Redox pathway leading to the alkylation of DNA by the anthracycline, antitumor drugs adriamycin and daunomycin.
Redox pathway leading to the alkylation of DNA by the anthracycline, antitumor drugs adriamycin and daunomycin.
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DOI：
10.1021/jm960835d
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发表时间：
1997-04
影响因子：
7.3
通讯作者：
D. Taatjes;G. Gaudiano;K. Resing;T. Koch
中科院分区：
文献类型：
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作者：
D. Taatjes;G. Gaudiano;K. Resing;T. Koch
在还原剂二硫苏糖醇、氧化剂过氧化氢或烷基化剂甲醛存在下，蒽环类、抗肿瘤药物阿霉素和道诺霉素与自互补DNA寡核苷酸GCGCGCGC， （GC）4反应，得到类似的DNA-药物加合物混合物。负离子电喷雾质谱表明，加合物的形成是通过亚甲基将DNA偶联到蒽环类药物上，并且主要的加合物是包含两个蒽环类药物分子的双链DNA，每个分子通过亚甲基结合到DNA的单独链上。亚甲基的来源是甲醛。基于光谱数据和相关的晶体结构，提出了一种分子结构，每个蒽环类嵌入在5‘-CpG-3’位点，并从其3'-氨基与2'-脱氧鸟苷核苷酸的2-氨基共价结合。（GC）4与蒽环类药物和甲醛反应形成DNA-药物加合物的平衡混合物，经稀释后向游离DNA转移。结果表明，还原激活的阿霉素和道诺霉素有抑制转录的途径。在氧气存在下的还原活化产生过氧化氢；过氧化氢将反应混合物中的成分氧化为甲醛；甲醛将药物与DNA结合。在这种情况下，过氧化氢与阿霉素在13位通过Baeyer-Villiger反应生成2,3和甲醛。甲醛也可以通过过氧化氢氧化转录缓冲液和精胺（一种体内通常与DNA相关的多胺）中的Tris [Tris（羟甲基）氨基甲烷]产生，可能是通过芬顿反应。
Reaction of the anthracycline, antitumor drugs adriamycin and daunomycin with the self-complementary DNA oligonucleotide GCGCGCGC, (GC)4, in the presence of the reducing agent dithiothreitol, the oxidizing agent hydrogen peroxide, or the alkylating agent formaldehyde gives a similar mixture of DNA-drug adducts. Negative ion electrospray mass spectra indicate that adduct formation involves coupling of the DNA to the anthracycline via a methylene group and that the major adduct is duplex DNA containing two molecules of anthracycline, each bound to a separate strand of the DNA via a methylene group. The source of the methylene group is formaldehyde. A molecular structure with each anthracycline intercalated at a 5'-CpG-3' site and covalently bound from its 3'-amino group to a 2-amino group of a 2'-deoxyguanosine nucleotide is proposed based upon spectral data and a relevant crystal structure. The reaction of (GC)4 with the anthracyclines and formaldehyde forms an equilibrium mixture with DNA-drug adducts which is shifted toward free DNA by dilution. The results suggest a pathway to the inhibition of transcription by reductively activated adriamycin and daunomycin. Reductive activation in the presence of oxygen yields hydrogen peroxide; hydrogen peroxide oxidizes constituents in the reaction mixture to formaldehyde; and formaldehyde couples the drug to DNA. In this regard, hydrogen peroxide reacts with adriamycin via Baeyer-Villiger reactions at the 13-position to yield 2, 3, and formaldehyde. Formaldehyde also results from hydrogen peroxide oxidation of Tris [tris(hydroxymethyl)aminomethane] present in transcription buffer and spermine, a polyamine commonly associated with DNA in vivo, presumably via the Fenton reaction.