Base specific and regioselective chemical cross-linking of daunorubicin to DNA

被引:57
作者
Leng, FF
Savkur, R
Fokt, I
Przewloka, T
Priebe, W
Chaires, JB
机构
[1] UNIV MISSISSIPPI, MED CTR, DEPT BIOCHEM, JACKSON, MS 39216 USA
[2] UNIV TEXAS, MD ANDERSON CANCER CTR, HOUSTON, TX 77030 USA
关键词
D O I
10.1021/ja9542606
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The potent anticancer drug daunorubicin binds to DNA by the process of intercalation. Formaldehyde (HCOH) was found to rapidly and efficiently cross-link the drug to DNA in solution in a reaction the rate of which was strongly dependent upon HCOH concentration. The cross-linked drug remains intercalated into DNA, as judged from the results of absorbance, fluorescence, and circular dichroic spectroscopic studies and thermal denaturation studies. Comparative studies using a series of anthracycline derivatives showed that the 3'-NH(2) group on the daunosamine moiety is absolutely required for cross-linking. Comparative studies using synthetic deoxypolynucleotides of defined sequence showed that the N2 amino group of guanine is absolutely required for cross-linking. In restriction enzyme inhibition assays using pBR322 DNA as a substrate, cross-linked daunorubicin was found to completely, inhibit cutting by Nae I (recognition site 5'GCCGGC3') but not by Dra I (recognition site 5'TTTAAA3'). These results (a) extend, into solution, previous reports of the cross-linking of daunorubicin to oligonucleotides in crystals; (b) show that daunorubicin can be chemically cross-linked to natural DNA samples as well as to poly- and oligonucleotides, and (c) demonstrate the base- and regioselectivity of the cross-linking reaction.
引用
收藏
页码:4731 / 4738
页数:8
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