Publications by authors named "Abraha Habtemariam"

76 Publications

Photoactivated Osmium Arene Anticancer Complexes.

Inorg Chem 2021 Sep 9. Epub 2021 Sep 9.

Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K.

Half-sandwich Os-arene complexes exhibit promising anticancer activity, but their photochemistry has hardly been explored. To exploit the photocytotoxicity and photochemistry of Os-arenes, -chelated complexes [Os(η--cymene)(Curc)Cl] (, Curc = curcumin) and [Os(η-biphenyl)(Curc)Cl] (), and -chelated complexes [Os(η-biphenyl)(dpq)I]PF (, dpq = pyrazino[2,3-][1,10]phenanthroline) and [Os(η-biphenyl)(bpy)I]PF (, bpy = 2,2'-bipyridine), have been investigated. The Os-arene curcumin complexes showed remarkable photocytotoxicity toward a range of cancer cell lines (blue light IC: 2.6-5.8 μM, photocytotoxicity index PI = 23-34), especially toward cisplatin-resistant cancer cells, but were nontoxic to normal cells. They localized mainly in mitochondria in the dark but translocated to the nucleus upon photoirradiation, generating DNA and mitochondrial damage, which might contribute toward overcoming cisplatin resistance. Mitochondrial damage, apoptosis, ROS generation, DNA damage, angiogenesis inhibition, and colony formation were observed when A549 lung cancer cells were treated with . The photochemistry of these Os-arene complexes was investigated by a combination of NMR, HPLC-MS, high energy resolution fluorescence detected (HERFD), X-ray adsorption near edge structure (XANES) spectroscopy, total fluorescence yield (TFY) XANES spectra, and theoretical computation. Selective photodissociation of the arene ligand and oxidation of Os(II) to Os(III) occurred under blue light or UVA excitation. This new approach to the design of novel Os-arene complexes as phototherapeutic agents suggests that the novel curcumin complex , in particular, is a potential candidate for further development as a photosensitizer for anticancer photoactivated chemotherapy (PACT).
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http://dx.doi.org/10.1021/acs.inorgchem.1c00241DOI Listing
September 2021

Osmium(ii) tethered half-sandwich complexes: pH-dependent aqueous speciation and transfer hydrogenation in cells.

Chem Sci 2021 Jul 10;12(27):9287-9297. Epub 2021 Jun 10.

IMDEA Nanociencia Faraday 9 28049 Madrid Spain

Aquation is often acknowledged as a necessary step for metallodrug activity inside the cell. Hemilabile ligands can be used for reversible metallodrug activation. We report a new family of osmium(ii) arene complexes of formula [Os(η-CH(CH)OH)(XY)Cl] () bearing the hemilabile η-bound arene 3-phenylpropanol, where XY is a neutral N,N or an anionic N,O bidentate chelating ligand. Os-Cl bond cleavage in water leads to the formation of the hydroxido/aqua adduct, Os-OH(H). In spite of being considered inert, the hydroxido adduct unexpectedly triggers rapid tether ring formation by attachment of the pendant alcohol-oxygen to the osmium centre, resulting in the alkoxy tethered complex [Os(η-arene--κ)(XY)] . Complexes of formula [Os(η:κ-CH(CH)OH/O)(XY)] are fully characterised, including the X-ray structure of cation . Tether-ring formation is reversible and pH dependent. Osmium complexes bearing picolinate N,O-chelates () catalyse the hydrogenation of pyruvate to lactate. Intracellular lactate production upon co-incubation of complex (XY = 4-Me-picolinate) with formate has been quantified inside MDA-MB-231 and MCF7 breast cancer cells. The tether Os-arene complexes presented here can be exploited for the intracellular conversion of metabolites that are essential in the intricate metabolism of the cancer cell.
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http://dx.doi.org/10.1039/d1sc01939bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278929PMC
July 2021

Platinum(IV)-azido monocarboxylato complexes are photocytotoxic under irradiation with visible light.

Dalton Trans 2021 Aug;50(30):10593-10607

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. and Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Complexes trans,trans,trans-[Pt(N3)2(OH)(OCOR)(py)2] where py = pyridine and where OCOR = succinate (1); 4-oxo-4-propoxybutanoate (2) and N-methylisatoate (3) have been synthesized by derivation of trans,trans,trans-[Pt(OH)2(N3)2(py)2] (4) and characterised by NMR and EPR spectroscopy, ESI-MS and X-ray crystallography. Irradiation of 1-3 with green (517 nm) light initiated photoreduction to Pt(ii) and release of the axial ligands at a 3-fold faster rate than for 4. TD-DFT calculations showed dissociative transitions at longer wavelengths for 1 compared to 4. Complexes 1 and 2 showed greater photocytotoxicity than 4 when irradiated with 420 nm light (A2780 cell line IC50 values: 2.7 and 3.7 μM) and complex 2 was particularly active towards the cisplatin-resistant cell line A2780cis (IC50 3.7 μM). Unlike 4, complexes 1-3 were phototoxic under green light irradiation (517 nm), with minimal toxicity in the dark. A pKa(H2O) of 5.13 for the free carboxylate group was determined for 1, corresponding to an overall negative charge during biological experiments, which crucially, did not appear to impede cellular accumulation and photocytotoxicity.
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http://dx.doi.org/10.1039/d1dt01730fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335519PMC
August 2021

Structure-activity relationships for osmium(II) arene phenylazopyridine anticancer complexes functionalised with alkoxy and glycolic substituents.

