title: Unprecedented head-to-head conformers of d(GpG) bound to the antitumor active compound tetrakis (mu-carboxylato)dirhodium(II,II).
abstract: The N7/O6 equatorial binding interactions of the antitumor active complex Rh(2)(OAc)(4)(H(2)O)(2) (OAc(-) = CH(3)CO(2)(-)) 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 (pK(a) approximately 5.7 as compared to 8.5 for N7 only bound platinum adducts), suggested by the pH dependence titrations of the purine H8 (1)H NMR resonances for Rh(2)(OAc)(2)(9-EtG)(2) and Rh(2)(OAc)(2-)[d(GpG)],are consistent with bidentate N7/O6 binding of the guanine nucleobases. The pK(a) values estimated for N1-H (de)protonation, from the pH dependence studies of the C6 and C2 (13)C NMR resonances for the Rh(2)(OAc)(2)(9-EtG)(2) isomers, concur with those derived from the H8 (1)H NMR resonance titrations. Comparison of the (13)C NMR resonances of C6 and C2 for the dirhodium adducts Rh(2)(OAc)(2)(9-EtG)(2) and Rh(2)(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 Deltadelta approximately 11.0 and 6.0 ppm for C6 and C2, respectively; the latter 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 Rh(2)(OAc)(2)[d(GpG)] indicate head-to-head arrangement of the guanine bases. The Rh(2)(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 Rh(2)(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.
authors.affiliation: Department of Chemistry, Texas A&M University, College Station, TX 77843, USA. chifotides@mail.chem.tamu.edu
authors.forename: Helen T
authors.initials: HT
authors.lastname: Chifotides
authors.forename: Karl M
authors.initials: KM
authors.lastname: Koshlap
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Pérez
authors.forename: Kim R
authors.initials: KR
authors.lastname: Dunbar
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D002247:Carbon Isotopes; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000737:chemistry* / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D009690:Nucleic Acid Conformation; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002247:Carbon Isotopes; D018736:DNA Adducts; D015226:Dinucleoside Phosphates; D009942:Organometallic Compounds; C034298:deoxyguanylyl-(3'-5')-guanosine; D006147:Guanine; C014542:9-ethylguanine; C062962:dirhodium tetraacetate