DNA Adducts of 9-Anilinoacridine Mustards: Characterization by NMR

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• 作者：Jun-Yao Fan ; Stephen J. Ohms ; Maruta Boyd ; and William A. Denny
• 刊名：Chemical Research in Toxicology
• 出版年：1999
• 出版时间：December 1999
• 年：1999
• 卷：12
• 期：12
• 页码：1166 - 1172
• 全文大小：93K
• 年卷期：v.12,no.12(December 1999)
• ISSN：1520-5010

文摘

Two types of 9-anilinoacridine-linked mustards, containing aniline mustard side chains linkedeither at the 4-position of the intercalating acridine chromophore (type A) or at the 1'-positionof the 9-anilino group (type B), were reacted with calf thymus DNA. Adducts were isolated bypreparative TLC, and their structures were determined by a variety of one-dimensional andtwo-dimensional NMR experiments. The only isolated product from the reaction of the 4-linkedmustard (type A) was a guanine N7 adduct (55% yield), arising from alkylation in the majorgroove. In contrast, the major product (57% yield) from reaction of the 1'-linked mustard (typeB) was an adenine N3 adduct from alkylation in the minor groove, with a smaller proportion(20%) of guanine N7 adduct. Computer modeling studies of drug-DNA alkylation complexesresulted in minimum-energy structures and averaged molecular dynamics structures thatagreed with the adduct studies. The models suggest the aniline ring of the carrier is locatedin the DNA minor groove, with the acridine ring intercalated between two base pairs with the4-position pointing into the major groove.