Sequence selectivity for the guanine alkylation by DNA alkylating intercalators

In order to gain insight into molecular basis for the sequence selective gu anine alkylation by natural products aflatoxin St oxide and kapurimycin A(3 ), we have synthesized epoxides with napthopyranone and anthrapyranone ring s. Alkylation of guanine in DNA by these models proceeds with sequence sele ctivity similar to those of natural products. Absolute configuration of the epoxide side chain is significantly effective for the efficiency of guanin e alkylation. Guanine alkylation most effectively proceeded at Gs in GG seq uence, but G in the GC sequence was the least reactive site for the alkylat ion. The order of calculated energy levels of highest occupied molecular or bital (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.