TY - JOUR
T1 - Base specific and regioselective chemical cross-linking of daunorubicin to DNA
AU - Leng, Fenfei
AU - Savkur, Rajesh
AU - Fokt, Izabela
AU - Przewloka, Teresa
AU - Priebe, Waldemar
AU - Chaires, Jonathan B.
N1 - Copyright:
Copyright 2004 Elsevier Science B.V., Amsterdam. All rights reserved.
PY - 1996/5/22
Y1 - 1996/5/22
N2 - 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'-NH2 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.
AB - 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'-NH2 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.
UR - http://www.scopus.com/inward/record.url?scp=4243119742&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4243119742&partnerID=8YFLogxK
M3 - Article
AN - SCOPUS:4243119742
SN - 0002-7863
VL - 118
SP - X-4737
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 20
ER -