Organometallic Ruthenium(II) Diamine Anticancer Complexes:  Arene-Nucleobase Stacking and Stereospecific Hydrogen-Bonding in Guanine Adducts

• Published in: Journal of the American Chemical Society 2002-03, Vol.124 (12), p.3064-3082
• Main Authors: Chen, Haimei, Parkinson, John A, Parsons, Simon, Coxall, Robert A, Gould, Robert O, Sadler, Peter J
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Condensed matter: structure, mechanical and thermal properties; Crystallography, X-Ray; Exact sciences and technology; Guanine - analogs & derivatives; Guanine - chemistry; Guanine - metabolism; Hydrogen Bonding; Inorganic compounds; Magnetic Resonance Spectroscopy; Metal complexes; Models, Chemical; Molecular Structure; Organometallic Compounds - chemistry; Organometallic Compounds - metabolism; Organometallic Compounds - pharmacology; Physics; Ruthenium - chemistry; Ruthenium - pharmacology; Single-crystal and powder diffraction; Stereoisomerism; Structure of solids and liquids; crystallography; Structure of specific crystalline solids; Substrate Specificity; X-ray diffraction and scattering
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja017482e

Organometallic ruthenium(II) arene anticancer complexes of the type [(η6-arene)Ru(II)(en)Cl][PF6] (en = ethylenediamine) specifically target guanine bases of DNA oligomers and form monofunctional adducts (Morris, R., et al. J. Med. Chem. 2001). We have determined the structures of monofunctional adducts of the “piano-stool” complexes [(η6-Bip)Ru(II)(en)Cl][PF6] (1, Bip = biphenyl), [(η6-THA)Ru(II)(en)Cl][PF6] (2, THA = 5,8,9,10-tetrahydroanthracene), and [(η6-DHA)Ru(II)(en)Cl][PF6] (3, DHA = 9,10-dihydroanthracene) with guanine derivatives, in the solid state by X-ray crystallography, and in solution using 2D [1H,1H] NOESY and [1H,15N] HSQC NMR methods. Strong π−π arene-nucleobase stacking is present in the crystal structures of [(η6-C14H14)Ru(en)(9EtG-N7)][PF6]2·(MeOH) (6) and [(η6-C14H12)Ru(en)(9EtG-N7)][PF6]2·2(MeOH) (7) (9EtG = 9-ethylguanine). The anthracene outer ring (C) stacks over the purine base at distances of 3.45 Å for 6 and 3.31 Å for 7, with dihedral angles of 3.3° and 3.1°, respectively. In the crystal structure of [(η6-biphenyl)Ru(en)(9EtG-N7)][PF6]2·(MeOH) (4), there is intermolecular stacking between the pendant phenyl ring and the purine six-membered ring at a distance of 4.0 Å (dihedral angle 4.5°). This stacking stabilizes a cyclic tetramer structure in the unit cell. The guanosine (Guo) adduct [(η6-biphenyl)Ru(en)(Guo-N7)][PF6]2·3.75(H2O) (5) exhibits intramolecular stacking of the pendant phenyl ring with the purine five-membered ring (3.8 Å, 23.8°) and intermolecular stacking of the purine six-membered ring with an adjacent pendant phenyl ring (4.2 Å, 23.0°). These occur alternately giving a columnar-type structure. A syn orientation of arene and purine is present in the crystal structures 5, 6, and 7, while the orientation is anti for 4. However, in solution, a syn orientation predominates for all the biphenyl adducts 4, 5, and the guanosine 5‘-monophosphate (5‘-GMP) adduct 8 [(η6-biphenyl)Ru(II)(en)(5‘-GMP-N7)], as revealed by NMR NOE studies. The predominance of the syn orientation both in the solid state and in solution can be attributed to hydrophobic interactions between the arene and purine rings. There are significant reorientations and conformational changes of the arene ligands in [(η6-arene)Ru(II)(en)(G-N7)] complexes in the solid state, with respect to those of the parent chloro-complexes [(η6-arene)Ru(II)(en)Cl]+. The arene ligands have flexibility through rotation around the arene-Ru π-bonds, propeller twisting for Bi