Nitric oxide delivery platforms derived from a photoactivatable Mn(II) nitrosyl complex: Entry to photopharmacology.

The manganese nitrosyl complex derived from a designed pentadentate ligand with one carboxamido group N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-carboxamide (PaPyH; H is the dissociable carboxamide H), namely, [Mn(PaPy)(NO)]ClO (1), serves as an excellent biocompatible source of nitric oxide (NO) when exposed to low power (10-100 mW/cm) visible light. This complex has afforded a series of NO delivery platforms that could find applications in combating chronic infections by drug-resistant bacteria under the control of light.

Carbon Monoxide Inhibits Cytochrome P450 Enzymes CYP3A4/2C8 in Human Breast Cancer Cells, Increasing Sensitivity to Paclitaxel.

Paclitaxel (PTX) is a first-line treatment in breast cancer, though resistance develops quickly and frequently. Cytochrome P450 enzymes CYP3A4 and CYP2C8, which metabolically inactivate PTX in hepatic tissue, are overexpressed in malignant breast tissues. CYP3A4 expression correlates with PTX therapy failure and poor outcomes, though no direct evidence of CYP3A4 contributing to PTX sensitivity exists.

Gold Drugs with {Au(PPh )} Moiety: Advantages and Medicinal Applications.

Following the success of Auranofin as an anti-arthritic drug, search for novel gold drugs has afforded a large number of [L-Au(PPh )] complexes that exhibit notable salutary effects. Unlike Au(III)-containing species, these gold complexes with {Au(PPh )} moiety are stable in biological media and readily exchange L with S- and Se-containing enzymes or proteins. Such exchange leads to rapid reduction of microbial loads or induction of apoptotic cell death at malignant sites.

Enhanced Bactericidal Effects of Pyrazinamide Toward and upon Conjugation to a {Au(I)-triphenylphosphine} Moiety.

As part of the quest for new gold drugs, we have explored the efficacy of three gold complexes derived from the tuberculosis drug pyrazinamide (PZA), namely, the gold(I) complex [Au(PPh)(PZA)]OTf (, OTf = trifluoromethanesulfonate) and two gold(III) complexes [Au(PZA)Cl] () and [Au(PZO)Cl] (, PZO = pyrazinoic acid, the metabolic product of PZA) against two mycobacteria, and . Only complex with the {Au(PPh)} moiety exhibits significant bactericidal activity against both strains. In the presence of thiols, gives rise to free PZA and {Au(PPh)}-thiol polymeric species.

Diminished viability of human ovarian cancer cells by antigen-specific delivery of carbon monoxide with a family of photoactivatable antibody-photoCORM conjugates.

Carbon monoxide (CO)-releasing antibody conjugates were synthesized utilizing a photoactivatable CO-releasing molecule (photoCORM) and mouse monoclonal antibodies linked by a biotin-streptavidin system. Different monoclonal antibodies raised against different surface-expressed antigens that are implicated in ovarian cancer afforded a family of antibody-photoCORM conjugates (Ab-photoCORMs). In an immunosorbent/cell viability assay, Ab-photoCORMs accumulated onto ovarian cancer cells expressing the target antigens, delivering cytotoxic doses of CO .

Reaction of carbon monoxide with cystathionine β-synthase: implications on drug efficacies in cancer chemotherapy.

Photo-activatable carbon monoxide (CO)-releasing molecules (photoCORMs), have recently provided help to identify the salutary effects of CO in human pathophysiology. Among them notable is the ability of CO to sensitize chemotherapeutic-resistant cancer cells. Findings from our group have shown CO to mitigate drug resistance in certain cancer cells by the inhibition of cystathionine β-synthase (CBS), a key regulator of redox homeostasis in the cell.

Therapeutic Potential of Two Visible Light Responsive Luminescent photoCORMs: Enhanced Cellular Internalization Driven by Lipophilicity.

