title: Binding of two novel bisdaunorubicins to DNA studied by NMR spectroscopy.
abstract: In the search for new generations of anthracycline drugs, lower cytotoxic side effects and higher activity against resistant cancer cells are two major goals. A new class of bis-intercalating anthracycline drugs has been designed, synthesized, and shown to have promising activity against multidrug-resistant cells. Two daunorubicins symmetrically linked together via a p-xylenyl group, either at their N3' (compound WP631) or N4' sites (compound WP652), exhibit extraordinary DNA binding affinities. We have used high-resolution NRM studies to understand the DNA binding mode of these two new bis-daunorubicin anticancer compounds. The structures of the WP631-d(ACGTACGT)2 and the WP652-d(TGTACA)2 complexes have been determined by NOE-restrained refinement. WP631 binds strongly to the 5'-CG(A/T)(A/T)CG hexanucleotide sequence, with the aglycons intercalated between the two CpG sites at both ends of the hexanucleotide sequence. The overall conformation of the WP631-d(CGTACG)2 part is remarkably similar to the crystal structure of the 2:1 complex of daunorubicin and d(CGTACG)2, as predicted previously [Gao, Y.-G., & Wang, A.H.H. (1996), J. Biomol. Struct. Dyn. 13, 103-117]. In contrast, the related bis-intercalator WP652 prefers the 5'-PyGTPu tetranucleotide sequence, with the aglycons intercalated between the PypG and TpPu sites. The binding of WP652 to DNA results in a severely distroted B-DNA duplex with the p-xylenyl tether moiety significantly protruded away from the bottom of the minor groove. While WP652 in some ways behaves similarly to other anticancer bis-intercalating antibiotics (e.g., triostine A and echinomycin), the detailed interactions between those two classes of bis-intercalators are quite different.
authors.affiliation: Department of Cell & Structural Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: H
authors.initials: H
authors.lastname: Robinson
authors.forename: W
authors.initials: W
authors.lastname: Priebe
authors.forename: J B
authors.initials: JB
authors.lastname: Chaires
authors.forename: A H
authors.initials: AH
authors.lastname: Wang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000378:metabolism*; D001665:Binding Sites; D004247:DNA / Q000378:metabolism*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D007364:Intercalating Agents / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D017422:Sequence Analysis, DNA
chemical_list: D000903:Antibiotics, Antineoplastic; D007364:Intercalating Agents; C104426:WP 631; C107650:WP 652; D004247:DNA; D003630:Daunorubicin