Guanine alkylation

Another effect on DNA can result when alkylated bases are lost from the DNA polymer. For example, guanine alkylated in the N7 position has a much weakened bond to DNA and may split off from the DNA molecule ... 

Schematic representation of the actions of alkylating agents. The drug (—) may be bifunclional, resulting m DNA cross-links (left) or monofunctional, resulting in guanine alkylation (right).

Pereira TN, Webb RL, Reilly PE, Seawright AA, Prakash AS (1998) Dehydromonocrotaline generates sequence-selective N-7 guanine alkylation and heat and alkali stable multiple fragment DNA crosslinks. Nucleic Acids Res 26 5441-5447... 

Guanine, 9-/3-D-ribofuranosyl-, 5, 536 Guanine, 6-thio-tautomerism, 5, 509 toxicity, 1, 141 Guanine, 8-trifluoromethyl-synthesis, 5, 574 Guanines, thio-synthesis, 5, 572 Guanosine arylation, 5, 538 dipole moment, 5, 522 free radical alkylation, 5, 543 hydrobromide... 

Amine bases in nucleic acids can react with alkylating agents in typical Sjsj2 reactions. Look at the following electrostatic potential maps, and tell which is the better nucleophile, guanine or adenine. The reactive positions in each are indicated. 

The different possible adducts formed between mitomycin C and DNA have been isolated by degradation of DNA after in vitro alkylation/crosslinking reactions and structurally characterized. Monoadduct 21 (Scheme 11.3), derived from alkylation at C-l only [53], and monoadducts 22 [54] and 23 [55, 56] (derived from C-10 alkylation by 16 at N-7 or N-2 of guanine, respectively) have been isolated, together with bisadducts 24 [57] and 25 [58], derived from interstrand and intrastrand crosslinks, respectively, and adduct 26 [59], formed by addition of a molecule of water to C-10 instead of the second guanine. All of these adducts have also been isolated from DNA after in vivo crosslinking [60, 61]. 

A crosslinking mechanism based on these data was proposed. Initial monoalkylation at guanine is followed by a template-directed alkylation at either guanine or adenine two base pairs away on the opposite strand. In support of this, Armstrong... 

Saito et al. achieved the first direct confirmation of double alkylation of purine bases by azinomycin B [140]. They incubated azinomycin B with the self-comple-mentary DNA duplex d(TAGCTA)2 and monitored the reaction by HPLC and ion spray MS. They observed initial formation of a monoadduct that was then converted into a crosslinked bisadduct. The crosslink position was identified as between the guanine of one strand and the 5 -adenine on the other strand by thermo-lytic depurination. Further decomposition prevented structural analysis of the azi-... 

It was concluded that the crosslinking reaction proceeded through initial alkylation of N-7 of adenine by the aziridine ring, followed by guanine N-7 alkylation by the epoxide (Figure 11.12). This seems inconsistent with Armstrong s earlier conclusions, but the very short oligonucleotides used by Saito et al. may influence the DNA alkylation chemistry. 

Depurination - N7 alkylation may cause cleavage of the imidazole ring and excision of the guanine residue, leading to DNA strand breakage. 

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