Methylselenocysteine Treatment Leads to Diselenide Formation in Human Cancer Cells: Evidence from X-ray Absorption Spectroscopy Studies

The selenoamino acids methylselenocysteine (MeSeCys) and selenomethionine (SeMet) have disparate efficacies as anticancer agents. Herein, we use X-ray absorption spectroscopy to determine the chemical form of selenium in human neuroblastoma cells. Cells treated with MeSeCys contain a significant diselenide component, which is absent from SeMet-treated cells and suggests that metabolites of MeSeCys are capable of altering the redox status of the cells. The differences in the speciation of Se in the selenoamino acid-treated cells may provide insight into the differing anticancer activities of MeSeCys and SeMet

Solid-State Structural Studies of Chromium(III) Nicotinato Nutritional Supplements

While Cr­(III) dietary supplements are widely consumed, some commercial supplements have yet to be structurally characterized. X-ray absorption spectroscopy and other spectroscopic methods were used to characterize Cr­(III) nicotinato nutritional supplements that have long been used in complementary medicine. Different ratios of nicotinic acid and CrCl₃·6H₂O (<i>trans</i>-[CrCl₂(OH₂)₄]­Cl·2H₂O) at different pH values gave a range of products. The local structures of Cr­(III) nicotinato complexes obtained at pH 7 and of the patented complex were characterized by performing multiple-scattering analysis of their EXAFS spectra as well as EPR, UV–vis, and IR spectroscopies. For the first time, these complexes have been definitively characterized as nicotinato-bridged polymers of dihydroxido-bridged dinuclear Cr­(III) cores. In the patented complex used in commercial preparations, each Cr is octahedral with an additional terminal O-bound nicotinato ligand, two bridging nicotinato (one O and one N bound), and an aqua ligand. The other species also have two or three bridging nicotinato ligands and an aqua and, in some cases, a terminal hydroxido ligand, which is dependent upon the stoichiometry of the reactants and the pH value of the solution in which they are prepared

Influence of Equatorial and Axial Carboxylato Ligands on the Kinetic Inertness of Platinum(IV) Complexes in the Presence of Ascorbate and Cysteine and within DLD‑1 Cancer Cells

The rapid and premature reduction of platinum­(IV) complexes in vivo is a significant impediment to these complexes being successfully employed as anticancer prodrugs. This study investigates the influence of the platinum­(IV) coordination sphere on the ease of reduction of the platinum center in various biological contexts. In the presence of the biological reductants, ascorbate and cysteine, platinum­(IV) complexes with dicarboxylato equatorial ligands were observed to exhibit lower reduction potentials and slower reduction rates than analogous platinum­(IV) complexes with dichlorido equatorial ligands. Diaminetetracarboxylatoplatinum­(IV) complexes exhibited unusually long half-lives in the presence of excess reductants; however, the complexes exhibited moderate potency in vitro, indicative of rapid reduction within the intracellular environment. By use of XANES spectroscopy, <i>trans</i>-[Pt­(OAc)₂(ox)­(en)] and <i>trans</i>-[PtCl₂­(OAc)₂(en)] were observed to be reduced at a similar rate within DLD-1 cancer cells. This large variability in kinetic inertness of diamine­tetracarboxylato­platinum­(IV) complexes in different biological contexts has significant implications for the design of platinum­(IV) prodrugs

Biotransformations of Antidiabetic Vanadium Prodrugs in Mammalian Cells and Cell Culture Media: A XANES Spectroscopic Study

The antidiabetic activities of vanadium­(V) and -(IV) prodrugs are determined by their ability to release active species upon interactions with components of biological media. The first X-ray absorption spectroscopic study of the reactivity of typical vanadium (V) antidiabetics, vanadate ([V^VO₄]^3–, <b>A</b>) and a vanadium­(IV) bis­(maltolato) complex (<b>B</b>), with mammalian cell cultures has been performed using HepG2 (human hepatoma), A549 (human lung carcinoma), and 3T3-L1 (mouse adipocytes and preadipocytes) cell lines, as well as the corresponding cell culture media. X-ray absorption near-edge structure data were analyzed using empirical correlations with a library of model vanadium­(V), -(IV), and -(III) complexes. Both <b>A</b> and <b>B</b> ([V] = 1.0 mM) gradually converged into similar mixtures of predominantly five- and six-coordinate V^V species (∼75% total V) in a cell culture medium within 24 h at 310 K. Speciation of V in intact HepG2 cells also changed with the incubation time (from ∼20% to ∼70% V^IV of total V), but it was largely independent of the prodrug used (<b>A</b> or <b>B</b>) or of the predominant V oxidation state in the medium. Subcellular fractionation of A549 cells suggested that V^V reduction to V^IV occurred predominantly in the cytoplasm, while accumulation of V^V in the nucleus was likely to have been facilitated by noncovalent bonding to histone proteins. The nuclear V^V is likely to modulate the transcription process and to be ultimately related to cell death at high concentrations of V, which may be important in anticancer activities. Mature 3T3-L1 adipocytes (unlike for preadipocytes) showed a higher propensity to form V^IV species, despite the prevalence of V^V in the medium. The distinct V biochemistry in these cells is consistent with their crucial role in insulin-dependent glucose and fat metabolism and may also point to an endogenous role of V in adipocytes