J Inorg Biochem 2020 09 24;210:111154. Epub 2020 Jun 24.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. Electronic address:

Twenty-four novel organometallic osmium(II) phenylazopyridine (AZPY) complexes have been synthesised and characterised; [Os(η-arene)(5-RO-AZPY)X]Y, where arene = p-cym or bip, AZPY is functionalized with an alkoxyl (O-R, R = Me, Et, Pr, Pr, Bu) or glycolic (O-{CHCHO}R*, n = 1-4, R* = H, Me, or Et) substituent on the pyridyl ring para to the azo-bond, X is a monodentate halido ligand (Cl, Br or I), and Y is a counter-anion (PF, CFSO or IO). X-ray crystal structures of two complexes confirmed their 'half-sandwich' structures. Aqueous solubility depended on X, the AZPY substituents, arene, and Y. Iodido complexes are highly stable in water (X = I ⋙ Br > Cl), and exhibit the highest antiproliferative activity against A2780 (ovarian), MCF-7 (breast), SUNE1 (nasopharyngeal), and OE19 (oesophageal) cancer cells, some attaining nanomolar potency and good cancer-cell selectivity. Their activity and distinctive mechanism of action is discussed in relation to hydrophobicity (RP-HPLC capacity factor and Log P), cellular accumulation, electrochemical reduction (activation of azo bond), cell cycle analysis, apoptosis and induction of reactive oxygen species (ROS). Two complexes show ca. 4× higher activity than cisplatin in the National Cancer Institute (NCI) 60-cell line five-dose screen. The COMPARE algorithm of their datasets reveals a strong correlation with one another, as well as anticancer agents olivomycin, phyllanthoside, bouvardin and gamitrinib, but only a weak correlation with cisplatin, indicative of a different mechanism of action.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111154DOI Listing
September 2020

Structurally Strained Half-Sandwich Iridium(III) Complexes As Highly Potent Anticancer Agents.

J Med Chem 2020 04 1;63(8):4005-4021. Epub 2020 Apr 1.

IMDEA Nanociencia, Faraday 9, 28049 Madrid, Spain.

Six complexes of formula [Ir(η:κ-CMeCHpy)(C,N)]PF, where CMeCHpy is 2-((2,3,4,5-tetramethylcyclopentadienyl)methyl)pyridine, and C,N is 2-phenylpyridine (), 7,8-benzoquinoline (), 1-phenylisoquinoline (), 2-(-tolyl)pyridine (), 4-chloro-2-phenylquinoline (), or 2-(2,4-difluorophenyl)pyridine (), have been synthesized. The cyclopentadienyl ligand bears a tethered pyridine that binds to the metal center, resulting in an Ir(η:κ-MeCHpy) tether-ring structure, as confirmed by the X-ray crystal structures of , , , , and . Nontether versions of and were synthesized to aid unambiguous correlation between structure and activity. While nontether complexes are highly potent toward MCF7 cancer cells (similar to cisplatin), complexes bearing the tether-ring structure, -, are exceptionally more potent (1-2 orders of magnitude). Additionally, - disrupt mitochondrial membrane potential (ΔΨ) and induce oxidative stress. Internalization studies strongly correlate intracellular accumulation and anticancer activity in tether and nontether complexes. We present a new class of organo-iridium drug candidates bearing a structural feature that results in a leap in anticancer potency.
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http://dx.doi.org/10.1021/acs.jmedchem.9b02000DOI Listing
April 2020

Strategies for conjugating iridium(III) anticancer complexes to targeting peptides via copper-free click chemistry.

Inorganica Chim Acta 2020 Apr 23;503:119396. Epub 2019 Dec 23.

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.

We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged 'piano-stool' configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes.
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http://dx.doi.org/10.1016/j.ica.2019.119396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610455PMC
April 2020

Photoactivatable Cell-Selective Dinuclear trans-Diazidoplatinum(IV) Anticancer Prodrugs.

Inorg Chem 2018 Nov 26;57(22):14409-14420. Epub 2018 Oct 26.

Department of Chemistry , University of Warwick , Coventry CV4 7AL , U.K.

A series of dinuclear octahedral Pt complexes trans, trans, trans-[{Pt(N)(py)(OH)(OC(O)CHCHC(O)NH)}R] containing pyridine (py) and bridging dicarboxylate [R = -CHCH- (1), trans-1,2-CH- (2), p-CH- (3), -CHCHCHCH- (4)] ligands have been synthesized and characterized, including the X-ray crystal structures of complexes 1·2MeOH and 4, the first photoactivatable dinuclear Pt complexes with azido ligands. The complexes are highly stable in the dark, but upon photoactivation with blue light (420 nm), they release the bridging ligand and mononuclear photoproducts. Upon irradiation with blue light (465 nm), they generate azidyl and hydroxyl radicals, detected using a 5,5-dimethyl-1-pyrroline N-oxide electron paramagnetic resonance spin trap, accompanied by the disappearance of the ligand-to-metal charge-transfer (N → Pt) band at ca. 300 nm. The dinuclear complexes are photocytotoxic to human cancer cells (465 nm, 4.8 mW/cm, 1 h), including A2780 human ovarian and esophageal OE19 cells with IC values of 8.8-78.3 μM, whereas cisplatin is inactive under these conditions. Complexes 1, 3, and 4 are notably more photoactive toward cisplatin-resistant ovarian A2780cis compared to A2780 cells. Remarkably, all of the complexes were relatively nontoxic toward normal cells (MRC5 lung fibroblasts), with IC values >100 μM, even after irradiation. The introduction of an aromatic bridging ligand (3) significantly enhanced cellular uptake. The populations in the stages of the cell cycle remained unchanged upon treatment with complexes in the dark, while the population of the G2/M phase increased upon irradiation, suggesting that DNA is a target for these photoactivated dinuclear Pt complexes. Liquid chromatography-mass spectrometry data show that the photodecomposition pathway of the dinuclear complexes results in the release of two molecules of mononuclear platinum(II) species. As a consequence, DNA binding of the dinuclear complexes after photoactivation in cell-free media is, in several respects, qualitatively similar to that of the photoactivated mononuclear complex FM-190. After photoactivation, they were 2-fold more effective in quenching the fluorescence of EtBr bound to DNA, forming DNA interstrand cross-links and unwinding DNA compared to the photoactivated FM-190.
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http://dx.doi.org/10.1021/acs.inorgchem.8b02599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257630PMC
November 2018

Transfer Hydrogenation and Antiproliferative Activity of Tethered Half-Sandwich Organoruthenium Catalysts.

