An NMR study of [d(CGCGAATTCGCG)]2 containing an interstrand cross-link derived from a distamycin-pyrrole conjugate

Patricia A. Fagan; H. Peter Spielmann; Snorri Th Sigurdsson; Stacia M. Rink; Paul B. Hopkins; David E. Wemmer

doi:10.1093/nar/24.8.1566

An NMR study of [d(CGCGAATTCGCG)]₂ containing an interstrand cross-link derived from a distamycin-pyrrole conjugate

Patricia A. Fagan, H. Peter Spielmann, Snorri Th Sigurdsson, Stacia M. Rink, Paul B. Hopkins, David E. Wemmer^*

^*Corresponding author for this work

Faculty of Physical Sciences

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

Minor groove binding compounds related to distamycin A bind DNA with high sequence selectivity, recognizing sites which contain various combinations of A·T and G·C base pairs. These molecules have the potential to deliver cross-linking agents to the minor groove of a target DNA sequence. We have studied the covalent DNA-DNA cross-linked complex of 2,3-bis(hydroxymethyl)pyrrole-distamycin and [d(CGCGAATTCGCG)]₂. The alkylating pyrrole design is based on the pharmacophore of mitomycin C and is similar in substructure to another important class of natural products, the oxidatively activated pyrrolizidine alkaloids. Ligand-DNA NOEs confirm that the tri(pyrrole-carboxamide) unit of the ligand is bound in the minor groove of the central A+T tract. Unexpectedly, it is shifted by 1 bp with respect to the distamycin A binding site on this DNA sequence. The cross-link bridges the 2-amino position of two guanine residues, G₄ and G₂₂. The C₃·G₂₂ and G₄·C₂₁ base pairs exhibit Watson-Crick base pairing, with some local distortion, as evidenced by unusual intensities observed for DNA-DNA NOE cross-peaks. The model is compared with a related structure of a cross-linked mitomycin C:DNA complex.

Original language	English
Pages (from-to)	1566-1573
Number of pages	8
Journal	Nucleic Acids Research
Volume	24
Issue number	8
DOIs	https://doi.org/10.1093/nar/24.8.1566
Publication status	Published - 1996

Bibliographical note

Funding Information:
This work was supported in part by National Institutes of Health grants GM-43219 (DEW) and GM-45804 (PBH), post-doctoral fellowship GM-14966 (HPS), through instrumentation grants from the US Department of Energy, DE FG05-86ER75281, and the National Science Foundation, DMB 86-09305 and BBS 87-20134, and by the Director, Office of Biological and Environmental Research, General Sciences Division of the US Department of Energy under contract no. DE-AC03-76SF00098 (DEW).

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10.1093/nar/24.8.1566

Cite this

@article{a0eb0ce23e1c4d5084ce3f4e451d6a07,

title = "An NMR study of [d(CGCGAATTCGCG)]2 containing an interstrand cross-link derived from a distamycin-pyrrole conjugate",

abstract = "Minor groove binding compounds related to distamycin A bind DNA with high sequence selectivity, recognizing sites which contain various combinations of A·T and G·C base pairs. These molecules have the potential to deliver cross-linking agents to the minor groove of a target DNA sequence. We have studied the covalent DNA-DNA cross-linked complex of 2,3-bis(hydroxymethyl)pyrrole-distamycin and [d(CGCGAATTCGCG)]2. The alkylating pyrrole design is based on the pharmacophore of mitomycin C and is similar in substructure to another important class of natural products, the oxidatively activated pyrrolizidine alkaloids. Ligand-DNA NOEs confirm that the tri(pyrrole-carboxamide) unit of the ligand is bound in the minor groove of the central A+T tract. Unexpectedly, it is shifted by 1 bp with respect to the distamycin A binding site on this DNA sequence. The cross-link bridges the 2-amino position of two guanine residues, G4 and G22. The C3·G22 and G4·C21 base pairs exhibit Watson-Crick base pairing, with some local distortion, as evidenced by unusual intensities observed for DNA-DNA NOE cross-peaks. The model is compared with a related structure of a cross-linked mitomycin C:DNA complex.",

