Synthesis of Guanine Derivatives Substituted in the O6-Position by Mitomycin C

✍ Scribed by Brian F. McGuinness; Koji Nakanishi; Roselyn Lipman; Maria Tomasz

• Publisher: Elsevier Science
• Year: 1988
• Tongue: French
• Weight: 277 KB
• Volume: 29
• Category: Article
• ISSN: 0040-4039
• DOI: 10.1016/s0040-4039(00)80577-8

✦ Synopsis

Although adducts resulting from the reaction of mitomycin C (MC) and DNA have been characterized as guanine derivatives covalently linked to MC at the guanine N2-and/or 06-positions, lack of material and of protons on the guanine nucleus had led to difficulties in product characterization. Authentic 06-MC guanosine derivatives have been synthesized and comparison shows that N2-adducts and not OG-adducts are the major products from reactions of reduced MC with DNA. Determination of the substitution patterns of alkylated nucleotides presents a challenge because the covalent attachment point between a drug and a DNA base often cannot be directly obtained by proton NMR, due to lack of protons in the nucleotide moiety. Further, often only pg quantities of the modified base are available. Elucidation of the alkylation site of the chemotherapeutic agent mitomycin C (MC; la) has suffered from the problems stated above. Early work with this antibiotic indicated that, upon reduction, MC preferentially crosslinked GC-rich DNA.' Subsequently, several authors pointed to the 06-position of guanine as the putative covalent binding site.2l3