NMR Solution Structure of a DNA Decamer Containing an Interstrand Cross-link of the Antitumor Drugcis-diamminedichloroplatinum(II)

Abstract

A 10 base pairs double-stranded oligonucleotide with the sequence d(CCTCG.CTCTC). d(GAGAG.CGAGG) containing a single interstrand cross-link resulting from chelation of the N7 position of two guanine residues on the opposite strands of DNA at the d(G.C/G.C) site by a cis-diammineplatinum(II) residue was analyzed by 1H NMR spectroscopy. All the exchangeable and nonexchangeable protons resonance lines (except some H5'-H5") were assigned. NOESY spectra and chemical shifts indicated that the cross-linkage of the guanines of G.5 and G.6 induced extrahelicity of C5 and C6. Moreover, several unusual proximities were observed such as: (i) NOE cross-peaks between the H2'-H2" of G.5 or G.6 and the aromatic proton of their 5' neighbor C4 or A7 (ii) the absence of cross-peak for the steps G.5-C6, C6-T7 and C5-G4 (iii) a strong NOESY connectivity between H8(G.5) and H2(A7). All these data allowed us to describe the head to tail arrangement of the two cross-linked guanines as well as their stacking with flanking neighbor nucleotides (G.5 with T7.A7 base pair and G.6 with C4.G4 base pair). Using all the NOESY and TOCSY data (208 constraints), we have obtained a solution structure of the cross-linked duplex by using the NMR-constrained molecular mechanics program JUMNA. The reversal position of the two cross-linked guanines placed the cis-diammineplatinum(II) residue in the minor groove. The stacking of the two cross-linked guanines with the surrounding bases induced a bend of 40 degrees toward the minor groove. The locally left-helix formation, the extrusion of the cytosines and the stacking of the platinated guanines led to an unwinding of 76 degrees. This value is in good agreement with the values deduced from gel electrophoresis experiments.

Unique Properties of DNA Interstrand Cross‐Links of Antitumor Oxaliplatin and the Effect of Chirality of the Carrier Ligand

“…For instance, the deoxyriboguanosine residues that are interstrand cross-linked by cisplatin are not paired with hydrogen bonds to the complementary deoxyribocytidines, which are located outside the duplex and not stacked with the other aromatic bases; all other base residues are paired. [29,46] Consistent with this characterization is the strong reactivity of chemical probes with cytosine residues complementary to the platinated guanine residues [27] ( Figure 5 and Table 2). As the same strong reactivity of chemical probes is also observed in the case of the interstrand CLs of…”

Metals in Medicine

“…In the solution NMR structure of the interstrand cross-linked [{Pt(NH 3 ) 2 } 2 }-{d(CCTCG*CTCTC)´d(GAGAG*CGAGG)}], the cis-{Pt-(NH 3 ) 2 } 2 moiety is also located in the minor groove. [95] The stacking of the two cross-linked guanine residues with the surrounding bases induces a bend of 408 towards the minor groove. A similar bend occurs in the X-ray crystal structure of this interstrand cross-link.…”

The First Pure ΛHT Rotamer of a Complex with a cis‐[Metal(nucleotide)2] Unit: A cis‐[Pt(amine)2(nucleotide)2] ΛHT Rotamer with Unique Molecular Structural Features

“…[9][10][11][12][13][14][15][16][17][18][19][20][21][22] However, there is some evidence that head-to-tail (HT) crosslinks form for both intrastrand [9] and interstrand crosslinks. [23,24] Such HT adducts could contribute to anticancer activity, and evidence exists that many Pt compounds incapable of forming the main DNA HH adducts made by cisplatin exhibit anticancer activity. [2,25,26] In DNA and oligonucleotide HT adducts and for all related HT forms characterized by solid-state crystallography, the chirality of the HT conformer typically found is D. All known cis-[metal(6-oxopurine nucleotide) 2 ] adducts (involving 5'-GMP, 5'-IMP, and their phosphate methyl esters) crystallize in the DHT conformation, not only for square-planar Pt with several carrier ligands, but also for examples of square-planar and octahedral complexes of Co, Cu, Zn, Cd, and Pd.…”