Effect of cysteine thiols on the catalytic and anticancer activity of Ru(II) sulfonyl-ethylenediamine complexes.

We have synthesized a series of novel substituted sulfonyl ethylenediamine (en) Ru arene complexes 1-8 of [(η-arene)Ru(R-SO-EnBz)X], where the arene is benzene, HO(CH)O-phenyl or biphenyl (biph), X = Cl or I, and R is phenyl, 4-Me-phenyl, 4-NO-phenyl or dansyl. The 'piano-stool' structure of complex 3, [(η-biph)Ru(4-Me-phenyl-SO-EnBz)I], was confirmed by X-ray crystallography. The values of their aqua adducts were determined to be high (9.

NMR studies of group 8 metallodrugs: Os-enriched organo-osmium half-sandwich anticancer complex.

We report the synthesis of the organo-osmium anticancer complex [Os(η--cym)(,-azpy-NMe)Br]PF (1) containing natural abundance Os (1.96%), and isotopically-enriched (98%) [Os]-1. Complex 1 and [Os]-1 contain a π-bonded -cymene (-cym), a chelated 4-(2-pyridylazo)-,-dimethylaniline (azpy-NMe), and a monodentate bromide as ligands.

Photoactivated Osmium Arene Anticancer Complexes.

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

New activation mechanism for half-sandwich organometallic anticancer complexes.

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.

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

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.

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

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.

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

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.

Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes.

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 .

Asymmetric transfer hydrogenation by synthetic catalysts in cancer cells.

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.

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

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] ().

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

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).

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

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.

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

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.

Supramolecular Photoactivatable Anticancer Hydrogels.

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.

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

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).

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

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.

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

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.