Herein we report the synthesis, characterization, and cellular internalization properties of two visible-light active luminescent Mn-based photoCORMs. The enhanced membrane permeability of the photoactive Mn carbonyl complex (photoCORM) derived from a designed lipophilic ligand namely, [Mn(CO)(Imdansyl)()](CFSO) () (where = a diazabutadiene-based ligand containing two highly lipophilic adamantyl motifs, Imdansyl = dansylimidazole) promoted rapid internalization within human colorectal adenocarcinoma (HT-29) cells compared to [Mn(CO)(Imdansyl)()](CFSO) () (where = a diazabutadiene ligand bearing two hydrophilic 1,3,5-triazaadamantyl group). Colocalization experiments using membrane stain indicate different extents of localization of the two CO complexes within the cellular matrix.

Peroxynitrite-Mediated Dimerization of 3-Nitrotyrosine: Unique Chemistry along the Spectrum of Peroxynitrite-Mediated Nitration of Tyrosine.

Peroxynitrite (ONOO, PN) has long been considered a potent nitrating agent implicated in numerous inflammation-mediated diseases. The current work highlights an unexplored oxidation chemistry initiated under conditions of sustained PN exposure. Impetus for this investigation developed from mass spectral results that suggested dimerization of a model peptide with a single tyrosine residue that was first nitrated following extended exposure to PN generated .

Carbon monoxide sensitizes cisplatin-resistant ovarian cancer cell lines toward cisplatin via attenuation of levels of glutathione and nuclear metallothionein.

Cisplatin resistance remains a major impediment to effective treatment of ovarian cancer. Despite initial platinum responsiveness, thiol-containing peptides and proteins, glutathione (GSH) and metallothionein (MT), bind and inactivate cisplatin in cancer cells. Indeed, high levels of GSH and MT in ovarian cancers impart cisplatin resistance and are predictive of poor prognosis.

A mononuclear nonheme {FeNO} complex: synthesis and structural and spectroscopic characterization.

While the synthesis and characterization of {FeNO} complexes have been well documented in heme and nonheme iron models, {FeNO} complexes have been less clearly understood. Herein, we report the synthesis and structural and spectroscopic characterization of mononuclear nonheme {FeNO} and iron(iii)-nitrito complexes bearing a tetraamido macrocyclic ligand (TAML), such as [(TAML)Fe(NO)] and [(TAML)Fe(NO)], respectively. First, direct addition of NO to [Fe(TAML)] results in the formation of [(TAML)Fe(NO)], which is sensitive to moisture and air.

Cationic Au(I) complexes with aryl-benzothiazoles and their antibacterial activity.

Two cationic Au(I) complexes derived from aryl-benzothiazoles, namely [(PPh)Au(pbt)](OTf) (1) and [(PPh)Au(qbt)](OTf) (2) (where pbt = 2‑(pyridyl)benzothiazole and qbt = (quinolyl)benzothiazole, and OTf = trifluoromethanesulfonate anion), have been synthesized and structurally characterized by X-ray crystallography. Both complexes exhibit strong antibacterial effects against Gram-negative bacteria such as Acinetobacter baumannii and Pseudomonas Aeruginosa. Results of examination of the reactions of 1 and 2 indicate that these cationic Au(I) complexes rapidly cross the bacterial membrane and exert drug action by disrupting cellular function(s) through binding of cytosolic thiol-containing peptides (such as glutathione) and proteins to the highly reactive (PPh)Au intermediate formed upon in situ dissociation of pbt or qbt.

Incorporation of a Theranostic "Two-Tone" Luminescent Silver Complex into Biocompatible Agar Hydrogel Composite for the Eradication of ESKAPE Pathogens in a Skin and Soft Tissue Infection Model.

Microbial invasion and colonization of the skin and underlying soft tissues are among the most common types of infections, becoming increasingly prevalent in hospital settings. Systemic antibiotic chemotherapies are now extremely limited due to emergence of drug-resistant Gram-positive and multidrug-resistant Gram-negative bacterial strains. Topical administration of antimicrobials provides an effective route for the treatment of skin and soft tissue infections (SSTIs).

A Luminescent Manganese PhotoCORM for CO Delivery to Cellular Targets under the Control of Visible Light.

A photoactive manganese carbonyl complex derived from dansylimidazole (Imdansyl), namely, [Mn(Imdansyl)(CO)(phen)](CFSO) (1), has been synthesized and structurally characterized. This is the first luminescent manganese carbonyl-based photoCORM reported in the literature. This complex exhibits CO release under the exclusive control of low-power broadband visible light.