Organometallics 2018 May 23;37(10):1555-1566. Epub 2018 Apr 23.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, U.K.

We report the synthesis and characterization of four neutral organometallic tethered complexes, [Ru(η-Ph(CH)-ethylenediamine--R)Cl], where R = methanesulfonyl (Ms, ), toluenesulfonyl (Ts, ), 4-trifluoromethylbenzenesulfonyl (Tf, ), and 4-nitrobenzenesulfonyl (Nb, ), including their X-ray crystal structures. These complexes exhibit moderate antiproliferative activity toward human ovarian, lung, hepatocellular, and breast cancer cell lines. Complex in particular exhibits a low cross-resistance with cisplatin. The complexes show potent catalytic activity in the transfer hydrogenation of NAD to NADH with formate as hydride donor in aqueous solution (310 K, pH 7). Substituents on the chelated ligand decreased the turnover frequency in the order Nb > Tf > Ts > Ms. An enhancement of antiproliferative activity (up to 22%) was observed on coadministration with nontoxic concentrations of sodium formate (0.5-2 mM). Complex binds to nucleobase guanine (9-EtG), but DNA appears not to be the target, as little binding to calf thymus DNA or bacterial plasmid DNA was observed. In addition, complex reacts rapidly with glutathione (GSH), which might hamper transfer hydrogenation reactions in cells. Complex induced a dose-dependent G cell cycle arrest after 24 h exposure in A2780 human ovarian cancer cells while promoting an increase in reactive oxygen species (ROS), which is likely to contribute to its antiproliferative activity.
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http://dx.doi.org/10.1021/acs.organomet.8b00132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989272PMC
May 2018

New activation mechanism for half-sandwich organometallic anticancer complexes.

Chem Sci 2018 Mar 1;9(12):3177-3185. Epub 2018 Mar 1.

Department of Chemistry , University of Warwick , Gibbet Hill Road , Coventry CV4 7AL , UK . Email:

The Cp C-H protons in certain organometallic Rh half-sandwich anticancer complexes [(η-Cp )Rh(,')Cl], where Cp = Cp*, phenyl or biphenyl-MeCp, and ,' = bipyridine, dimethylbipyridine, or phenanthroline, can undergo rapid sequential deuteration of all 15 Cp* methyl protons in aqueous media at ambient temperature. DFT calculations suggest a mechanism involving abstraction of a Cp* proton by the Rh-hydroxido complex, followed by sequential H/D exchange, with the Cp* rings behaving like dynamic molecular 'twisters'. The calculations reveal the crucial role of p orbitals of ,'-chelated ligands in stabilizing deprotonated Cp ligands, and also the accessibility of Rh-fulvene intermediates. They also provide insight into why biologically-inactive complexes such as [(Cp*)Rh(en)Cl] and [(Cp*)Ir(bpy)Cl] do not have activated Cp* rings. The thiol tripeptide glutathione (γ-l-Glu-l-Cys-Gly, GSH) and the activated dienophile -methylmaleimide, (NMM) did not undergo addition reactions with the proposed Rh-fulvene, although they were able to control the extent of Cp* deuteration. We readily trapped and characterized Rh-fulvene intermediates by Diels-Alder [4+2] cyclo-addition reactions with the natural biological dienes isoprene and conjugated (9,11)-linoleic acid in aqueous media, including cell culture medium, the first report of a Diels-Alder reaction of a metal-bound fulvene in aqueous solution. These findings will introduce new concepts into the design of organometallic Cp* anticancer complexes with novel mechanisms of action.
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http://dx.doi.org/10.1039/c7sc05058eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916112PMC
March 2018

Reversible pH-Responsive Behavior of Ruthenium(II) Arene Complexes with Tethered Carboxylate.

Inorg Chem 2018 May 24;57(9):5657-5668. Epub 2018 Apr 24.

IMDEA Nanociencia, Faraday 9 , Ciudad Universitaria de Cantoblanco , Madrid 28049 , Spain.

Five complexes of formula [Ru(η-CHCHCOOH)(XY)Cl]Cl/Na (XY = ethylenediamine (1), o-phenylenediamine (2), phenanthroline (3), and oxalato (4)) and [Ru(η:κ-CHCHCOO)(tmen)]Cl (tmen = N, N, N', N'-tetramethylethylenediamine, 5C) have been synthesized and fully characterized. Five new X-ray crystal structures ([Ru(η-CHCHCOOH)(μ-Cl)Cl], 1, 3, 4, and 5C·PF) have been determined, which are the first examples of ruthenium(II) structures with phenylacetic acid as arene ligand. Furthermore, 5C·PF is the first example of a five-membered tether ring with a Ru(η:κ-arene:O) bond. The tether ring in these complexes opens in acidic pH (<5) and closes reversibly in aqueous solution. The chlorido open-form undergoes aquation, and the aqua adduct can be observed (prior to ring closure) by NMR. The speciation has an attractive complexity in the pH range 0-12, showing interconversion of the three species (chlorido, aqua, and closed tether), dependent on the proton concentration and the nature of the XY chelating ligand. The closed tether version of 3, complex 3C, with σ-donor/π-acceptor phenanthroline as chelating ligand, opens up more readily (pH 4), while the tether ring in complex 5C hardly opens even at pH as low as 1. We have determined the p K of the pendant carboxylic group and that of the aqua adduct (ca. 3 and ca. 7, respectively), which can be finely tuned by the appropriate choice of XY. Complexes 1 and 2, which predominate in their inactive (closed-tether) form in intracellular conditions, show some cytotoxic activity (IC 130 and 117 μM, respectively) in A2780 ovarian cancer cells. Complex 1 catalyzes the reduction through transfer hydrogenation of pyruvate to lactate and NAD to NADH in the presence of formate as H-source. Co-incubation with sodium formate decreases the IC value of 1 in A2780 cancer cells significantly.
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http://dx.doi.org/10.1021/acs.inorgchem.8b00625DOI Listing
May 2018

Half-Sandwich Arene Ruthenium(II) and Osmium(II) Thiosemicarbazone Complexes: Solution Behavior and Antiproliferative Activity.

