The organometallic anticancer complex [(eta6-bip)Ru(en)Cl]+ (1; bip = biphenyl, en = ethylenediamine) selectively binds to guanine (N7) bases of DNA (Novakova, O.; Chen, H.; Vrana, O.; Rodger, A.; Sadler, P. J.; Brabec, V. Biochemistry 2003, 42, 11544-11554). In this work, competition between the tripeptide glutathione (gamma-L-Glu-L-Cys-Gly; GSH) and guanine (as guanosine 3',5'-cyclic monophosphate, cGMP) for complex 1 was investigated using HPLC, LC-MS and 1H,15N NMR spectroscopy. In unbuffered solution (pH ca. 3), the reaction of 1 with GSH gave rise to three intermediates: an S-bound thiolato adduct [(eta6-bip)Ru(en)(GS-S)] (4) and two carboxylate-bound glutathione products [(eta6-bip)Ru(en)(GSH-O)]+ (5, 6) during the early stages (<6 h), followed by en displacement and formation of a tri-GS-bridged dinuclear Ru(II) complex [((eta6-bip)Ru)2(GS-mu-S)3]2- (7). Under physiologically relevant conditions (micromolar Ru concentrations, pH 7, 22 mM NaCl, 310 K), the thiolato complex 4 was unexpectedly readily oxidized by dioxygen to the sulfenato complex [(eta6-bip)Ru(en)(GS(O)-S)] (8) instead of forming the dinuclear complex 7. Under these conditions, competitive reaction of complex 1 with GSH and cGMP gave rise to the cGMP adduct [(eta6-bip)Ru(en)(cGMP-N7)]+ (10) as the major product, accounting for ca. 62% of total Ru after 72 h, even in the presence of a 250-fold molar excess of GSH. The oxidation of coordinated glutathione in the thiolato complex 4 to the sulfenate in 8 appears to provide a facile route for displacement of S-bound glutathione by G N7. Redox reactions of cysteinyl adducts of these Ru(II) arene anticancer complexes could therefore play a significant role in their biological activity.

Ruthenium(II) arene complexes of the type [(h 6 -arene)Ru-(en)Cl] + (arene = e.g. p-cymene or biphenyl; en = ethylenediamine) can exhibit anticancer activity in vitro and in vivo. [1] They are pseudooctahedral, half-sandwich, "piano-stool" complexes with one reactive coordination site (the RuÀCl bond). Analysis of the distribution of ruthenium in cancer cells in culture [2] shows that the level of DNA ruthenation is similar to that of platination by the anticancer drug cisplatin. The binding of cisplatin to DNA gives rise to DNA bending, followed by protein recognition and induction of apoptosis. [3] Ruthenium arene complexes are not cross-resistant with cisplatin.[1] This may indicate that structural distortions induced in DNA by ruthenium arenes differ significantly from those induced by cisplatin. Calculations [4] on adducts of Ru II arene complexes with DNA have suggested that this is the case, but experimental evidence is needed. The extent of DNA ruthenation and the nature of the structural distortions in DNA appear to correlate with cytotoxic potency, [5] and also influence protein recognition.[6] The studies reported herein reveal novel and varied modes of interaction of [(h 6 -biphenyl)Ru(en)Cl] + (1) with duplex DNA. We chose duplex III for study because an NMR analysis has previously been carried out and the kinking induced by GG platination of strand I by cisplatin has been characterized.

Herein we report the first photochromic polyoxometalate (POM)-based diarylethene (DAE) coordination complex, prepared by ligation of two cobalt(III)-incorporated borotungstates [BWOCo] with the ditopic pyridyl-containing diarylethene (CHNFS). The solution-state composition, structure, and stability of the assembly were probed using H andF nuclear magnetic resonance spectroscopy (NMR), electrospray ionization quadrupolar time-of-flight mass spectrometry (ESI-QTOF-MS), ultraviolet-visible spectroscopy (UV-vis), and small-angle X-ray scattering (SAXS), revealing that the complex self-organizes to adopt a molecular dumbbell structure due to electrostatic and steric considerations. This conformation is a prerequisite for the photocyclization reaction. The assembly was found to be switchable between two states using visible light due to the perturbation of the DAE electronic structure on coordination to the POM. We present photophysical data, including the reaction quantum efficiency of the molecular switch in both directions measured using a custom-built quantum yield determination setup in addition to fatigue resistance on prolonged irradiation.

