(S)-2-Carb-oxy-ethyl l-cysteinyl sulfone.

The title compound {systematic name: (2S)-2-aza-niumyl-3-[(2-carb-oxy-ethane)-sulfon-yl]propano-ate}, C6H11NO6S, forms enanti-opure crystals in the monoclinic space group P21 and exists as a zwitterion, with a protonated α-amino group and a deprotonated α-carboxyl group. Both the carboxyl groups and the amino group are involved in an extensive multicentered inter-molecular hydrogen-bonding scheme. In the crystal, the diperiodic network of hydrogen bonds propagates parallel to (101) and involves inter-connected heterodromic R 4 3(10) rings. Electrostatic forces are major contributors to the structure energy, which was estimated by DFT calculations as E total = -333.5 kJ mol-1.

Structural and Functional Studies of S-(2-Carboxyethyl)-L-Cysteine and S-(2-Carboxyethyl)-l-Cysteine Sulfoxide.

Insecticidal non-proteinogenic amino acid S-(2-carboxyethyl)-L-cysteine (ß-CEC) and its assumed metabolite, S-(2-carboxyethyl)-l-cysteine sulfoxide (ß-CECO), are present abundantly in a number of plants of the legume family. In humans, these amino acids may occur as a result of exposure to environmental acrylonitrile or acrylamide, and due to consumption of the legumes. The ß-CEC molecule is a homolog of S-carboxymethyl-l-cysteine (carbocisteine, CMC), a clinically employed antioxidant and mucolytic drug. We report here detailed structural data for ß-CEC and ß-CECO, as well as results of in vitro studies evaluating cytotoxicity and the protective potential of the amino acids in renal tubular epithelial cells (RTECs) equipped with reporters for activity of seven stress-responsive transcription factors. In RTECs, ß-CEC and the sulfoxide were not acutely cytotoxic, but activated the antioxidant Nrf2 pathway. ß-CEC, but not the sulfoxide, induced the amino acid stress signaling, which could be moderated by cysteine, methionine, histidine, and tryptophan. ß-CEC enhanced the cytotoxic effects of arsenic, cadmium, lead, and mercury, but inhibited the cytotoxic stress induced by cisplatin, oxaliplatin, and CuO nanoparticles and acted as an antioxidant in a copper-dependent oxidative DNA degradation assay. In these experiments, the structure and activities of ß-CEC closely resembled those of CMC. Our data suggest that ß-CEC may act as a mild activator of the cytoprotective pathways and as a protector from platinum drugs and environmental copper cytotoxicity.

Structural, Spectroscopic, and Computational Analysis of Heterometallic Thorium Phosphinidiide Complexes.

To synthesize complexes with thorium-phosphorus multiple-bond character, reactions of (C5Me5)2Th[P(H)Mes]2 with monovalent alkali-metal bases, MN(SiMe3)2, as well as CuMes, have been investigated. The results with MN(SiMe3)2 are phosphinidiide complexes of the form {(C5Me5)2Th[µ2-P(Mes)][µ2-P(H)Mes]M(L)n}2 (M = Na, n = 0; M = K, L = THF, n = 1; M = Rb, L = THF, n = 1; M = Cs, L = Et2O, n = 1). With CuMes, the product is a Th2Cu3P5 heterometallic structure, {(C5Me5)2Th[(µ2-P(H)Mes)P(Mes)]Cu}2Cu[µ2-P(H)Mes]. All complexes have been characterized using heteronuclear NMR and IR spectroscopy, density functional theory calculations, and their solid-state structure identified by X-ray crystallography. We also report the structure of {(C5Me5)2Th[(µ2-As(H)Mes)As(Mes)]Cu}2Cu[µ2-As(H)Mes] obtained from (C5Me5)2Th[As(H)Mes]2 with CuMes.

Backbonding in Thorium(IV) and Uranium(IV) Diarsenido Complexes with tBuNC and CO.

