Pt^II Coordination to N1 of 9‐Methylguanine: Why it Facilitates Binding of Additional Metal Ions to the Purine Ring

Abstract

The preparation and X-ray crystal structure analysis of {trans-[Pt(MeNH(2))(2)(9-MeG-N1)(2)]}⋅{3 K(2)[Pt(CN)(4)]}⋅6 H(2)O (3 a) (with 9-MeG being the anion of 9-methylguanine, 9-MeGH) are reported. The title compound was obtained by treating [Pt(dien)(9-MeGH-N7)](2+) (1; dien=diethylenetriamine) with trans-[Pt(MeNH(2))(2)(H(2)O)(2)](2+) at pH 9.6, 60 °C, and subsequent removal of the [(dien)Pt(II)] entities by treatment with an excess amount of KCN, which converts the latter to [Pt(CN)(4)](2-). Cocrystallization of K(2)[Pt(CN)(4)] with trans-[Pt(MeNH(2))(2)(9-MeG-N1)(2)] is a consequence of the increase in basicity of the guanine ligand following its deprotonation and Pt coordination at N1. This increase in basicity is reflected in the pK(a) values of trans-[Pt(MeNH(2))(2)(9-MeGH-N1)(2)](2+) (4.4±0.1 and 3.3±0.4). The crystal structure of 3 a reveals rare (N7,O6 chelate) and unconventional (N2,C2,N3) binding patterns of K(+) to the guaninato ligands. DFT calculations confirm that K(+) binding to the sugar edge of guanine for a N1-platinated guanine anion is a realistic option, thus ruling against a simple packing effect in the solid-state structure of 3 a. The linkage isomer of 3 a, trans-[Pt(MeNH(2))(2)(9-MeG-N7)(2)] (6 a) has likewise been isolated, and its acid-base properties determined. Compound 6 a is more basic than 3 a by more than 4 log units. Binding of metal entities to the N7 positions of 9-MeG in 3 a has been studied in detail for [(NH(3))(3)Pt(II)], trans-[(NH(3))(2)Pt(II)], and [(en)Pd(II)] (en=ethylenediamine) by using (1)H NMR spectroscopy. Without exception, binding of the second metal takes place at N7, but formation of a molecular guanine square with trans-[(Me(2)NH(2))Pt(II)] cross-linking N1 positions and trans-[(NH(3))(2)Pt(II)] cross-linking N7 positions could not be confirmed unambiguously, despite the fact that calculations are fully consistent with its existence.

Pyriplatin-Boron-Dipyrromethene Conjugates for Imaging and Mitochondria-Targeted Photodynamic Therapy

“…This rather unusual chelation could occur through the N 7 and O 6 atoms of 9-EtG by displacing the ammine group of the pyriplatin core with the bidentate monoanionic 9-EtG giving a mass peak with m / z value of 715.2740 assignable to [Pt II (NH 3 )­(L)­(9-EtG)] + with characteristic isotopic distribution (Scheme S1, Figures S59–S66, Supporting Information). A similar speciation of the related platinum complexes was observed in our earlier study and also reported in the literature. ,− A new peak at 8.25 ppm suggested the formation of the hydrolyzed intermediate species (Scheme S1, Figures S59–S66, Supporting Information). The mechanistic data reveal the DNA cross-linking potential of the complexes, and this property could enhance their overall cytotoxicity when compared to that of the free ligands, thus highlighting the important role of platinum.…”

“…The monofunctional platinum­(II) complexes are known to form single covalent adduct with the nuclear DNA by the loss of the chloride ligand. ,− The binding ability of the complexes 1 – 4 with a model nucleobase, namely, 6-amino-9-ethyl-2-hydroxypurine (9-ethylguanine, 9-EtG), was studied by NMR and HRMS spectroscopy. The N7 atom of guanine is the binding position of the metal, and a downfield chemical shift of the H8 proton which is immediate next to the N7 atom is known to occur in the 1 H NMR spectrum.…”

Nucleotide Binding Preference of the Monofunctional Platinum Anticancer‐Agent Phenanthriplatin

“…Unlike 9-methylguanine, for which only the N 7 platinum adduct is commonly reported, [38][39][40][41][42][43] both the N 7 and N 1 positions of adenine [44][45][46][47][48] frequently form adducts with platinum. We therefore inferred that the two species observed by HPLC correspond to N 1 and N 7 linkagei somers of the platinatedn ucleobase.…”

Monofunctional BODIPY-Appended Imidazoplatin for Cellular Imaging and Mitochondria-Targeted Photocytotoxicity

“…Monofunctional platinum­(II) complexes are known to form covalent adducts with nucleotide bases predominantly at the N7 position of guanosine and consequently do not unwind or bend the structure of the DNA duplex. − Unlike classical bifunctional platinum­(II) complexes like cisplatin and its analogues, which induce distortion in DNA and inhibit cellular processes, monofunctional platinum­(II) complexes show unconventional mode of action. Therefore, the formation of Pt­(II)-DNA adduct was studied using 9-ethylguanine (9-EtG) as a model nucleobase by ESI-MS and 1 H NMR spectroscopy.…”