Sequence Selectivity for the Guanine Alkylation by DNA-Alkylating Intercalators.

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  • Nakatani Kazuhiko
    Department of Synthetic Chemistry and Biological Chemistry, Faculty of Engineering, Kyoto University
  • Saito Isao
    Department of Synthetic Chemistry and Biological Chemistry, Faculty of Engineering, Kyoto University

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  • ＤＮＡインターカレーターによるグアニンアルキル化の配列選択性
  • DNA インターカレーター ニ ヨル グアニン アルキルカ ノ ハイレツ センタクセイ

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Abstract

In order to gain insight into molecular basis for the sequence selective guanine alkylation by natural products aflatoxin B1 oxide and kapurimycin A3 we have synthesized epoxides with napthopyranone and anthrapyranone rings. Alkylation of guanine in DNA by these models proceeds with sequence selectivity similar to those of natural products. Absolute configuration of the epoxide side chain is significantly effective for the efficiency of guanine alkylation. Guanine alkylation most effectively proceeded at Gs in GG sequence, but G in the GC sequence was the least reactive site for the alkylation. The order of calculated energy levels of highest occupied molecular orbital (HOMO) for dinucleotide base pairs were in a good agreement with the G alkylation susceptibility experimentally obtained by our synthetic models. With these data we concluded that interaction of HOMO of DNA and LUMO of drugs is responsible for the sequence selectivity of guanine alkylation.

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