Attenuation of Antioxidant Capacity in Human Breast Cancer Cells by Carbon Monoxide through Inhibition of Cystathionine β-Synthase Activity: Implications in Chemotherapeutic Drug Sensitivity.

Drug resistance is a major impediment to effective treatment of breast cancer. Compared to normal cells, cancer cells have an increased antioxidant potential due to an increased ratio of reduced to oxidized glutathione (GSH/GSSG). This is known to confer therapeutic resistance.

Eradication of HT-29 colorectal adenocarcinoma cells by controlled photorelease of CO from a CO-releasing polymer (photoCORP-1) triggered by visible light through an optical fiber-based device.

The gaseous signaling molecule carbon monoxide (CO) has recently been recognized for its wide range of physiological activity as well as its antineoplastic properties. However, site-specific delivery of this noxious gas presents a major challenge in hospital settings. In this work, a visible light-sensitive CO-releasing molecule (photoCORM) derived from manganese(I) and 2-(quinolyl)benzothiazole (qbt) namely, [Mn(CO)(qbt)(4-vpy)](CFSO) (1), has been co-polymerized within a gas-permeable HEMA/EGDMA hydrogel.

Five- and Six-Coordinated Silver(I) Complexes Derived from 2,6-(Pyridyl)iminodiadamantanes: Sustained Release of Bioactive Silver toward Bacterial Eradication.

Silver(I) complexes of two designed tridentate ligands, namely, 2,6-(pyridyl)iminoditriazaadamantane (pydTAm) and 2,6-(pyridyl)iminodiadamantane (pydAm), have been synthesized and structurally characterized. [Ag(pydTAm)](CFSO) (1), the hitherto unknown mer isomer of a silver(I) octahedral complex, crystallizes in a highly symmetric body-centered cubic I4Ì…3m space group. Quite in contrast, the Ag center in the analogous [Ag(pydAm)](CFSO) (2) complex resides in a trigonal-bipyramidal geometry and crystallizes in a triclinic P1Ì… space group with two crystallographically independent molecules in the asymmetric unit.

Luminescent Re(I) Carbonyl Complexes as Trackable PhotoCORMs for CO delivery to Cellular Targets.

A family of Re(I) carbonyl complexes of general formula [ReX(CO)(phen)] (where X = Cl, CFSO, MeCN, PPh, and methylimidazole) derived from 1,10-phenanthroline (phen) exhibits variable emission characteristics depending on the presence of the sixth ancillary ligand/group (X). All complexes but with X = MeCN exhibit moderate CO release upon irradiation with low-power UV light and are indefinitely stable in anaerobic/aerobic environment in solution as well as in solid state when kept under dark condition. These CO donors liberate three, one, or no CO depending on the nature of sixth ligand upon illumination as studied with the aid of time-dependent IR spectroscopy.

Synthesis, Structures, and CO Release Capacity of a Family of Water-Soluble PhotoCORMs: Assessment of the Biocompatibility and Their Phototoxicity toward Human Breast Cancer Cells.

Two manganese(I) carbonyl complexes derived from 2-(pyridyl)benzothiazole (pbt) and 1,10-phenanthroline (phen) release carbon monoxide (CO) under low-power broad-band visible-light illumination. CO photorelease from [Mn(CO)(pbt)(PTA)]CFSO (1, where PTA = 1,3,5-triaza-7-phosphaadamantane) is accompanied by an emergence of a strong fluorescence around 400 nm from almost nonfluorescent preirradiated 1. However, [Mn(CO)(phen)(PTA)]CFSO (2) showed no such phenomenon upon prolonged illumination under similar experimental conditions.

L-Edge X-ray Absorption Spectroscopic Investigation of {FeNO}: Delocalization vs Antiferromagnetic Coupling.

NO is a classic non-innocent ligand, and iron nitrosyls can have different electronic structure descriptions depending on their spin state and coordination environment. These highly covalent ligands are found in metalloproteins and are also used as models for Fe-O systems. This study utilizes iron L-edge X-ray absorption spectroscopy (XAS), interpreted using a valence bond configuration interaction multiplet model, to directly experimentally probe the electronic structure of the S = 0 {FeNO} compound [Fe(PaPy)NO] (PaPy = N,N-bis(2-pyridylmethyl)amine-N-ethyl-2-pyridine-2-carboxamide) and the S = 0 [Fe(PaPy)CO] reference compound.

