Head‐to‐Head Cross‐Linked Adduct between the Antitumor Unit Bis(μ‐N,N′‐di‐p‐tolylformamidinato)dirhodium(II,II) and the DNA Fragment d(GpG)

Abstract

Reactions of the compound cis-[Rh2(DTolF)2(CH3CN)6](BF4)2, a formamidinate derivative of the class of antitumor compounds [Rh2(O2CR)4] (R=Me, Et, Pr), with 9-ethylguanine (9-EtGuaH) or the dinucleotide d(GpG) proceed by substitution of the acetonitrile groups, with the guanine bases spanning the Rh--Rh bond, in a bridging fashion, through sites N7/O6. In the case of 9-EtGuaH, both head-to-head (HH) and head-to-tail (HT) isomers are formed, whereas with the tethered bases in d(GpG), only one right-handed conformer HH1R [Rh2(DTolF)2{d(GpG)}] is present in solution. For both cis-[Rh2(DTolF)2(9-EtGuaH)2](BF4)2 and [Rh2(DTolF)2{d(GpG)}], the absence of N7 protonation at low pH and the substantial decrease of the pKa values for N1-H deprotonation, support N7/O6 binding of the bases to the dirhodium core. The N7/O6 binding of the bases is further corroborated by the downfield shift by Deltadelta approximately 4.0 ppm of the 13C NMR resonances for the C6 nuclei as compared to the corresponding resonances of the free ligands. The HH arrangement of the guanine bases in [Rh2(DTolF)2{d(GpG)}] is indicated by the intense H8/H8 ROE cross-peaks in the 2D ROESY NMR spectrum. Complete characterization of the [Rh2(DTolF)2{d(GpG)}] conformer by 2D NMR spectroscopy supports anti-orientation and N (C3'-endo) conformation for both deoxyribose residues. The N-pucker for the 5'-G base is universal in such cross-links, but it is very unusual for platinum and unprecedented for dirhodium HH cross-linked adducts to have both deoxyribose residues in the N-type conformation. The bulk, the nonlabile character, and the electron-donating ability of the formamidinate bridging groups spanning the dirhodium core affect the nature of the preferred dirhodium DNA adducts. Molecular modeling studies performed on [Rh2(DTolF)2{d(GpG)}] corroborate the structural features obtained by NMR spectroscopy.

Transition Metal Ion Complexes of N-alkylguanines

“…Dunbar et al [62] have indeed found that, when complexes cis-[Rh II 2 (dtolf) 2 (O 2 CCF 3 ) 2 ] or cis-[Rh II 2 (dtolf) 2 (NCCH 3 ) 6 ] (dtolf = anion of N,N'-di-p-tolylformamidinate) were treated with 9-ethylguanine, coordination proceeded by substitution of the carboxylate or acetonitrile groups, respectively, to afford the corresponding bis-nucleobase adduct cis-[Rh II 2 (dtolf) 2 (He 9 gua) 2 ](BF 4 ) 2 (110) in which the nucleobases adopted both HH and HT orientations. The 1 H-NMR spectrum recorded for (110) displayed two guaninyl H-8 proton resonances due to the presence of both the HH and HT isomers in solution, Scheme (15) [61]. A pH-dependent 1 H-NMR titration experiment also revealed that the guaninyl ligands Half-sandwich tetrahedral (T-4) ( 6 -p-cymene)-ruthenium(II) and -osmium(II) complexes (101-108) [56,57].…”

“…The photolysis ( irr > 345 nm, 10 min) of Ru(II) complex(62) in the presence of single-stranded 15-mer oligonuclotides, 5Dinuclear platinum(II)-ruthenium(II) and platinum(II)-iridium(III) complexes(59)(60)(61) [42,43].…”

Head‐to‐Head Right‐Handed Cross‐Links of the Antitumor‐Active Bis(μ‐N,N′‐di‐p‐tolylformamidinato)dirhodium(II,II) Unit with the Dinucleotides d(GpA) and d(ApG)

“…In the case of dirhodium, findings in our laboratories have unequivocally established that guanine bases bind to the metal core in a manner involving unprecedented equatorial ( eq ) bridging interactions through N7 and O6 13. Head‐to‐head (HH)31a cross‐links with eq bidentate (N7/O6) guanine bases bridging the RhRh bond were also identified in the dinucleotide dirhodium adducts [Rh 2 (O 2 CCH 3 ) 2 {d(GpG)}],22 [Rh 2 (O 2 CCH 3 ) 2 {d(pGpG)}],23 and [Rh 2 (DTolF) 2 {d(GpG)}] 24. Notable features of the adducts are the deprotonation of the guanine N1 site, that is, stabilization of the enolate form of guanine, and a substantial increase in the acidity of the N1H sites as a result of bidentate N7/O6 coordination 13.…”

“…Notable features of the adducts are the deprotonation of the guanine N1 site, that is, stabilization of the enolate form of guanine, and a substantial increase in the acidity of the N1H sites as a result of bidentate N7/O6 coordination 13. 22–24 In the aforementioned d((p)GpG) complexes, the presence of intense H8/H8 ROE (rotating frame nuclear Overhauser effect) cross‐peaks in the 2D ROESY NMR spectra indicate a HH arrangement for the tethered guanine bases. The [Rh 2 (O 2 CCH 3 ) 2 {d(GpG)}] complex exhibits two major right‐handed conformers HH1R (≈75 %) and HH2R (≈25 %),22 as opposed to only one right‐handed HH1R conformer for [Rh 2 (DTolF) 2 {d(GpG)}] 24.…”

Synthesis and X-ray crystal structure of the dirhenium complex Re2(i-C3H7COO)4Cl2 and its interactions with the DNA purine nucleobases

“…The substituted guanine and adenine nucleobases span the dirhenium unit in a bridging fashion at eq positions via N7/O6 and N1/N6 sites, respectively. The reported substituted guanine derivatives and the nucleotides span the dirhodium metal-metal bond via the positions N7/O6[22,23] but the substituted adenine derivatives and the nucleotides bind via N7/N6 sites to the dirhodium core[35][36][37]. The adenine sites N1/N6 are involved in hydrogen bonding with thymine in double-stranded DNA; thus, binding of the adenine bases to the dirhenium core induces disruption of the nucleobase hydrogen bonding.…”