The coordination of tBuNC and CO with the diarsenido complexes (C5 Me5 )2 An(η2 -As2 Mes2 ), An=Th, U, has been investigated. For the first time, a comparison between isostructural complexes of ThIV and UIV has been possible with CO; density functional calculations indicated an appreciable amount of π backbonding that originates from charge transfer from an actinide-arsenic sigma bond. The calculated CO stretching frequencies in the ThIV and UIV diarsenido complexes are consistent with the experimental measurements, both show large shifts to lower frequency. We demonstrate that the π backbonding is crucial to explaining the red shifts of CO frequency upon AnIV complex formation. Interestingly, this interaction essentially correlates to the parallel orientation of π*(C-O) orbitals relative to the An-As bond.

Systematic Investigation of the Molecular and Electronic Structure of Thorium and Uranium Phosphorus and Arsenic Complexes.

In continuing to examine the interaction of actinide-ligand bonds with soft donor ligands, a comparative investigation with phosphorus and arsenic was conducted. A reaction of (C5Me5)2AnMe2, An = Th, U, with 2 equiv of H2AsMes, Mes = 2,4,6-Me3C6H2, forms the primary bis(arsenido) complexes, (C5Me5)2An[As(H)Mes]2. Both exhibit thermal instability at room temperature, leading to the elimination of H2, and the formation of the diarsenido species, (C5Me5)2An(η2-As2Mes2). The analogous diphosphido complexes, (C5Me5)2An(η2-P2Mes2), could not be synthesized via the same route, even upon heating the bis(phosphido) species to 100 °C in toluene. However, they were accessible via the reaction of dimesityldiphosphane, MesP(H)P(H)Mes, with (C5Me5)2AnMe2 at 70 °C in toluene. When (C5Me5)2AnMe2 is reacted with 1 equiv of H2AsMes, the bridging µ2-arsinidiide complexes [(C5Me5)2An]2(µ2-AsMes)2 are formed. Upon reaction of (C5Me5)2UMe2 with 1 equiv of H2PMes, the phosphinidiide [(C5Me5)2U(µ2-PMes)]2 is isolated. However, the analogous thorium reaction leads to a phosphido and C-H bond activation of the methyl on the mesityl group, forming {(C5Me5)2Th[P(H)(2,4-Me2C6H2-6-CH2)]}2. The reactivity of [(C5Me5)2An(µ2-EMes)]2 was investigated with OPPh3 in an effort to produce terminal phosphinidene or arsinidene complexes. For E = As, An = U, a U(III) cation-anion pair [(C5Me5)2U(η2-As2Mes2)][(C5Me5)2U(OPPh3)2] is isolated. The reaction of [(C5Me5)2Th(µ2-AsMes)]2 with OPPh3 does not result in a terminal arsinidene but, instead, eliminates PPh3 to yield a bridging arsinidiide/oxo complex, [(C5Me5)2Th]2(µ2-AsMes)(µ2-O). Finally, the combination of [(C5Me5)2U(µ2-PMes)]2 and OPPh3 yields a terminal phosphinidene, (C5Me5)2U(═PMes)(OPPh3), featuring a short U-P bond distance of 2.502(2) Å. Electrochemical measurements on the uranium pnictinidiide complexes demonstrate only a 0.04 V difference with phosphorus as a slightly better donor. Magnetic measurements on the uranium complexes show more excited-state mixing and therefore higher magnetic moments with the arsenic-containing compounds but no deviation from uncoupled U(IV) behavior. Finally, a quantum theory of atoms in molecules analysis shows highly polarized actinide-pnictogen bonds with similar bonding characteristics, supporting the electrochemical and magnetic measurements of similar bonding between actinide-phosphorus and actinide-arsenic bonds.

A New, Second Generation Trithiol Bifunctional Chelate for 72,77As: Trithiol(b)-(Ser)2-RM2.