Silver complexes of ligands derived from adamantylamines: Water-soluble silver-donating compounds with antibacterial properties.

Two new silver(I) complexes, namely [Ag(qyAm)](CFSO) (1) and [Ag(qyTAm)](CFSO) (2), (qyAm=2-(quinonyl)iminoadamantane, qyTAm=2-(quinonyl)iminotriazaadamantane) have been synthesized and characterized by elemental analyses, H NMR, IR, electronic absorption spectroscopy, and X-ray diffraction. The coordination geometry of the silver center in both complexes is distorted tetrahedral where their respective qyAm and qyTAm ligand bind in a bidentate fashion using the imine and quinoline nitrogen atoms. Complex 2 is soluble in water and exhibits strong antimicrobial actions on both Gram-negative (E.

Tracking silver delivery to bacteria using turn-on fluorescence.

Herein we present a novel silver complex [Ag(qBODIPY)(CFSO)] (1) that exhibits dramatic increase in fluorescence upon silver release. Complex 1 has a minimum inhibitory concentration comparable to that of silver nitrate. Confocal microscopy was used to track the delivery of silver to bacterial targets.

Synthesis and assessment of CO-release capacity of manganese carbonyl complexes derived from rigid α-diimine ligands of varied complexity.

Four manganese carbonyl complexes of the type [MnBr(CO)(NˆN)] (NˆN = α-diimine ligands) namely [MnBr(CO)(bpy)] (), [MnBr(CO)(phen)] (), [MnBr(CO)(dafo)] () and [MnBr(CO)(pyzphen)] () (where bpy = bipyridine, phen = 1,10-phenanthroline, dafo = 4,5-diazafluoren-9-one and pyzphen = pyrazino[2,3-f][1,10]-phenanthroline) have been synthesized and structurally characterized. These four complexes containing the -[Mn(CO)] motif release CO upon illumination with low power visible and UV light. The CO release rates and the absorption maxima of the complexes are however very similar despite systematic increase in structural complexity in the rigid α-diimine ligand frames.

Light-triggered CO delivery by a water-soluble and biocompatible manganese photoCORM.

The discovery of salutary effects of low doses of carbon monoxide (CO) has spurred interest in designing exogenous molecules that can deliver CO to biological targets under controlled conditions. Herein we report a water-soluble photosensitive manganese carbonyl complex [MnBr(CO)3(pyTAm)] (2) (pyTAm = 2-(pyridyl)imino-triazaadamantane) that can be triggered to release CO upon exposure to visible light. Inclusion of a triazaadamantyl pharmacophore into the coligand of 2 improves its stability and solubility in water.

A Theranostic Two-Tone Luminescent PhotoCORM Derived from Re(I) and (2-Pyridyl)-benzothiazole: Trackable CO Delivery to Malignant Cells.

A Re(I) carbonyl complex derived from 2-(2-pyridyl)-benzothiazole (pbt), [Re(H2O)(CO)3(pbt)](CF3SO3) (1), rapidly releases CO under low-power UV illumination. CO photorelease from 1 is accompanied by a change in luminescence from orange to deep blue. These two distinct luminescence signals have been successfully employed to track (a) the entry of the pro-drug 1 into cancer cells and (b) the end of the CO (drug) delivery step within the target.

Exceptionally rapid CO release from a manganese(I) tricarbonyl complex derived from bis(4-chloro-phenylimino)acenaphthene upon exposure to visible light.

Two manganese(i) carbonyl complexes derived from α,α'-diimine ligands with extended conjugated framework namely [MnBr(CO)3(BIAN)] () and [MnBr(CO)3(MIAN)] (), have been synthesized and structurally characterized. Unlike the previously reported photoactive CO-releasing molecules (photoCORMs), these two complexes exhibit unusually high sensitivity toward low power (0.3-10 mW) visible light (λ ≥ 520 nm) even in the solid state and rapidly release carbon monoxide (CO) upon illumination.