Intracellular Targeting and Pharmacological Activity of the Superoxide Dismutase Mimics MnTE-2-PyP⁵⁺ and MnTnHex-2-PyP⁵⁺ Regulated by Their Porphyrin Ring Substituents

Manganese porphyrin-based drugs are potent mimics of the enzyme superoxide dismutase. They exert remarkable efficacy in disease models and are entering clinical trials. Two lead compounds, MnTE-2-PyP⁵⁺ and MnTnHex-2-PyP⁵⁺, have similar catalytic rates, but differ in their alkyl chain substituents (ethyl vs <i>n</i>-hexyl). Herein we demonstrate that these changes in ring substitution impact upon drug intracellular distribution and pharmacological mechanism, with MnTnHex-2-PyP⁵⁺ superior in augmenting menadione toxicity. These findings establish that both catalytic activity and intracellular distribution determine drug action

A Two-Step Valence Tautomeric Transition in a Dinuclear Cobalt Complex

A dinuclear cobalt complex with cobalt centers bridged by a bis­(dioxolene) ligand exhibits a rare two-step valence tautomeric transition

A Two-Step Valence Tautomeric Transition in a Dinuclear Cobalt Complex

A dinuclear cobalt complex with cobalt centers bridged by a bis­(dioxolene) ligand exhibits a rare two-step valence tautomeric transition

Redox Activity and Two-Step Valence Tautomerism in a Family of Dinuclear Cobalt Complexes with a Spiroconjugated Bis(dioxolene) Ligand

A family of dinuclear cobalt complexes with bridging bis­(dioxolene) ligands derived from 3,3,3′,3′-tetramethyl-1,1′-spirobis­(indane-5,5′,6,6′-tetrol) (spiroH₄) and ancillary ligands based on tris­(2-pyridylmethyl)­amine (tpa) has been synthesized and characterized. The bis­(dioxolene) bridging ligand is redox-active and accessible in the (spiro^cat–cat)^4–, (spiro^SQ–cat)^3–, and (spiro^SQ–SQ)^2– forms, (cat = catecholate, SQ = semiquinonate). Variation of the ancillary ligand (Me_<i>n</i>tpa; <i>n</i> = 0–3) by successive methylation of the 6-position of the pyridine rings influences the redox state of the complex, governing the distribution of electrons between the cobalt centers and the bridging ligands. Pure samples of salts of the complexes [Co₂(spiro)­(tpa)₂]²⁺ (<b>1</b>), [Co₂(spiro)­(Metpa)₂]²⁺ (<b>2</b>), [Co₂(spiro)­(Me₂tpa)₂]²⁺ (<b>3</b>), [Co₂(spiro)­(Me₃tpa)₂]²⁺ (<b>4</b>), [Co₂(spiro)­(tpa)₂]³⁺ (<b>5</b>), and [Co₂(spiro)­(tpa)₂]⁴⁺ (<b>6</b>) have been isolated, and <b>1</b>, <b>4</b>, and <b>6</b> have been characterized by single crystal X-ray diffraction. Studies in the solid and solution states using multiple techniques reveal temperature invariant redox states for <b>1</b>, <b>2</b>, and <b>4</b>–<b>6</b> and provide clear evidence for four different charge distributions: <b>1</b> and <b>2</b> are Co^III-(spiro^cat–cat)-Co^III, <b>4</b> is Co^II-(spiro^SQ–SQ)-Co^II, <b>5</b> is Co^III-(spiro^SQ–cat)-Co^III, and <b>6</b> is Co^III-(spiro^SQ–SQ)-Co^III. Of the six complexes, only <b>3</b> shows evidence of temperature dependence of the charge distribution, displaying a rare thermally induced two-step valence tautomeric transition from the Co^III-(spiro^cat–cat)-Co^III form to Co^II-(spiro^SQ–cat)-Co^III and then to Co^II-(spiro^SQ–SQ)-Co^II in both solid and solution states. This is the first time a two-step valence tautomeric (VT) transition has been observed in solution. Partial photoinduction of the VT transition is also possible in the solid. Magnetic and spectroscopic studies of <b>5</b> and <b>6</b> reveal that spiroconjugation of the bis­(dioxolene) ligand allows electronic interaction across the spiro bridge, suggesting that thermally activated vibronic coupling between the two cobalt-dioxolene moieties plays a key role in the two-step transition evident for <b>3</b>