Organometallics 2018 Mar 20;37(6):891-899. Epub 2018 Feb 20.

Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale and CIRCMSB (Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici), University of Parma, Parco Area delle Scienze 11/A, 43124 Parma, Italy.

We report the synthesis, characterization, and antiproliferative activity of organo-osmium(II) and organo-ruthenium(II) half-sandwich complexes [(η--cym)Os(L)Cl]Cl ( and ) and [(η--cym)Ru(L)Cl]Cl ( and ), where L = -(2-hydroxy)-3-methoxybenzylidenethiosemicarbazide () or -(2,3-dihydroxybenzylidene)-3-phenylthiosemicarbazide (), respectively. X-ray crystallography showed that all four complexes possess half-sandwich pseudo-octahedral "three-legged piano-stool" structures, with a neutral N,S-chelating thiosemicarbazone ligand and a terminal chloride occupying three coordination positions. In methanol, / isomerization of the coordinated thiosemicarbazone ligand was observed, while in an aprotic solvent like acetone, partial dissociation of the ligand occurs, reaching complete displacement in a more coordinating solvent like DMSO. In general, the complexes exhibited good activity toward A2780 ovarian, A2780Cis cisplatin-resistant ovarian, A549 lung, HCT116 colon, and PC3 prostate cancer cells. In particular, ruthenium complex does not present cross-resistance with the clinical drug cisplatin in the A2780 human ovarian cancer cell line. The complexes were more active than the free thiosemicarbazone ligands, especially in A549 and HCT116 cells with potency improvements of up to 20-fold between organic ligand and ruthenium complex .
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http://dx.doi.org/10.1021/acs.organomet.7b00875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908187PMC
March 2018

Effect of sulfonamidoethylenediamine substituents in Ru arene anticancer catalysts on transfer hydrogenation of coenzyme NAD by formate.

Dalton Trans 2018 May;47(21):7178-7189

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.

A series of neutral pseudo-octahedral RuII sulfonamidoethylenediamine complexes [(η6-p-cym)Ru(N,N')Cl] where N,N' is N-(2-(R1,R2-amino)ethyl)-4-toluenesulfonamide (TsEn(R1,R2)) R1,R2 = Me,H (1); Me,Me (2); Et,H (3); benzyl,H (Bz, 4); 4-fluorobenzyl,H (4-F-Bz, 5) or naphthalen-2-ylmethyl,H (Naph, 6), were synthesised and characterised including the X-ray crystal structure of 3. These complexes catalyse the reduction of NAD+ regioselectively to 1,4-NADH by using formate as the hydride source. The catalytic efficiency depends markedly on the steric and electronic effects of the N-substitutent, with turnover frequencies (TOFs) increasing in the order: 1 < 2 < 3, 6 < 4, 5, achieving a TOF of 7.7 h-1 for 4 with a 95% yield of 1,4-NADH. The reduction rate was highest between pH* (deuterated solvent) 6 and 7.5 and improved with an increase in formate concentration (TOF of 18.8 h-1, 140 mM formate). The calculations suggested initial substitution of an aqua ligand by formate, followed by hydride transfer to RuII and then to NAD+, and indicated specific interactions between the aqua complex and both NAD+ and NADH, the former allowing a preorganisation involving interaction between the aqua ligand, formate anion and the pyridine ring of NAD+. The complexes exhibited antiproliferative activity towards A2780 human ovarian cancer cells with IC50 values ranging from 1 to 31 μM, the most potent complex, [(η6-p-cym)Ru(TsEn(Bz,H))Cl] (4, IC50 = 1.0 ± 0.1 μM), having a potency similar to the anticancer drug cisplatin. Co-administration with sodium formate (2 mM), increased the potency of all complexes towards A2780 cells by 20-36%, with the greatest effect seen for complex 6.
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http://dx.doi.org/10.1039/c8dt00438bDOI Listing
May 2018

Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes.

Chem Sci 2017 Dec 20;8(12):8271-8278. Epub 2017 Oct 20.

Department of Chemistry , University of Warwick , Coventry CV4 7AL , UK . Email:

Mitochondria generate energy but malfunction in many cancer cells, hence targeting mitochondrial metabolism is a promising approach for cancer therapy. Here we have designed cyclometallated iridium(iii) complexes, containing one TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) spin label [CHNOIr·PF]˙ () and two TEMPO spin labels [CHNOIr·PF]˙ (). Electron paramagnetic resonance (EPR) spectroscopy revealed spin-spin interactions between the TEMPO units in . Both and showed bright luminescence with long lifetimes ( 35-160 ns); while displayed monoexponential decay kinetics, the biexponential decays measured for indicated the presence of more than one energetically-accessible conformation. This observation was further supported by density functional theory (DFT) calculations. The antiproliferative activity of towards a range of cancer cells was much greater than that of , and also the antioxidant activity of is much higher against A2780 ovarian cancer cells when compared with . Most notably was particularly potent towards PC3 human prostate cancer cells (IC = 0.53 μM), being 8× more active than the clinical drug cisplatin, and 15× more selective towards cancer cells normal cells. Confocal microscopy showed that both and localise in the mitochondria of cancer cells.
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http://dx.doi.org/10.1039/c7sc03216aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857930PMC
December 2017

Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells.

Nat Chem 2018 03 8;10(3):347-354. Epub 2018 Jan 8.

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.

