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

Author (Your Name)

Mabaera Rodwell, Colby College

Date of Award

2002

Document Type

Honors Thesis (Open Access)

Department

Colby College. Chemistry Dept.

Advisor(s)

Stephen U. Dunham

Second Advisor

Shari U. Dunham

Abstract

6-Thioguanine (65G) 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 ?sG. Research has shown that ?sG is incorporated into DNA during replication after which it may exert its cytotoxicity by inducing rapid mutation or by affecting DNA-protein interactions. 65G 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 65G and its metabolite methyl-6-thioguanine (Me65G), we have studied and compared the thermodynamic properties of the 11 base pair duplex dCCGTTAGATGCC).CGGCATCTAAGC) to duplexes in which the central G residue is replaced by either 65G or Me65G using temperature dependent UV-Vis experiments. Results suggest that duplexes with 65G are very similar in stability to those containing normal G while the duplexes with Me65G are considerably destabilized compared to G or 65G.

Keywords

Antineoplastic agents, DNA -- Structure, DNA-drug interactions, Purines

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