author = "Fagan, {Patricia A.} and Spielmann, {H. Peter} and Sigurdsson, {Snorri Th} and Rink, {Stacia M.} and Hopkins, {Paul B.} and Wemmer, {David E.}",

note = "Funding Information: This work was supported in part by National Institutes of Health grants GM-43219 (DEW) and GM-45804 (PBH), post-doctoral fellowship GM-14966 (HPS), through instrumentation grants from the US Department of Energy, DE FG05-86ER75281, and the National Science Foundation, DMB 86-09305 and BBS 87-20134, and by the Director, Office of Biological and Environmental Research, General Sciences Division of the US Department of Energy under contract no. DE-AC03-76SF00098 (DEW).",

year = "1996",

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AU - Fagan, Patricia A.

AU - Spielmann, H. Peter

AU - Sigurdsson, Snorri Th

AU - Rink, Stacia M.

AU - Hopkins, Paul B.

AU - Wemmer, David E.

N1 - Funding Information: This work was supported in part by National Institutes of Health grants GM-43219 (DEW) and GM-45804 (PBH), post-doctoral fellowship GM-14966 (HPS), through instrumentation grants from the US Department of Energy, DE FG05-86ER75281, and the National Science Foundation, DMB 86-09305 and BBS 87-20134, and by the Director, Office of Biological and Environmental Research, General Sciences Division of the US Department of Energy under contract no. DE-AC03-76SF00098 (DEW).

PY - 1996

Y1 - 1996

N2 - Minor groove binding compounds related to distamycin A bind DNA with high sequence selectivity, recognizing sites which contain various combinations of A·T and G·C base pairs. These molecules have the potential to deliver cross-linking agents to the minor groove of a target DNA sequence. We have studied the covalent DNA-DNA cross-linked complex of 2,3-bis(hydroxymethyl)pyrrole-distamycin and [d(CGCGAATTCGCG)]2. The alkylating pyrrole design is based on the pharmacophore of mitomycin C and is similar in substructure to another important class of natural products, the oxidatively activated pyrrolizidine alkaloids. Ligand-DNA NOEs confirm that the tri(pyrrole-carboxamide) unit of the ligand is bound in the minor groove of the central A+T tract. Unexpectedly, it is shifted by 1 bp with respect to the distamycin A binding site on this DNA sequence. The cross-link bridges the 2-amino position of two guanine residues, G4 and G22. The C3·G22 and G4·C21 base pairs exhibit Watson-Crick base pairing, with some local distortion, as evidenced by unusual intensities observed for DNA-DNA NOE cross-peaks. The model is compared with a related structure of a cross-linked mitomycin C:DNA complex.

AB - Minor groove binding compounds related to distamycin A bind DNA with high sequence selectivity, recognizing sites which contain various combinations of A·T and G·C base pairs. These molecules have the potential to deliver cross-linking agents to the minor groove of a target DNA sequence. We have studied the covalent DNA-DNA cross-linked complex of 2,3-bis(hydroxymethyl)pyrrole-distamycin and [d(CGCGAATTCGCG)]2. The alkylating pyrrole design is based on the pharmacophore of mitomycin C and is similar in substructure to another important class of natural products, the oxidatively activated pyrrolizidine alkaloids. Ligand-DNA NOEs confirm that the tri(pyrrole-carboxamide) unit of the ligand is bound in the minor groove of the central A+T tract. Unexpectedly, it is shifted by 1 bp with respect to the distamycin A binding site on this DNA sequence. The cross-link bridges the 2-amino position of two guanine residues, G4 and G22. The C3·G22 and G4·C21 base pairs exhibit Watson-Crick base pairing, with some local distortion, as evidenced by unusual intensities observed for DNA-DNA NOE cross-peaks. The model is compared with a related structure of a cross-linked mitomycin C:DNA complex.

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