues alkylated weakly with little sequence preference, and the dimethyl analogues were essentially unreactive in this system.

Model transition states for methane diazonium ion methylation of guanine runs in oligomeric DNA

“…This is similar to experimental data indicating that the middle guanines in 3G runs are the most reactive toward MeNU and other simple alkylating agents such as MNNG and N-nitrosomethylamines. [19][20][21][23][24][25][26][27] In MeNU reactions with DNA sequences containing three GC's, the average reactivity of the N7 of the middle guanine is 2.0 and 7.2 times larger than the reactivity at the 3 0 -and the 5 0 -ends, respectively. 19 For System G, the calculated reactivity of the N7 atom of the 3 0 -guanine is 1.4 times greater than the reactivity at the 5 0 -guanine.…”

“…The higher calculated reactivity of both interior guanines in System H also agrees with the experimental alkylation patterns reported for reactions of guanine N7 with chloroethylnitrosoureas and triazenes. 24,27 The histograms on the left of the top three rows in Figure 4 also show the calculated reactivity patterns of guanine O 6 atoms in nucleotides containing two (System C), three (System G), and four (System H) GC base pairs with counterions in a reaction field. The reactivities of the guanine O 6 atoms relative to that of the most reactive N7 atom in each sequence are indicated by solid lines.…”

Triazenes: A Versatile Tool in Organic Synthesis

“…The most well‐known triazene in anticancer study is 1‐phenyl‐3,3‐dimethyltriazene ( 1 ) 2, 12–15. Several groups have provided strong evidence for enzyme‐catalyzed demethylation as the initial step of metabolism, followed by rearrangement of the resulting disubstituted triazene and proteolytic loss of an aniline to generate a methyldiazonium ion (Scheme ) 2, 13, 18–20. This species can then methylate DNA with the loss of dinitrogen 14, 15, 20…”

Site-Specific Stabilization of DNA by a Tethered Major Groove Amine, 7-Aminomethyl-7-deaza-2′-deoxyguanosine

“…53−55 Similar patterns have been observed for nitrogen mustards, 56 N -nitrosoureas, 57,58 and triazenes. 59 These effects are muted if the alkylation is conducted in ssDNA versus dsDNA. 60 Collectively, these data suggest that at the microscopic level, the electrostatic landscape of DNA exhibits major groove sequence specificity, 61 in addition to the counterion condensation theory of overall DNA charge neutralization, 1−3 which is not predicted to exhibit sequence specificity.…”