The organometallic anticancer complex [(η(6)-bip)Ru(en)Cl](+) (1; bip = biphenyl, en = ethylenediamine) selectively binds to N7 of guanine bases of oligonucleotides and native DNA. However, under physiologically relevant conditions (micromolar Ru concentrations, pH 7, 22 mM NaCl, 310 K), the tripeptide glutathione (γ-L-Glu-L-Cys-Gly; GSH) is kinetically competitive with guanine (as guanosine 3',5'-cyclic monophosphate, cGMP) for coordination with complex 1, and gives rise to a ruthenium thiolato adduct. This thiolato adduct can subsequently undergo oxidation to a sulfenate intermediate, providing a facile route for the formation of a final cGMP adduct via the displacement of S-bound glutathione by G N7 (F. Y. Wang, J. J. Xu, A. Habtemariam, J. Bella and P. J. Sadler, J. Am. Chem. Soc., 2005, 127, 17734). In this work, the competition between GSH and the single-stranded 14-mer oligonucleotide 5'-TATGTACCATGTAT-3' (I) and duplex III (III = I + II, II = 5'-ATACATGGTACATA) for complex 1 and its analogue [(η(6)-tha)Ru(en)Cl](+) (2, tha = tetrahydroanthracene) under physiologically relevant conditions was investigated using conventional ESI-MS and high resolution ESI-FTICR-MS coupled to conventional HPLC and nanoscale HPLC, respectively. The results indicate that whether there was high excess of GSH or not in the reaction mixtures, the reaction of complex 1 or 2 with single-stranded oligonucleotide I always gave rise to mono-ruthenated oligonucleotide, and the reaction of complex 1 or 2 with duplex III gave rise to the mono-ruthenated duplex oligonucleotide. Furthermore, the ruthenation of duplex III by complex 1 showed no significant discrimination between the complementary strands I and II, but complex 2 appeared to bind preferentially to strand II compared to strand I as revealed by the high resolution FTICR-MS analysis. GSH is highly abundant in cells at millimolar concentrations and is well known to be involved in the deactivation of the clinical drug cisplatin and in platinum resistance. Our findings reveal a potentially contrasting role for GSH in the mechanism of action of these ruthenium anticancer complexes that may contribute to the lack of cross-resistance with platinum drugs.

Going OS: Oxygenation of thiolate sulfur atoms can control biological signaling processes. Rare examples of a monodentate sulfenate ligands stabilized by hydrogen bonding to a diamine ligand within organometallic ruthenium arene complexes of pharmaceutical interest and their unusual acid/base properties are reported.

Reactions of the anticancer complex [(eta(6)-bip)Ru(en)Cl](+) (where bip is biphenyl and en is ethylenediamine) with the tripeptide glutathione (gamma-L-Glu-L-Cys-Gly; GSH), the abundant intracellular thiol, in aqueous solution give rise to two ruthenium cluster complexes, which could not be identified by electrospray mass spectrometry (ESI-MS) using a quadrupole mass analyzer. Here we use Fourier transform ion cyclotron mass spectrometry (nanoLC-FT-ICR MS) to identify the clusters separated by nanoscale liquid chromatography as the tetranuclear complex [{(eta(6)-bip)Ru(GSO(2))}(4)](2-) (2) and dinuclear complex [{(eta(6)-bip)Ru(GSO(2))(2)}(2)](8-) (3) containing glutathione sulfinate (GSO(2)) ligands. Use of (18)OH(2) showed that oxygen from water can readily be incorporated into the oxidized glutathione ligands. These data illustrate the power of high-resolution MS for identifying highly charged multinuclear complexes and elucidating novel reaction pathways for metallodrugs, including ligand-based redox reactions.

Ruthenium(II) arene complexes of the type [(h 6 -arene)Ru-(en)Cl] + (arene = e.g. p-cymene or biphenyl; en = ethylenediamine) can exhibit anticancer activity in vitro and in vivo. [1] They are pseudooctahedral, half-sandwich, "piano-stool" complexes with one reactive coordination site (the RuÀCl bond). Analysis of the distribution of ruthenium in cancer cells in culture [2] shows that the level of DNA ruthenation is similar to that of platination by the anticancer drug cisplatin. The binding of cisplatin to DNA gives rise to DNA bending, followed by protein recognition and induction of apoptosis. [3] Ruthenium arene complexes are not cross-resistant with cisplatin.[1] This may indicate that structural distortions induced in DNA by ruthenium arenes differ significantly from those induced by cisplatin. Calculations [4] on adducts of Ru II arene complexes with DNA have suggested that this is the case, but experimental evidence is needed. The extent of DNA ruthenation and the nature of the structural distortions in DNA appear to correlate with cytotoxic potency, [5] and also influence protein recognition.[6] The studies reported herein reveal novel and varied modes of interaction of [(h 6 -biphenyl)Ru(en)Cl] + (1) with duplex DNA. We chose duplex III for study because an NMR analysis has previously been carried out and the kinking induced by GG platination of strand I by cisplatin has been characterized.

A catalytic enantioselective formal [2+2] cycloaddition between a-halo acroleins and electronically diverse arylalkenes is described. In the presence of (S)-oxazaborolidinium cation as the catalyst, densely functionalized cyclobutanes containing two vicinal tetrasubstituted stereocenters were produced in high yields and high diastereoselectivities with excellent enantioselectivities. Mechanistic studies revealed that the cis isomer could be transformed into the trans isomer via an enantiocontrolled process. A gram-scale reaction of this catalytic method was used to demonstrate its synthetic potential. Scheme 1. Chiral Lewis acid catalyzed asymmetric [2+2] cycloadditions.