Guanine Nucleobase Adducts Formed by [Pt(di-(2-picolyl)amine)Cl]Cl: Evidence That a Tridentate Ligand with Only in-Plane Bulk Can Slow Guanine Base Rotation

Abstract

Pt(II) complexes bind preferentially at N7 of G residues of DNA, causing DNA structural distortions associated with anticancer activity. Some distortions induced by difunctional cisplatin are also found for monofunctional Pt(II) complexes with carrier ligands having bulk projecting toward the guanine base. This ligand bulk can be correlated with impeded rotation about the Pt-N7(guanine) bond. Pt(N(H)dpa)(G) adducts (N(H)dpa = di-(2-picolyl)amine, G = 5'-GMP, 5'-GDP, 5'-GTP, guanosine, 9-EtG, and 5'-IMP) were used to assess whether a tridentate carrier ligand having bulk concentrated in the coordination plane can impede guanine nucleobase rotation. Because the Pt(N(H)dpa) moiety contains a mirror plane but is unsymmetrical with respect to the coordination plane, Pt(N(H)dpa)(G) adducts can form anti or syn rotamers with the guanine O6 and the central N-H of N(H)dpa on the opposite or the same side of the coordination plane, respectively. The observation of two sharp, comparably intense guanine H8 NMR signals provided evidence that these Pt(N(H)dpa)(G) adducts exist as mixtures of syn and anti rotamers, that rotational interchange is impeded by N(H)dpa, and that the key interactions involves steric repulsions between the pyridyl and guanine rings. The relative proximity of the guanine H8 to the anisotropic pyridyl rings allowed us to conclude that the syn rotamer was usually more abundant. However, the anti rotamer was more abundant for the Pt(N(H)dpa)(5'-GTP) adduct, in which a hydrogen bond between the 5'-GTP γ-phosphate group and the N(H)dpa central N-H is geometrically possible. In all previous examples of the influence of hydrogen bond formation on rotamer abundance in Pt(II) guanine adducts, these hydrogen bonding interactions occurred between ligand groups in cis positions. Thus, the role of a trans ligand group in influencing rotamer abundance, as found here, is unusual.

Linear Bidentate Ligands (L) with Two Terminal Pyridyl N-Donor Groups Forming Pt(II)LCl2 Complexes with Rare Eight-Membered Chelate Rings

“…The structural features of complexes with M–N­(sulfonamide) bonds reported in the literature, including the Cu cyclam complexes just discussed, suggest a reason why potentially tridentate ligands 1 and 2 coordinate in a bidentate fashion in Pt­(II) complexes 5 and 6 , respectively, even when the complexes are prepared using synthetic approaches known to be successful with related ligands having a central amine N-donor. ,, These observations lead us to propose that a nitrogen atom in a central tertiary sulfonamide group with two adjacent five-membered chelate rings can act as a donor in a tridentate ligand only when the ligand is facially coordinated.…”

“…The relevance of binding at G residues in DNA by anticancer-active Pt­(II) compounds ,,,, has led to many studies of adduct formation of guanine derivatives ( G ). Mono- and bifunctional Pt­(II) chloro complexes bearing carrier ligands with five- and six-membered chelate rings readily form G adducts in various solvents. ,, Upon adduct formation, guanine ligands can even disrupt and open a chelate ring . Surprisingly, the new Pt­(II) compounds do not readily form G adducts.…”

Synthesis and characterization of water-soluble, heteronuclear ruthenium(III)/ferrocene complexes and their interactions with biomolecules

“…are given in Tables 1 and 2 and molecular views of each are shown in Figures 1, 2, and 3, for RuL1, RuL2, and RuL3, respectively. Bond lengths and angles are reasonable for ruthenium(III) species [6,[8][9][10]41,46]. RuL1 forms a dimeric structure in the solid state with the sodium facilitating interactions between a chloride ligand and the ruthenium bound DMSO oxygen of one complex with the oxygen atom of the ester group on a neighboring complex ( Figure 1).…”

“…Metal containing pharmaceuticals are much sought after in recent years [1][2][3][4] given the the success of certain bioinorganic platinum compounds, especially the hallmark anticancer drug, cisplatin. These compounds have been the subject of many mechanistic studies with the generally accepted mechanism being the binding of the platinum to guanine of DNA in the cell and thus causing cell death by apoptosis [5][6][7][8][9][10]. Recently, new platinum compounds and compounds with metal centers other than platinum have been investigated as a result of cisplatin's severe side-effects and problems with drug resistance [11][12][13][14][15][16][17].…”

“…Ruthenium has been one metal that has been targeted as a replacement for platinumbased drugs due to its generally reduced host toxicity and interesting redox properties [1][2][3][4]26,27]. Both ruthenium(III) and organometallic ruthenium(II) species [5][6][7][8][9][10][28][29][30][31][32][33][34][35] have been studied and two ruthenium(III) complexes, NAMI-A and KP1019, [11][12][13][14][15][16][17]27,36] have completed phase I clinical trials. [18][19][20][21][22][23][24][25][37][38][39][40][41][42] In recent years, bioorganometallic compounds (defined as biologically active organometallic species)…”