Catalytic anticancer metallodrugs active at low doses could minimize side-effects, introduce novel mechanisms of action that combat resistance and widen the spectrum of anticancer-drug activity. Here we use highly stable chiral half-sandwich organometallic Os(II) arene sulfonyl diamine complexes, [Os(arene)(TsDPEN)] (TsDPEN, N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine), to achieve a highly enantioselective reduction of pyruvate, a key intermediate in metabolic pathways. Reduction is shown both in aqueous model systems and in human cancer cells, with non-toxic concentrations of sodium formate used as a hydride source. The catalytic mechanism generates selectivity towards ovarian cancer cells versus non-cancerous fibroblasts (both ovarian and lung), which are commonly used as models of healthy proliferating cells. The formate precursor N-formylmethionine was explored as an alternative to formate in PC3 prostate cancer cells, which are known to overexpress a deformylase enzyme. Transfer-hydrogenation catalysts that generate reductive stress in cancer cells offer a new approach to cancer therapy.
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http://dx.doi.org/10.1038/nchem.2918DOI Listing
March 2018

Halide Control of Coordination versus -Cyclometalation and Stereospecific Phenyl Ring Deuteration of Osmium(II) -Cymene Phenylazobenzothiazole Complexes.

Organometallics 2017 Nov 9;36(22):4367-4375. Epub 2017 Nov 9.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, U.K.

We report the synthesis of halido Os(II) -cymene complexes bearing bidentate chelating phenylazobenzothiazole (AZBTZ) ligands. Unlike the analogous phenylazopyridine (AZPY) complexes, AZBTZ-NMe is capable of both -coordination to Os(II) and cyclometalation to form -coordinated species. -Coordination occurs via an azo nitrogen and an ortho carbon on the aniline ring, as identified by H NMR and X-ray crystallography of [Os(-cym)(-AZBTZ-NMe)Cl]PF (), [Os(-cym)(-AZBTZ-NMe)Br]PF (), [Os(-cym)(-AZBTZ-NMe)Br] (), and [Os(-cym)(-AZBTZ-NMe)I] (). The -coordinated species is more stable and is not readily converted to the -coordinated complex. Analysis of the crystal structures suggests that their formation is influenced by steric interactions between the -cym and AZBTZ-NMe ligands: in particular, larger monodentate halide ligands favor -coordination. The complexes [Os(-cym)(-Me-AZBTZ-NH)Cl]PF () and [Os(-cym)(-Me-AZBTZ-NH)I]PF () were synthesized with methyl groups blocking the ortho positions on the aniline ring, forcing an -coordination geometry. H NMR NOE experiments confirmed hindered rotation of the arene ligand and steric crowding around the metal center. Complex exhibited unexpected behavior under acidic conditions, involving regiospecific deuteration of the aniline ring at the meta position, as observed by H NMR and high-resolution ESI-MS. Deuterium exchange occurs only under acidic conditions, suggesting an associative mechanism. The calculated partial charges on show that the meta carbon is significantly more negatively charged, which may account for the regiospecificity of deuterium exchange.
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http://dx.doi.org/10.1021/acs.organomet.7b00501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726741PMC
November 2017

Cyclic Peptide-Polymer Nanotubes as Efficient and Highly Potent Drug Delivery Systems for Organometallic Anticancer Complexes.

Biomacromolecules 2018 01 14;19(1):239-247. Epub 2017 Dec 14.

Department of Chemistry, University of Warwick , Gibbet Hill Road, Coventry CV4 7AL, United Kingdom.

Functional drug carrier systems have potential for increasing solubility and potency of drugs while reducing side effects. Complex polymeric materials, particularly anisotropic structures, are especially attractive due to their long circulation times. Here, we have conjugated cyclic peptides to the biocompatible polymer poly(2-hydroxypropyl methacrylamide) (pHPMA). The resulting conjugates were functionalized with organoiridium anticancer complexes. Small angle neutron scattering and static light scattering confirmed their self-assembly and elongated cylindrical shape. Drug-loaded nanotubes exhibited more potent antiproliferative activity toward human cancer cells than either free drug or the drug-loaded polymers, while the nanotubes themselves were nontoxic. Cellular accumulation studies revealed that the increased potency of the conjugate appears to be related to a more efficient mode of action rather than a higher cellular accumulation of iridium.
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http://dx.doi.org/10.1021/acs.biomac.7b01491DOI Listing
January 2018

Organoiridium Photosensitizers Induce Specific Oxidative Attack on Proteins within Cancer Cells.

Angew Chem Int Ed Engl 2017 11 19;56(47):14898-14902. Epub 2017 Oct 19.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

Strongly luminescent iridium(III) complexes, [Ir(C,N) (S,S)] (1) and [Ir(C,N) (O,O)] (2), containing C,N (phenylquinoline), O,O (diketonate), or S,S (dithione) chelating ligands, have been characterized by X-ray crystallography and DFT calculations. Their long phosphorescence lifetimes in living cancer cells give rise to high quantum yields for the generation of O , with large 2-photon absorption cross-sections. 2 is nontoxic to cells, but potently cytotoxic to cancer cells upon brief irradiation with low doses of visible light, and potent at sub-micromolar doses towards 3D multicellular tumor spheroids with 2-photon red light. Photoactivation causes oxidative damage to specific histidine residues in the key proteins in aldose reductase and heat-shock protein-70 within living cancer cells. The oxidative stress induced by iridium photosensitizers during photoactivation can increase the levels of enzymes involved in the glycolytic pathway.
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http://dx.doi.org/10.1002/anie.201709082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698709PMC
November 2017

Combatting AMR: photoactivatable ruthenium(ii)-isoniazid complex exhibits rapid selective antimycobacterial activity.

Chem Sci 2017 Jan 30;8(1):395-404. Epub 2016 Aug 30.

Department of Chemistry , University of Warwick , Gibbet Hill Road , Coventry CV4 7AL , UK . Email:

The novel photoactive ruthenium(ii) complex -[Ru(bpy)(INH)][PF] (·2PF, INH = isoniazid) was designed to incorporate the anti-tuberculosis drug, isoniazid, that could be released from the Ru(ii) cage by photoactivation with visible light. In aqueous solution, rapidly released two equivalents of isoniazid and formed the photoproduct -[Ru(bpy)(HO)] upon irradiation with 465 nm blue light. We screened for activity against bacteria containing the three major classes of cell envelope: Gram-positive , Gram-negative , and using blue and multi-colored LED multi-well arrays. Complex is inactive in the dark, but when photoactivated is 5.5× more potent towards compared to the clinical drug isoniazid alone. Complementary pump-probe spectroscopy measurements along with density functional theory calculations reveal that the mono-aqua product is formed in <500 ps, likely facilitated by a MC state. Importantly, complex is highly selective in killing mycobacteria normal human cells, towards which it is relatively non-toxic. This work suggests that photoactivatable prodrugs such as are potentially powerful new agents in combatting the global problem of antibiotic resistance.
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http://dx.doi.org/10.1039/c6sc03028aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365061PMC
January 2017

Supramolecular Photoactivatable Anticancer Hydrogels.

