Effect of 6-Thioguanine and Methyl-6-Thioguanine on stability of DNA duplexes

6-Thioguanine (isG) has been used for the past thirty years as an anti-cancer agent in maintenance chemotherapy for childhood acute lymphoblastic leukemia as well as acute myeloid leukemia. Despite its long-standing clinical use, little is understood of the molecular basis of the cytotoxicity associated with 6SG. Research has shown that 6SG is incorporated into DNA during replication after which it may exert its cytotoxicity by inducing rapid mutation or by affecting DNA-protein interactions. 6SG has also been shown to impair HIV replication by inhibiting HlV-l reverse transcriptase and to inhibit human telomerase activity. To further understand the structural changes associated with DNA duplexes containing 6SG and its metabolite methyl-6-thiogua.n.ine (G), we have studied and compared the thermodynamic properties of the 11 base pair duplex dCCGTIAGATGCC)eCGGCATCTAAGC) to duplexes in which the central G residue is replaced by either 6SG or Me6SG using temperature dependent UV-Vis experiments. Results suggest that duplexes with 6SG are very similar in stability to those containing nonnal G while the duplexes with Me6SG are considerably destabilized compared to G or 6SG.