Showing papers by "Robert J. Deeth published in 2009"

Ruthenium(II) arene anticancer complexes with redox-active diamine ligands.

Abstract: The synthesis and characterization of ruthenium(II) arene complexes of the general formula [(eta(6)-arene)Ru(XY)Z](+), where arene = p-cymene (p-cym), hexamethyl benzene (hmb), or biphenyl (bip), XY = o-phenylenediamine (o-pda), o-benzoquinonediimine (o-bqdi), or 4,5-dimethyl-o-phenylenediamine (dmpda), and Z = Cl, Br, or l, are reported (complexes 1-6). In addition, the X-ray crystal structures of [(eta(6)-p-cym)Ru(o-pda)Cl]PF6 (1) and [(eta(6)-hmb)Ru-(o-bqdi)Cl]PF6 (3PF(6)) are described. The Ru-N distances in 3PF(6) are significantly shorter [2.033(4) and 2.025(4) angstrom] compared to those in 1 [2.141(2) and 2.156(2) angstrom], All of the imine complexes (3-5) exhibit a characteristic broad H-1 NMR NH resonance at ca. delta 14-15. Complex 1 undergoes concomitant ligand-based oxidation and hydrolysis (38% after 24 h) in water. The oxidation also occurs in methanol. The iodido complex [(eta(6)-p-cym)Ru(o-bqdi)l]l (4) did not undergo hydrolysis, whereas the chlorido complex 3 showed relatively fast hydrolysis (t(1/2) = 7.5 min). Density functional theory calculations showed that the total bonding energy of 9-EtG in [(eta(6)-p-cym)Ru(o-pda)(9-EtG-N7)](2+) (1EtG) is 23.8 kJ/mol lower than that in [(eta(6)-p-cym)Ru(o-bqdi)(9-EtG-N7)](2+) (3EtG). The greater bonding energy is related to the contribution from strong hydrogen bonding between the NH proton of the chelating ligand and O6 of 9-EtG (1.69 angstrom). A loss of cytotoxic activity was observed upon oxidation of the amine ligand to an imine (e.g., IC50 = 11 mu M for 1 and IC50 > 100 mu M for 3, against A2780 ovarian cancer cells). The relationship between the cytotoxic activity and the solution and solid state structures of the imine and amine complexes is discussed.

Amide linkage isomerism as an activity switch for organometallic osmium and ruthenium anticancer complexes.

Abstract: We show that the binding mode adopted by picolinamide derivatives in organometallic OsII and RuII half-sandwich complexes can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in OsII (1, 3−5, 7, 9) and RuII (2, 6, 8, 10) complexes [(η6-arene)(Os/Ru)(XY)Cl]n+, where arene = p-cymene (1−8, 10) or biphenyl (9), can act as N,N- or N,O-donors. Electron-withdrawing substituents on the phenyl ring resulted in N,N-coordination and electron-donating substituents in N,O-coordination. Dynamic interconversion between N,O and N,N configurations can occur in solution and is time- and temperature- (irreversible) as well as pH-dependent (reversible). The neutral N,N-coordinated compounds (1−5 and 9) hydrolyzed rapidly (t1/2 ≤ min), exhibited significant (32−70%) and rapid binding to guanine, but no binding to adenine. The N,N-coordinated compounds 1, 3, 4, and 9 exhibited significant activity against colon, ovarian, and cisplatin-resistant ovarian human cancer cell lines (3 ≫ 4 > 1 > 9...

Is enantioselectivity predictable in asymmetric catalysis

Abstract: A range of computational methods have been applied to harmonize predicted ee values with experimental values. Novel ways of combining quantum mechanics and molecular mechanics feature prominently.

Synthesis, characterisation and photochemistry of PtIV pyridyl azido acetato complexes

Abstract: PtII azido complexes [Pt(bpy)(N3)2] (1), [Pt(phen)(N3)2] (2) and trans-[Pt(N3)2(py)2] (3) incorporating the bidentate diimine ligands 2,2′-bipyridine (bpy), 1,10-phenanthroline (phen) or the monodentate pyridine (py) respectively, have been synthesised from their chlorido precursors and characterised by X-ray crystallography; complex 3 shows significant deviation from square-planar geometry (N3–Pt–N3 angle 146.7°) as a result of steric congestion at the Pt centre. The novel PtIV complexes trans, cis-[Pt(bpy)(OAc)2(N3)2] (4), trans, cis-[Pt(phen)(OAc)2(N3)2] (5), trans, trans, trans-[Pt(OAc)2(N3)2(py)2] (6), were obtained from 1–3viaoxidation with H2O2 in acetic acid followed by reaction of the intermediate with acetic anhydride. Complexes 4–6 exhibit interesting structural and photochemical properties that were studied by X-ray, NMR and UV-vis spectroscopy and TD-DFT (time-dependent density functional theory). These PtIV complexes exhibit greater absorption at longer wavelengths (e = 9756 M−1 cm−1 at 315 nm for 4; e = 796 M−1 cm−1 at 352 nm for 5; e = 16900 M−1 cm−1 at 307 nm for 6, in aqueous solution) than previously reported PtIV azide complexes, due to the presence of aromatic amines, and 4–6 undergo photoactivation with both UVA (365 nm) and visible green light (514 nm). The UV-vis spectra of complexes 4–6 were calculated using TD-DFT; the nature of the transitions contributing to the UV-vis bands provide insight into the mechanism of production of the observed photoproducts. The UV-vis spectra of 1–3 were also simulated by computational methods and comparison between PtII and PtIV electronic and structural properties allowed further elucidation of the photochemistry of 4–6.