J Am Chem Soc 2017 04 17;139(16):5656-5659. Epub 2017 Apr 17.

Department of Chemistry, University of Warwick , Gibbet Hill Road, Coventry CV4 7AL, United Kingdom.

A photoactivatable dopamine-conjugated platinum(IV) anticancer complex (Pt-DA) has been incorporated into G-quadruplex GK borate hydrogels by using borate ester linkages (Pt-GKB hydrogel). These were characterized by B NMR, attenuated total reflection Fourier transform infrared spectroscopy, circular dichroism, scanning electron microscopy and transmission electron microscopy. Microscopy investigations revealed the transformation of an extended fiber assembly into discrete flakes after incorporation of Pt-DA. Pt-DA showed photocytotoxicity against cisplatin-resistant A2780Cis human ovarian cancer cells (IC 74 μM, blue light) with a photocytotoxic index <2, whereas Pt-GKB hydrogels exhibited more potent photocytotoxicity (IC 3 μM, blue light) with a photocytotoxic index >5. Most notably, Pt-DA and Pt-GKB hydrogels show selective phototoxicity for cancer cells versus normal fibroblast cells (MRC5).
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http://dx.doi.org/10.1021/jacs.7b00186DOI Listing
April 2017

In-Cell Activation of Organo-Osmium(II) Anticancer Complexes.

Angew Chem Int Ed Engl 2017 01 21;56(4):1017-1020. Epub 2016 Dec 21.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

The family of iodido Os arene phenylazopyridine complexes [Os(η -p-cym)(5-R -pyridylazo-4-R -phenyl))I] (where p-cym=para-cymene) exhibit potent sub-micromolar antiproliferative activity towards human cancer cells and are active in vivo. Their chemical behavior is distinct from that of cisplatin: they do not readily hydrolyze, nor bind to DNA bases. We report here a mechanism by which they are activated in cancer cells, involving release of the I ligand in the presence of glutathione (GSH). The X-ray crystal structures of two active complexes are reported, 1-I (R =OEt, R =H) and 2-I (R =H, R =NMe ). They were labelled with the radionuclide I (β /γ emitter, t 8.02 d), and their activity in MCF-7 human breast cancer cells was studied. 1-[ I] and 2-[ I] exhibit good stability in both phosphate-buffered saline and blood serum. In contrast, once taken up by MCF-7 cells, the iodide ligand is rapidly pumped out. Intriguingly, GSH catalyzes their hydrolysis. The resulting hydroxido complexes can form thiolato and sulfenato adducts with GSH, and react with H O generating hydroxyl radicals. These findings shed new light on the mechanism of action of these organo-osmium complexes.
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http://dx.doi.org/10.1002/anie.201610290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5412917PMC
January 2017

"Head-to-head" double-hamburger-like structure of di-ruthenated d(GpG) adducts of mono-functional Ru-arene anticancer complexes.

Dalton Trans 2016 Nov;45(46):18676-18688

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.

Guanine bases in DNA are targets for some Ru-arene anticancer complexes. We have investigated the structure of the novel di-ruthenated d(GpG) adduct Ru-GpG (where Ru = {(η-biphenyl)-Ru(en)} (1')) in aqueous solution. 2D NMR results indicate that there are two conformers, supported by modeling studies. The major conformer I is a novel double-hamburger-like structure with a "head-to-head" (HH) base arrangement involving hydrophobic interactions between neighboring arene rings, the first example of a HH d(GpG) adduct constructed by weak interactions. Hence there are significant differences compared to Pt-d(GpG) adducts formed by cisplatin. There is no obviously rigid bending for the major conformer I. The minor conformer II of Ru-GpG has a back-to-back structure, with two ruthenated guanine bases flipped away from each other. 19-23 base-pair oligodeoxyribonucleotides containing central TGGT sequences di-ruthenated by 1 show no directional bending, only slightly distorted di-ruthenated duplexes, consistent with the NMR data for conformer I. The structural differences and similarities of d(GpG) residues which are di-ruthenated or cross-linked by platination are discussed in the context of the biological activity of these metal complexes.
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http://dx.doi.org/10.1039/c6dt03356cDOI Listing
November 2016

Upconverting nanoparticles for the near infrared photoactivation of transition metal complexes: new opportunities and challenges in medicinal inorganic photochemistry.

Dalton Trans 2016 Aug;45(33):13012-20

CIC biomaGUNE, Paseo de Miramón 182, Donostia-San Sebastián, 20009, Spain. and Kimika Fakultatea, Euskal Herriko Unibertsitatea and Donostia International Physics Center (DIPC), P.K. 1072, Donostia-San Sebastián, 20080, Spain and Ikerbasque, Basque Foundation for Science, Bilbao, 48011, Spain.

The article highlights the emergent use of upconverting nanoparticles as tools for the near infrared photoactivation of transition metal complexes, identifying opportunities and challenges of this approach in the context of medicinal inorganic chemistry.
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http://dx.doi.org/10.1039/c6dt01428cDOI Listing
August 2016

Os2 -Os4 Switch Controls DNA Knotting and Anticancer Activity.