Trithiol chelates are suitable for labeling radioarsenic (72As: 2.49 MeV ß+, 26 h; 77As: 0.683 MeV ß-, 38.8 h) to form potential theranostic radiopharmaceuticals for positron emission tomography (PET) imaging and therapy. A trithiol(b)-(Ser)2-RM2 bioconjugate and its arsenic complex were synthesized and characterized. The trithiol(b)-(Ser)2-RM2 bioconjugate was radiolabeled with no-carrier-added 77As in over 95% radiochemical yield and was stable for over 48 h, and in vitro IC50 cell binding studies of [77As]As-trithiol(b)-(Ser)2-RM2 in PC-3 cells demonstrated high affinity for the gastrin-releasing peptide (GRP) receptor (low nanomolar range). Limited biodistribution studies in normal mice were performed with HPLC purified 77As-trithiol(b)-(Ser)2-RM2 demonstrating both pancreatic uptake and hepatobiliary clearance.

Structure, Antioxidant and Anti-inflammatory Activities of the (4R)- and (4S)-epimers of S-Carboxymethyl-L-cysteine Sulfoxide.

S-Carboxymethyl-L-cysteine (CMC) is an antioxidant and mucolytic commonly prescribed to patients with chronic obstructive pulmonary disease. In humans, CMC is rapidly metabolized to S-carboxymethyl-L-cysteine sulfoxide (CMCO). In this study, we assessed structural and functional similarities between CMC and CMCO. X-Ray diffraction analysis provided detailed structural information about CMCO, which exists as a 1:1 mixture of epimers, due to the emergence of a new chiral center at the sulfur atom. Both CMC and CMCO epimers protected model DNA from copper-mediated hydroxyl free radical damage. Using an insulated transposable construct for reporting activity of the cellular stress-responsive transcription factors Nrf2, p53, NF-κB, and AP-1, we demonstrate that CMCO, especially its (4R)-epimer, is comparable to CMC in their ability to mitigate the effects of oxidative stress and pro-inflammatory stimuli in human alveolar (A549) and bronchial epithelial (BEAS-2B) cells. The results of these in vitro studies suggest that CMCO retains, at least partially, the antioxidant potential of CMC and may inform pharmacodynamics considerations of CMC use in clinics.

Technetium and Rhenium Schiff Base Compounds for Nuclear Medicine: Syntheses of Rhenium Analogues to 99mTc-Furifosmin.

Rhenium, the third-row congener of technetium, is often used to develop the macroscopic chemistry of potential 99mTc diagnostic radiopharmaceuticals. The rhenium analogues to 99mTc-furifosmin are being developed for potential radiotherapy of multidrug-resistant tumors. Complexes of the form trans-[MIII(PR3)2(N2O2-Schiff base)]+ are of interest for the potential imaging and treatment of multidrug-resistant tumors. Reaction of the tetradentate Schiff ligand 4,4'-[(1 E,1' E)-[ethane-1,2-diylbis(azanylylidene)]bis(methanylylidene)]bis(2,2,5,5-tetramethyl-2,5-dihydrofuran-3-ol) (tmf2enH2) with the M(V) starting materials ( nBu4N)[TcOCl4] and ( nBu4N)[ReOCl4] gave the monomeric products trans-[TcOCl(tmf2en)] and trans-[ReOCl(tmf2en)], respectively. Reduction of in situ formed trans-[ReOCl(tmf2en)] by various tertiary phosphines yielded disubstitued Re(III) products of the general type trans-[ReIII(PR3)2(tmf2en)]+. The rhenium(III) compounds were found to be water-soluble and stable in aqueous solution. Reversible ReIII/ReIV and ReIII/ReII redox processes were observed at about 0.8-0.9 and -0.65 to -0.8 V, respectively, for each of the rhenium(III) species. Reaction of in situ formed trans-TcOCl(tmf2en) with triethylphosphine yielded the reduced, disubstituted trans-[Tc(PEt3)2(tmf2en)]PF6. A reversible TcIII/TcII redox couple was observed for the technetium(III) species, about 200 mV less negative than their rhenium(III) analogues, in addition to an irreversible TcIII/TcIV process. All compounds were characterized using conventional spectroscopic techniques, single-crystal X-ray crystallography, and cyclic voltammetry.

