Studies on the reactivity of organometallic Ru-, Rh- and Os-pta complexes with DNA model compounds

The reactions of arene-metal complexes (arene = p-cymene, benzene or pentamethylcyclopentadienyl, metal = Ru, Rh or Os), including 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decanephosphine (pta) and chloro co-ligands, with 9-methylguanine, adenine, and a series of nucleosides were studied in water to ascertain the binding modes. The products were characterized by NMR spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Tandem mass spectrometry was found to provide excellent information on preferential binding sites. In general, the N7 position on guanine (the most basic site) was the preferred donor atom for coordination to the metal complexes. The x-ray structures of the precursor complexes, [(h5-C10H15)RhCl(pta-Me)2]Cl2, [(h6-C10H14)OsCl(pta)2]Cl, and [(h6-C6H6)OsCl2(CH3CN)], are also reported.

From hydrolytically labile to hydrolytically stable Ru(II)-arene anticancer complexes with carbohydrate-derived co-ligands

Paul Joseph Dyson, Muhammad Hanif, Christian Hartinger, Alexey Nazarov

The synthesis, characterization, reactivity and in vitro anticancer activity of a series of Ru-II-arene complexes with carbohydrate-derived phosphite and biscarboxylato co-ligands are reported. The compounds were characterized by NMR spectroscopy and electrospray ionization (ESI) mass spectrometry, and the molecular structures of oxalato(eta(6)-p-cymene)(3,5,6-bicyclophosphite-1,2-O-isopropylidene-alpha-D-glucofuranoside)ruthenium(II) and oxalato(eta(6)-p-cymene)(3,5,6-bicyclophosphite-1,2-O-cyclohexylidene-alpha-D-glucofuranoside)ruthenium(II) were determined by X-ray diffraction analysis. In contrast to their dichlorido counterparts, the biscarboxylato complexes did not exhibit significant reactivity towards biomolecules, such as cysteine, methionine, ubiquitin or the DNA model 5'-GMP, and resist hydrolysis; no hydrolytic species were detected by H-1 and P-31(H-1) NMR spectroscopy over several days. These structural alterations led to a decrease in the tumor-inhibiting potency of the compounds in human cancer cell lines. (C) 2010 Elsevier Inc. All rights reserved.

2011

Binding of Organometallic Ruthenium(II) and Osmium(II) Complexes to an Oligonucleotide: A Combined Mass Spectrometric and Theoretical Study

Antoine Dorcier, Paul Joseph Dyson, Christian Gossens, Ursula Röthlisberger, Rosario Scopelliti, Ivano Tavernelli

Ru(II) and Os(II) p-cymene dichloride complexes with either a pta (1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane) or [pta-Me]Cl ligand which exhibit anticancer activity were prepd. and characterized by 1H and 31P NMR spectroscopy and mass spectrometry. Three of the complexes, viz. [Os(h6-p-cymene)Cl2(pta)] and [M(h6-p-cymene)Cl2(pta-Me)]Cl (M = Ru, Os), also were characterized by single-crystal x-ray diffraction. The pta complexes are selective anticancer agents, whereas the pta-Me+ complexes are indiscriminate and damage both cancer and healthy cells but represent models for the protonated pta adduct which was implicated in drug activity. To establish a link between their biol. activity and the effect they have on DNA (a likely in vivo target), the reactivity of the complexes toward a 14-mer oligonucleotide (5'-ATACATGGTACATA-3') was studied using electrospray ionization mass spectrometry. The complexes bind to the oligonucleotide with loss of chloride and in some cases loss of the arene. Loss of arene appears to be most facile with the Ru-pta complexes but also takes place with the Ru-pta-Me complexes, whereas arene loss is not obsd. for the Os complexes. As pH is reduced, increased binding to the oligonucleotide is obsd., as evidenced from mass spectrometric relative intensities. Binding energies between the metal centers and the surrounding ligands were calcd. using d. functional theory (DFT). The calcd. energies rationalize the exptl. obsd. tendencies for arene loss and show that the pta ligands are relatively strongly bound. Exchange of metal center (Ru vs. Os), methylation or protonation of the pta ligand, or change of the arene (p-cymene vs. benzene) results in significant differences in the metal-arene binding energies while leaving the metal-phosphine bond strength essentially unchanged. Significantly lower binding energies and reduced hapticity are predicted for the exchange of arene by nucleobases. The latter show higher binding energies for N s-bonding than for p-bonding. [on SciFinder (R)]

2005

Mannich products of kojic acid and N-heterocycles and their Ru(II)-arene complexes: Synthesis, characterization and stability

Paul Joseph Dyson, Christian Hartinger, Alexey Nazarov

Ru(II)-η6-p-cymene compds. bearing pyrone-derived ligands, which were obtained by Mannich reactions between kojic acid and piperidine or morpholine analogs, have been synthesized. The compds. were characterized by NMR spectroscopy, mass spectrometry, thermogravimetric anal. and, in the case of 2,6-dimethylmorpholine-derived ligand I, by x-ray diffraction anal. The chlorido complexes are prone to aquation in aq. soln. which results in the formation of dimers. Dimer formation can be inhibited by in situ replacement of the chlorido ligand by imidazole yielding compds. which are significantly more stable in water, as demonstrated by 1H NMR spectroscopy.

Elsevier2010

Binding of Organometallic Ruthenium(II) and Osmium(II) Complexes to an Oligonucleotide: A Combined Mass Spectrometric and Theoretical Study

Antoine Dorcier, Paul Joseph Dyson, Christian Gossens, Ursula Röthlisberger, Rosario Scopelliti, Ivano Tavernelli

2005