Angew Chem Int Ed Engl 2016 07 30;55(31):8909-12. Epub 2016 May 30.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

Dinuclear trihydroxido-bridged osmium-arene complexes are inert and biologically inactive, but we show here that linking dihydroxido-bridged Os(II) -arene fragments by a bridging di-imine to form a metallacycle framework results in strong antiproliferative activity towards cancer cells and distinctive knotting of DNA. The shortened spacer length reduces biological activity and stability in solution towards decomposition to biologically inactive dimers. Significant differences in behavior toward plasmid DNA condensation are correlated with biological activity.
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http://dx.doi.org/10.1002/anie.201602995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982093PMC
July 2016

Spin-labelled photo-cytotoxic diazido platinum(iv) anticancer complex.

Dalton Trans 2016 Aug;45(33):13034-7

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.

We report the synthesis and characterisation of the nitroxide spin-labelled photoactivatable Pt(iv) prodrug trans,trans,trans-[Pt(N3)2(OH)(OCOCH2CH2CONH-TEMPO)(Py)2] (Pt-TEMPO, where TEMPO = 2,2,6,6-tetramethylpiperidine 1-oxyl). Irradiation with blue visible light gave rise to Pt(ii) and azidyl as well as nitroxyl radicals. Pt-TEMPO exhibited low toxicity in the dark, but on photoactivation was as active towards human ovarian cancer cells as the clinical photosensitizer chlorpromazine and much more active than the anticancer drug cisplatin under the conditions used.
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http://dx.doi.org/10.1039/c6dt01382aDOI Listing
August 2016

Hydrosulfide Adducts of Organo-Iridium Anticancer Complexes.

Inorg Chem 2016 Mar 10;55(5):2324-31. Epub 2016 Feb 10.

Department of Chemistry, University of Warwick , Gibbet Hill Road, Coventry CV4 7AL, U. K.

Novel half-sandwich hydrosulfidoiridium(III) complexes [(η(5)-Cp*)Ir(phen)(SH)]PF6 (1), [(η(5)-Cp*)Ir(bpy)(SH)]PF6 (2), [(η(5)-Cp(biph))Ir(phen)(SH)]PF6 (3), and [(η(5)-Cp(biph))Ir(bpy)(SH)]PF6 (4) were prepared from the chlorido complexes by dechlorination and treatment with excess NaSH·xH2O; phen = 1,10-phenanthroline, bpy = 2,2'-bipyridine, Cp* = 1,2,3,4,5-pentamethylcyclopentadienyl, and Cp(biph) = 1,2,3,4-tetramethyl-5-biphenylcyclopentadienyl. Complexes 1-4 were characterized by various techniques including electrospray ionization mass spectrometry, NMR spectroscopy (δ(SH) ca. -2 ppm), and a single-crystal X-ray analysis. Complex [(η(5)-Cp*)Ir(phen)(SH)]BPh4 (1') shows a typical piano-stool geometry with Ir-S bond length of 2.388(2) Å. Cp(biph) complexes 3 (IC50 = 0.98 μM) and 4 (IC50 = 0.61 μM) showed significantly higher (p < 0.005) in vitro antiproliferative activity against A2780 human ovarian cancer cells, as compared with their Cp* analogues 1 (IC50 = 49.5 μM) and 2 (IC50 = 48.4 μM), and potency similar to the anticancer drug cisplatin. The complexes were relatively stable in aqueous solution toward hydrolysis and reactions with reduced glutathione (GSH), 9-ethylguanine, or 9-methyladenine. Interestingly, GSH was readily oxidized to glutathione disulfide in the presence of Cp(biph) complexes 3 and 4, as judged by (1)H NMR, perhaps indicative of a possible redox-linked mechanism of action.
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http://dx.doi.org/10.1021/acs.inorgchem.5b02697DOI Listing
March 2016

Upconverting Nanoparticles Prompt Remote Near-Infrared Photoactivation of Ru(II)-Arene Complexes.

Chemistry 2016 Feb 19;22(8):2801-11. Epub 2016 Jan 19.

CIC biomaGUNE, Paseo de Miramón182, 20009, Donostia-San Sebastián, Euskadi, Spain.

The synthesis and full characterisation (including X-ray diffraction studies and DFT calculations) of two new piano-stool Ru(II) -arene complexes, namely [(η(6) -p-cym)Ru(bpy)(m-CCH-Py)][(PF)6]2 (1) and [(η(6) -p-cym)Ru(bpm)(m-CCH-Py)][(PF)6]2 (2; p-cym=p-cymene, bpy=2,2'-bipyridine, bpm=2,2'-bipyrimidine, and m-CCH-Py=3-ethynylpyridine), is described and discussed. The reaction of the m-CCH-Py ligand of 1 and 2 with diethyl-3-azidopropyl phosphonate by Cu-catalysed click chemistry affords [(η(6) -p-cym)Ru(bpy)(P-Trz-Py)][(PF)6]2 (3) and [(η(6) -p-cym)Ru(bpm)(P-Trz-Py)][(PF)6]2 (4; P-Trz-Py=[3-(1-pyridin-3-yl-[1,2,3]triazol-4-yl)-propyl]phosphonic acid diethyl ester). Upon light excitation at λ=395 nm, complexes 1-4 photodissociate the monodentate pyridyl ligand and form the aqua adduct ions [(η(6) -p-cym)Ru(bpy)(H2O)](2+) and [(η(6) -p-cym)Ru(bpm)(H2O)](2+). Thulium -doped upconverting nanoparticles (UCNPs) are functionalised with 4, thus exploiting their surface affinity for the phosphonate group in the complex. The so-obtained nanosystem [email protected] undergoes near-infrared (NIR) photoactivation at λ=980 nm, thus producing the corresponding reactive aqua species that binds the DNA-model base guanosine 5'-monophosphate.
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http://dx.doi.org/10.1002/chem.201503991DOI Listing
February 2016

Half-sandwich rhodium(III) transfer hydrogenation catalysts: Reduction of NAD(+) and pyruvate, and antiproliferative activity.

