TY - JOUR
T1 - Unprecedented head-to-head conformers of d(GpG) bound to the antitumor active compound tetrakis (μ-carboxylato)dirhodium(II,II)
AU - Chifotides, Helen T.
AU - Koshlap, Karl M.
AU - Pérez, Lisa M.
AU - Dunbar, Kim R.
PY - 2003/9/3
Y1 - 2003/9/3
N2 - The N7/O6 equatorial binding interactions of the antitumor active complex Rh2(OAc)4(H2O)2 (OAc- = CH3CO2-) with the DNA fragment d(GpG) have been unambiguously determined by NMR spectroscopy. Previous X-ray crystallographic determinations of the head-to-head (HH) and head-to-tail (HT) adducts of dirhodium tetraacetate with 9-ethylguanine (9-EtGH) revealed unprecedented bridging N7/O6 guanine nucleobases that span the Rh - Rh bond. The absence of N7 protonation at low pH and the notable increase in the acidity of N1 - H (pKa ≈ 5.7 as compared to 8.5 for N7 only bound platinum adducts), suggested by the pH dependence titrations of the purine H8 1H NMR resonances for Rh2(OAc)2(9-EtG) 2 and Rh2(OAc)2{d(GpG)}, are consistent with bidentate N7/O6 binding of the guanine nucleobases. The pKa values estimated for N1 - H (de)protonation, from the pH dependence studies of the C6 and C2 13C NMR resonances for the Rh2(OAc) 2(9-EtG)2 isomers, concur with those derived from the H8 1H NMR resonance titrations. Comparison of the 13C NMR resonances of C6 and C2 for the dirhodium adducts Rh2(OAc) 2(9EtG)2 and Rh2(OAc)2{d(GpG)} with the corresponding resonances of the unbound ligands {at pH 7.0 for 9-EtGH and pH 8.0 for d(GpG)}, shows substantial downfield shifts of Δδ 11.0 and 6.0 ppm for C6 and C2, respectively; the lafter shifts reflect the effect of O6 binding to the dirhodium centers and the ensuing enhancement in the acidity of N1 - H. Intense H8/H8 ROE cross-peaks in the 2D ROESY NMR spectrum of Rh2(OAc)2{d(GpG)} indicate head-to-head arrangement of the guanine bases. The Rh2(OAc)2{d(GpG)} adduct exhibits two major right-handed conformers, HH1 R and HH2 R, with HH1 R being three times more abundant than the unusual HH2 R. Complete characterization of both adducts revealed repuckering of the 5′-G sugar rings to C3′-endo (N-type), retention of C2′-endo (S-type) conformation for the 3′-G sugar rings, and anti orientation with respect to the glycosyl bonds. The structural features obtained for Rh2(OAc)2{d(GpG)} by means of NMR spectroscopy are very similar to those for cis-[Pt(NH 3)2{d(GpG)}] and corroborate molecular modeling studies.
AB - The N7/O6 equatorial binding interactions of the antitumor active complex Rh2(OAc)4(H2O)2 (OAc- = CH3CO2-) with the DNA fragment d(GpG) have been unambiguously determined by NMR spectroscopy. Previous X-ray crystallographic determinations of the head-to-head (HH) and head-to-tail (HT) adducts of dirhodium tetraacetate with 9-ethylguanine (9-EtGH) revealed unprecedented bridging N7/O6 guanine nucleobases that span the Rh - Rh bond. The absence of N7 protonation at low pH and the notable increase in the acidity of N1 - H (pKa ≈ 5.7 as compared to 8.5 for N7 only bound platinum adducts), suggested by the pH dependence titrations of the purine H8 1H NMR resonances for Rh2(OAc)2(9-EtG) 2 and Rh2(OAc)2{d(GpG)}, are consistent with bidentate N7/O6 binding of the guanine nucleobases. The pKa values estimated for N1 - H (de)protonation, from the pH dependence studies of the C6 and C2 13C NMR resonances for the Rh2(OAc) 2(9-EtG)2 isomers, concur with those derived from the H8 1H NMR resonance titrations. Comparison of the 13C NMR resonances of C6 and C2 for the dirhodium adducts Rh2(OAc) 2(9EtG)2 and Rh2(OAc)2{d(GpG)} with the corresponding resonances of the unbound ligands {at pH 7.0 for 9-EtGH and pH 8.0 for d(GpG)}, shows substantial downfield shifts of Δδ 11.0 and 6.0 ppm for C6 and C2, respectively; the lafter shifts reflect the effect of O6 binding to the dirhodium centers and the ensuing enhancement in the acidity of N1 - H. Intense H8/H8 ROE cross-peaks in the 2D ROESY NMR spectrum of Rh2(OAc)2{d(GpG)} indicate head-to-head arrangement of the guanine bases. The Rh2(OAc)2{d(GpG)} adduct exhibits two major right-handed conformers, HH1 R and HH2 R, with HH1 R being three times more abundant than the unusual HH2 R. Complete characterization of both adducts revealed repuckering of the 5′-G sugar rings to C3′-endo (N-type), retention of C2′-endo (S-type) conformation for the 3′-G sugar rings, and anti orientation with respect to the glycosyl bonds. The structural features obtained for Rh2(OAc)2{d(GpG)} by means of NMR spectroscopy are very similar to those for cis-[Pt(NH 3)2{d(GpG)}] and corroborate molecular modeling studies.
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U2 - 10.1021/ja027779s
DO - 10.1021/ja027779s
M3 - Article
C2 - 12940756
AN - SCOPUS:0041854631
SN - 0002-7863
VL - 125
SP - 10703
EP - 10713
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 35
ER -