Synthesis of Tricyclic Nucleoside Analogue of O6-Methyl-2'-Deoxyguanosine

Alkylation at the O6-position of guanine leads to one of the most significant mutagenic lesions in DNA, O6-alkylguanine. The human protein O6-methylguanine-DNA methyltransferase (MGMT) repairs these lesions by transferring the alkyl group to an active site cysteine in an irreversible manner. The levels of MGMT are often higher in tumour cells which reduce the effectiveness of many chemotherapeutic agents that alkylate DNA. This has led to the development of inactivators of this protein for use in chemotherapy. To learn more about the repair mechanism carried out by MGMT, a high resolution MGMT-DNA structure is required which may enable the design of new inhibitors to improve current cancer treatments. Here we discribed the synthesis of 4-amino-2-(2'-deoxy-β-D-erythro-pentofuranosyl)-6-oxa-7,8, 9-trihydro-2,3,5-triazabenzo[cd]azulene (2), a tricyclic nucleoside analogue of O6-methyl-2'-deoxyguanosine