Unprecedented Head-to-Head Conformers of d(GpG) Bound to the Antitumor Active Compound Tetrakis (-carboxylato)dirhodium(II,II)
详细信息 查看全文
- 作者：Helen T. Chifotides ; Karl M. Koshlap ; Lisa M. Pé ; rez ; and Kim R. Dunbar
- 刊名：Journal of the American Chemical Society
- 出版年：2003
- 出版时间：September 3, 2003
- 年：2003
- 卷：125
- 期：35
- 页码：10703 - 10713
- 全文大小：340K
- 年卷期：v.125,no.35(September 3, 2003)
- ISSN：1520-5126
文摘
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 ofdirhodium tetraacetate with 9-ethylguanine (9-EtGH) revealed unprecedented bridging N7/O6 guaninenucleobases that span the Rh-Rh bond. The absence of N7 protonation at low pH and the notable increasein the acidity of N1-H (pKa 
mages/entities/ap.gif"> 5.7 as compared to 8.5 for N7 only bound platinum adducts), suggested bythe 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 valuesestimated for N1-H (de)protonation, from the pH dependence studies of the C6 and C2 13C NMRresonances for the Rh2(OAc)2(9-EtG)2 isomers, concur with those derived from the H8 1H NMR resonancetitrations. Comparison of the 13C NMR resonances of C6 and C2 for the dirhodium adducts Rh2(OAc)2(9-EtG)2 and Rh2(OAc)2{d(GpG)} with the corresponding resonances of the unbound ligands {at pH 7.0 for9-EtGH and pH 8.0 for d(GpG)}, shows substantial downfield shifts of mages/gifchars/Delta.gif" BORDER=0 >mages/gifchars/delta.gif" BORDER=0 > mages/entities/ap.gif"> 11.0 and 6.0 ppm for C6 andC2, respectively; the latter shifts reflect the effect of O6 binding to the dirhodium centers and the ensuingenhancement in the acidity of N1-H. Intense H8/H8 ROE cross-peaks in the 2D ROESY NMR spectrumof 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 timesmore abundant than the unusual HH2 R. Complete characterization of both adducts revealed repuckeringof the 5'-G sugar rings to C3'-endo (N-type), retention of C2'-endo (S-type) conformation for the 3'-G sugarrings, 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(NH3)2{d(GpG)}] andcorroborate molecular modeling studies.