Capturing the Trans Influence in Low-Spin d(8) Square-Planar Platinum(II) Systems using Molecular Mechanics.

Abstract: Molecular modeling of coordination complexes continues to present challenges for force field methods. Implicit or explicit treatment of the significant d electron effects is mandatory. Ligand field molecular mechanics is designed for coordination complexes by explicitly including the ligand field stabilization energy (LFSE) and it is applied here to model the trans influence in tetracoordinate Pt(II) complexes of general formulas PtX4, PtX3Y, cis-PtX2Y2, and trans-PtX2Y2, where X and Y are OH2, H(-), Cl(-), Br(-), PR3, SH2, NR3, and pyridine. Parameters have been developed within the Merck molecular force field using DFT structures and energies as reference data. Both geometric changes and relative energies are generally well-reproduced although PH3 and H(-) complexes show deviations. However, for phosphine complexes, replacing PH3 with PMe3 resolves all bar one of these. The LFSE associated with the low-spin d(8) configuration ensures planar coordination and provides an electronic connection between all the ligands, thus enabling a correct description of the trans influence. The parameters developed for NR3 and PR3 with R = H work well for R = Me and Et and, in agreement with experimental and/or DFT structures, display either a tetrahedral distortion or even ligand dissociation.

Synthesis, characterization, and reaction pathways for the formation of a GMP adduct of a cytotoxic thiocyanato ruthenium arene complex.

Abstract: The organoruthenium complex [(η6-hmb)Ru(en)(Cl)][PF6] (hmb is hexamethylbenzene, en is ethylenediamine) undergoes facile aquation and then reacts with KSCN in unbuffered solution to give the S-coordinated thiocyanato product [(η6-hmb)Ru(en)(S-SCN)]+ which slowly converts to the thermodynamically favored N-bound complex [(η6-hmb)Ru(en)(N-NCS)]+ (1+). Complex 1 was synthesized and characterized by X-ray crystallography and mass spectrometry. Despite its lack of hydrolysis over 24 h, complex 1 exhibits moderate cytotoxicity (IC50 24 μM) towards the human ovarian cancer cell line A2780, comparable with that of the chlorido analogue which is thought to be activated (towards potential target DNA) via a rapid aquation (Wang et. al. in Proc Natl Acad Sci USA 102:18269–18274, 2005). Detailed kinetic studies suggest that complex 1 binds to guanosine 5′-monophosphate (GMP) through direct N7 substitution of the N-bound SCN ligand. In the presence of a high concentration of chloride (104 mM), however, complex 1 may bind partly to GMP via Cl substitution.

Ist die Enantioselektivität bei der asymmetrischen Katalyse vorhersagbar

Abstract: Vorheersagekraft: Um berechnete ee-Werte mit experimentellen ee-Werten zur Deckung zu bringen, wurde eine Reihe von Rechenmethoden eingesetzt. Neue Verfahren, bei denen quantenmechanische und molekulmechanische Methoden kombiniert werden, sind sehr erfolgreich.

Apparent non-statistical binding in a ditopic receptor for guanosine

Abstract: Analysis of stepwise association constants for guests binding to more than one site in a receptor is expected to give a ratio of the first association constant to the second of about 4 : 1 on statistical grounds (since a second guest should have an equal chance of binding to a different site on the same, or a new molecule). Taking account of self-association in our analysis of a system in which the binding sites are close together, we observe a ratio closer to 1 : 1, indicative of non-statistical, or cooperative binding. The longer homologue built around two alkynes displays a very different ratio of stepwise association constants of about 7 : 1. We discuss the origins of this unusual behaviour in terms of steric interactions within the receptors and their corresponding complexes with guanosine derivatives.

Ligand field torque: a pi-type electronic driving force for determining ligand rotational preferences.

Abstract: Transition metal complexes with triply-degenerate T ground states are formally Jahn-Teller active but do not usually display the significant bond length distortions familiar from their E ground state counterparts like d(9) Cu(II) The electronic 'asymmetry' for T-state systems lies in the d(pi) orbitals, which interact with the ligands relatively weakly compared to the stronger sigma-type interactions for E-state systems However, in combination with asymmetric M-L pi bonding, T-type systems have an additional mechanism for relieving the electronic strain Density functional theory, ligand field theory and ligand field molecular mechanics calculations are used to show how rotations around the M-L bonds can affect their pi-pi (d(pi)-L-pi) interactions and lead to significant energy lowering For example, d(6) [ Fe(OH2)(6)](2+), which has a T-5(g) state in cubic T-h symmetry, 'distorts' to an S-6 structure 44 kcal mol(-1) lower in energy (by DFT) but with six equal Fe-O distances via Fe-O rotations of similar to 20 degrees and thus masquerades as an apparently regular geometry Using model systems, we show that this effect is not restricted to formally Jahn-Teller active complexes The combination of asymmetric p bonding and asymmetric d(pi) orbital occupations can generate an M-L 'torque' worth up to 6 kcal mol(-1) per bond which can 'lock' the ligand in a particular orientation relative to the partially-occupied d orbital(s) The effect is particularly marked for imidazole, the donor group of histidine, which, in a model low-spin d(5) Fe(III) system, shows almost no orientational preference in its neutral form but a very strong (similar to 6 kcal mol(-1)) orientational preference in its deprotonated form

Is Enantioselectivity Predictable in Asymmetric Catalysis

Abstract: A range of computational methods have been applied to harmonize predicted ee values with experimental values. Novel ways of combining quantum mechanics and molecular mechanics feature prominently.