J Inorg Biochem 2015 Dec 19;153:322-333. Epub 2015 Oct 19.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. Electronic address:

Organometallic complexes have the potential to behave as catalytic drugs. We investigate here Rh(III) complexes of general formula [(Cp(x))Rh(N,N')(Cl)], where N,N' is ethylenediamine (en), 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen) or N-(2-aminoethyl)-4-(trifluoromethyl)benzenesulfonamide (TfEn), and Cp(x) is pentamethylcyclopentadienyl (Cp*), 1-phenyl-2,3,4,5-tetramethylcyclopentadienyl (Cp(xPh)) or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (Cp(xPhPh)). These complexes can reduce NAD(+) to NADH using formate as a hydride source under biologically-relevant conditions. The catalytic activity decreased in the order of N,N-chelated ligand bpy > phen > en with Cp* as the η(5)-donor. The en complexes (1-3) became more active with extension to the Cp(X) ring, whereas the activity of the phen (7-9) and bpy (4-6) compounds decreased. [Cp*Rh(bpy)Cl](+) (4) showed the highest catalytic activity, with a TOF of 37.4±2h(-1). Fast hydrolysis of the chlorido complexes 1-10 was observed by (1)H NMR (<10min at 310K). The pKa* values for the aqua adducts were determined to be ca. 8-10. Complexes 1-9 also catalysed the reduction of pyruvate to lactate using formate as the hydride donor. The efficiency of the transfer hydrogenation reactions was highly dependent on the nature of the chelating ligand and the Cp(x) ring. Competition reactions between NAD(+) and pyruvate for reduction by formate catalysed by 4 showed a preference for reduction of NAD(+). The antiproliferative activity of complex 3 towards A2780 human ovarian cancer cells increased by up to 50% when administered in combination with non-toxic doses of formate, suggesting that transfer hydrogenation can induce reductive stress in cancer cells.
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http://dx.doi.org/10.1016/j.jinorgbio.2015.10.008DOI Listing
December 2015

Electrophilic Activation of Oxidized Sulfur Ligands and Implications for the Biological Activity of Ruthenium(II) Arene Anticancer Complexes.

Inorg Chem 2015 Dec 24;54(23):11574-80. Epub 2015 Nov 24.

The University of British Columbia , Department of Chemistry, Vancouver, BC V6T 1Z1, Canada.

Surprisingly, the anticancer activity of half-sandwich Ru arene complexes [(η(6)-arene)Ru(en)Cl](+) appears to be promoted and not inhibited by binding to the intracellular thiol glutathione. Labilization of the Ru-S bond allowing DNA binding appeared to be initiated by oxygenation of the thiolate ligand, although oxidation by itself did not seem to weaken the Ru-S bond. In this study, we have investigated the solvation and acidic perturbations of mono (sulfenato) and bis (sulfinato) oxidized species of [(η(6)-arene)Ru(en) (SR)](+) complex in the presence of Brønsted and Lewis acids. Sulfur K-edge X-ray absorption spectroscopy together with density functional theory calculations show that solvation and acidic perturbation of sulfenato species produce a significant decrease in the S3p character of the Ru-S bond (Ru4dσ* ← S1s charge donation). Also there is a drastic fall in the overall ligand charge donation to the metal center in both sulfenato and sulfinato species. Our investigation clearly shows that mono oxidized sulfenato species are most susceptible to ligand exchange, hence providing a possible pathway for in vivo activation and biological activity.
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http://dx.doi.org/10.1021/acs.inorgchem.5b02493DOI Listing
December 2015

Contrasting Anticancer Activity of Half-Sandwich Iridium(III) Complexes Bearing Functionally Diverse 2-Phenylpyridine Ligands.

Organometallics 2015 Jun 25;34(11):2683-2694. Epub 2015 Mar 25.

Department of Chemistry, University of Warwick , Gibbet Hill Road, Coventry, CV4 7AL, U.K.

We report the synthesis, characterization, and antiproliferative activity of 15 iridium(III) half-sandwich complexes of the type [(η-Cp*)Ir(2-(R'-phenyl)-R-pyridine)Cl] bearing either an electron-donating (-OH, -CHOH, -CH) or electron-withdrawing (-F, -CHO, -NO) group at various positions on the 2-phenylpyridine (2-PhPy) chelating ligand giving rise to six sets of structural isomers. The X-ray crystal structures of [(η-Cp*)Ir(2-(2'-fluorophenyl)pyridine)Cl] () and [(η-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] () exhibit the expected "piano-stool" configuration. DFT calculations showed that substituents caused only localized effects on the electrostatic potential surface of the chelating 2-PhPy ligand of the complexes. Hydrolysis of all complexes is rapid, but readily reversed by addition of NaCl. The complexes show preferential binding to 9-ethylguanine over 9-methyladenine and are active catalysts for the oxidation of NADH to NAD. Antiproliferative activity experiments in A2780 ovarian, MCF-7 breast, A549 lung, and HCT116 colon cancer cell lines showed IC values ranging from 1 to 89 μM, with the most potent complex, [(η-Cp*)Ir(2-(2'-methylphenyl)pyridine)Cl] () (A2780 IC = 1.18 μM), being 10× more active than the parent, [(η-Cp*)Ir(2-phenylpyridine)Cl], and 2× more active than [(η-Cp)Ir(2-phenylpyridine)Cl]. Intriguingly, contrasting biological activities are observed between structural isomers despite exhibiting similar chemical reactivity. For pairs of structural isomers both the nature and position of the functional group can affect the hydrophobicity of the complex. An increase in hydrophobicity resulted in enhanced cellular-iridium accumulation in A2780 ovarian cells, which generally gave rise to an increase in potency. The structural isomers [(η-Cp*)Ir(2-(4'-fluorophenyl)pyridine)Cl] () and [(η-Cp*)Ir(2-phenyl-5-fluoropyridine)Cl] () preferentially localized in the cytosol > membrane and particulate > nucleus > cytoskeleton. This work highlights the strong dependence of biological behavior on the nature and position of the substituent on the chelating ligand and shows how this class of organometallic anticancer complexes can be fine-tuned to increase their potency without using extended cyclopentadienyl systems.
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http://dx.doi.org/10.1021/acs.organomet.5b00097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482135PMC
June 2015
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