Singlet Oxygen Production and Tunable Optical Properties of Deacetylated Chitin-Porphyrin Crosslinked Films.

The increasing need for biocompatible materials as supports to immobilize photosensitizer molecules for photodynamic therapy (PDT), led us to investigate the use of chitin as a support for 4,4',4″,4‴-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) (mTCPP) for singlet oxygen production. Chitin was first extracted from shrimp shells using the ionic liquid 1-ethyl-3-methyl-imidazolium acetate ([C2mim][OAc]), coagulated as a floc into water, and then deacetylated to varying degrees of deacetylation using 4 M NaOH. The deacetylated chitin (DA-chitin) was dissolved in [C2mim][OAc] and mTCPP was covalently attached by reaction between the amino groups of DA-chitin and the carboxyl groups of mTCPP using N-(3-(dimethylamino)propyl)- N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) as activators. The resulting composite polymers were cast as a film and coagulated with water to remove IL and excess reagents, resulting in homogeneous DA-chitin/mTCPP films. Attempts to prepare films by coagulation from a solution containing chitin and mTCPP to physically entrap the porphyrin, resulted in aggregation of mTCPP in the film. The DA-chitin/mTCPP films had strong optical absorbance and their absorbance intensity could be tuned by changing the mTCPP content and degrees of deacetylation of DA-chitin in a predictive manner. In addition, metal ions (Cu2+, Zn2+, Gd3+, and Fe3+) could be easily chelated into the DA-chitin/mTCPP films through mixing metal salt solutions with the films and heating. After chelating metal ions, optical properties, such as absorption region and intensities, of the films changed, suggesting chelating metal ions could tune their optical properties. Moreover, the DA-chitin/mTCPP films could generate singlet oxygen under light irradiation and, hence, might serve as a photosensitizer in PDT. The methodology used in this study is also applicable for developing other functional biomaterial devices.

15N-, 13C- and ¹H-NMR Spectroscopy Characterization and Growth Inhibitory Potency of a Combi-Molecule Synthesized by Acetylation of an Unstable Monoalkyltriazene.

6-(3-Methyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione referred to as EG22 (8a), is an open-chain 3-alkyl-1,2,3-triazene termed "combi-molecule" designed to inhibit poly(adenosine diphosphate ribose) polymerase (PARP) and damage DNA. To delay its hydrolysis, acetylation of N3 was required. Being a monoalkyl-1,2,3-triazene, EG22 could assume two tautomers in solution or lose nitrogen during the reaction, thereby leading to several acetylated compounds. Instead, one compound was observed and to unequivocally assign its structure, we introduced isotopically labeled reagents in its preparation, with the purpose of incorporating 15N at N2 and 13C in the 3-methyl group. The results showed that the 1,2,3-triazene moiety remained intact, as confirmed by 15N-NMR, coupling patterns between the 15N-labeled N2 and the 13C-labeled methyl group. Furthermore, we undertook heteronuclear single quantum coherence (HSQC) and heteronuclear multiple bond correlation (HMBC) experiments that permitted the detection and assignment of all four nitrogens in 6-(3-acetyl-3-methyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione, referred to as ZSM02 (9a), whose structure was further confirmed by X-ray crystallography. The structure showed a remarkable coplanarity between the N-acetyltriazene and the naphtalimide moiety. Thus, we unequivocally assigned 9a as the product of the reaction and compared its growth inhibitory activity with that of its precursor, EG22. ZSM02 exhibited identical growth inhibitory profile as EG22, suggesting that it may be a prodrug of EG22.