Molecular Design of Nobel DNA Alkylating Agent at GG step

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We have synthesized naphthopyranone epoxide from D-isoascorbic acid together with its three diastereoisomers. DNA alkylation of ODNs containing 5'XGT3' and 5'TGY3' by (11R, 13R)-epoxide, where X and Y are any nucleotide bases, occurred at all G residues except at G of 5'TGC3' sequence. In contrast, other three diastereoisomers showed only weak G alkylation activity. Differential ^1H NMR NOE of drug-G adduct confirmed the G-N7 alkylation at the epoxide carbon with concomitant S_N2 ring opening of the epoxide. Quantitative HPLC analysis of G alkylation efficiency by showed the order of G alkylation susceptibility as TGGT 【approximately equal】 CGT >> TGA > AGT > TGT >> TGC.The order was fully consistent with those reported for aflatoxin B_1 oxide and kapurimycin A_3, suggesting that the sequence selectivity observed for these DNA alkylating agents is not structure dependent but most likely due to the intrinsic property of DNA sequences. We found that the order of G alkylation susceptibility obtained completely matched with the calculated HOMO energy level of G-containing sequences. These results underscore that our drug is a unique molecular probe for ranking HOMO level of G-containing sequences by well-known G alkylation chemistry and suggests that the intercalation of charge neutral intercalators is a HOMO-controlled process.