A Very Rare Example of a Structurally Characterized 3′-GMP Metal Complex. NMR and Synthetic Assessment of Adducts Formed by Guanine Derivatives with [Pt(L^tri)Cl]Cl Complexes with an N,N′,N″ Tridentate Ligand (L^tri) Terminated by Imidazole Rings

Abstract

[Pt(N(R)-1,1'-Medma)Cl]Cl complexes with tridentate ligands (bis(1-methyl-2-methylimidazolyl)amine, R = H; N-(methyl)bis(1-methyl-2-methylimidazolyl)amine, R = Me) were prepared in order to investigate Pt(N(R)-1,1'-Medma)G adducts (G = monodentate N9-substituted guanine or hypoxanthine derivative). Solution NMR spectroscopy is the primary tool for studying metal complexes of nucleosides and nucleotides because such adducts rarely crystallize. However, [Pt(N(H)-1,1'-Medma)(3'-GMPH)]NO·5HO (5) was crystallized, allowing, to our knowledge, the first crystallographic molecular structure determination for a 3'-GMP platinum complex. The structure is one of only a very few structures of a 3'-GMP complex with any metal. Complex 5 has the syn rotamer conformation, with 3'-GMP bound by N7. All Pt(N(R)-1,1'-Medma)G adducts exhibit two new downfield-shifted G H8 signals, consistent with G bound to platinum by N7 and a syn/anti rotamer mixture. Anticancer-active monofunctional platinum(II) complexes have bulky carrier ligands that cause DNA adducts to be distorted. Hence, understanding carrier-ligand steric effects is key in designing new platinum drugs. Ligand bulk can be correlated with the degree of impeded rotation of the G nucleobase about the Pt-N7 bond, as assessed by the observation of rotamers. The signals of syn and anti rotamers are connected by EXSY cross-peaks in 2D ROESY spectra of Pt(N(H)-1,1'-Medma)G adducts but not in spectra of Pt(N(H)dpa)G adducts (N(H)dpa = bis(2-picolyl)amine), indicating that rotamer interchange is more facile and carrier-ligand bulk is lower in Pt(N(H)-1,1'-Medma)G than in Pt(N(H)dpa)G adducts. The lower steric hindrance is a direct consequence of the greater distance of the G nucleobase from the H4/4' protons in the N(R)-1,1'-Medma carrier ligand in comparison to that from the H6/6' protons in the N(H)dpa carrier ligand. Although in 5 the nucleotide is 3'-GMP (not the usual 5'-GMP) and the N(H)-1,1'-Medma carrier ligand is very different from those typically present in structurally characterized Pt(II) G complexes, the rocking and canting angles in 5 adhere to long-recognized trends.

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

“…The Pt–N–centroid angles of 5 are similar to the values for other bifunctional Pt­(II) complexes of monodentate pyridyl ligands, which have five-membered, − , six-membered, , or seven-membered chelate rings and can adopt optimal metrics not limited by the chelate ring (see the Supporting Information). These structural metrics as well as the downfield shifts of NMR signals noted above indicate that 5 has enthalpically favorable pyridyl–Pt bonding interactions.…”

“…This angle, defined as the Pt–N–centroid angle (N = N1 or N3, centroid = aromatic ring center) should approach ∼180°. The Pt–N–centroid angle ranges from 164–180° for known Pt­(II) complexes of imidazolyl or pyridyl ligands bound in a monodentate, bidentate, or tridentate fashion. − ,− This angle averages 174.5° for 5 (Table ), which is similar to the value for monodentate ligands (176.7°; see the Supporting Information); this is another indication that the pyridyl rings in 5 are well-positioned to form a strong Pt–N bond.…”

“…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.…”

“…Previous studies have shown that N(H)dpa (Figure 2) and related ligands readily form [Pt(L tri )Cl] + complexes. 20,21 However, the new N(SO 2 R)Me n dpa ligands form Pt(II) complexes with bidentate N(SO 2 R)Me n dpa ligands having an eight-membered chelate ring, in which the tertiary sulfonamide nitrogen is not bound to Pt(II) but serves as an atom in the −CH 2 −N(SO 2 R)−CH 2 − chain of the chelate ring. Structural characterizations of Pt(II) complexes with bidentate ligands having eight-membered chelate rings such as those found here are very few in number compared with bifunctional Pt(II) complexes with smaller five-, six-, or seven-membered chelate rings of bidentate pyridyl/imidazolyl ligands 22−44 or with two pyridyl/imidazolyl monodentate ligands.…”

BODIPY–dipicolylamine complexes of platinum(ii): X-ray structure, cellular imaging and organelle-specific near-IR light type-II PDT

“…Platinum( ii ) complexes are known to bind to ds-DNA through intercalation or direct coordination or can show electrostatic binding to exert an anticancer effect (ds, double strand). 49 The present mono-functional platinum( ii ) complexes are designed to have a chloride ligand substitution to form a DNA adduct with the N7 position of guanine. The possibility of DNA crosslink formation was studied using complex 2 and a model nucleobase 9-ethylguanine (9-EtG).…”