Design and Synthesis of Thiourea-Conjugating Organic Arsenic D-Glucose with Anticancer Activities.

Organic arsenic compounds such as p-aminophenylarsine oxide (p-APAO) are easier for structural optimization to improve drug-like properties such as pharmacokinetic properties, therapeutic efficacy, and target selectivity. In order to strengthen the selectivity of 4-(1,3,2-dithiarsinan-2-yl) aniline 7 to tumor cell, a thiourea moiety was used to strengthen the anticancer activity. To avoid forming a mixture of α/ß anomers, the strategy of 2-acetyl's neighboring group participation was used to lock the configuration of 2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl isothiocyanate from 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide. 1-(4-(1,3,2-dithiarsinan-2-yl) aniline)-2-N-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranos-1-yl)-thiourea 2 can increase the selectivity of human colon cancer cells HCT-116 (0.82 ± 0.06 µM vs. 1.82 ± 0.07 µM) to human embryonic kidney 293T cells (1.38 ± 0.01 µM vs. 1.22 ± 0.06 µM) from 0.67 to 1.68, suggesting a feasible approach to improve the therapeutic index of arsenic-containing compounds as chemotherapeutic agents.

Semisynthesis of the Organoarsenical Antibiotic Arsinothricin.

Arsinothricin [AST (1)], a new broad-spectrum organoarsenical antibiotic, is a nonproteinogenic analogue of glutamate that effectively inhibits glutamine synthetase. We report the chemical synthesis of an intermediate in the pathway to 1, hydroxyarsinothricin [AST-OH (2)], which can be converted to 1 by enzymatic methylation catalyzed by the ArsM As(III) S-adenosylmethionine methyltransferase. This is the first report of semisynthesis of 1, providing a source of this novel antibiotic that will be required for future clinical trials.

Direct Vicinal Difunctionalization of Thiophenes Enabled by the Palladium/Norbornene Cooperative Catalysis.

Herein we report a direct vicinal difunctionalization of thiophenes via the palladium/norbornene (Pd/NBE) cooperative catalysis. A series of mono- and disubstituted thiophenes can be difunctionalized site-selectively and regioselectively at the C4 and C5 positions in good yields, enabled by an arsine ligand and a unique amide-based NBE. The synthetic utility has been shown in derivatizations of complex bioactive compounds and an open-flask gram-scale preparation. Preliminary results have been obtained in the difunctionalization of furans and a direct C4-selective arylation of 2-substituted thiophenes.

A mitochondria-targeted organic arsenical accelerates mitochondrial metabolic disorder and function injury.

Considering the vital role of mitochondria in the anti-cancer mechanism of organic arsenical, the mitochondria-targeted precursor PDT-PAO-TPP was designed and synthesized. PDT-PAO-TPP, as a delocalization lipophilic cation (DLCs) which mainly accumulated in mitochondria, contributed to improve anti-cancer efficacy and selectivity towards NB4 cells. In detail, PDT-PAO-TPP inhibited the activity of PDHC resulting in the suppression of ATP synthesis and thermogenesis disorder. Additionally, the inhibition of respiratory chain complex I and IV by short-time incubation of PDT-PAO-TPP also accelerated the respiration dysfunction and continuous generation of ROS. These results led to the release of cytochrome c and activation of caspase family-dependent apoptosis. Different from the mechanism of PDT-PAO in HL-60 cells, it mainly induced the mitochondrial metabolic disturbance resulting in the intrinsic apoptosis via inhibiting the activity of PDHC in NB4 cells, which also implied that the efficacy exertion of organic arsenical was a complex process involved in many aspects of cellular function. This study systematically clarifies the anti-cancer mechanism of mitochondria-targeted organic arsenical PDT-PAO-TPP and confirms the new target PDHC of organic arsenicals, which further supports the organic arsenical as a promising anticancer drug.

LDHA Suppression Altering Metabolism Inhibits Tumor Progress by an Organic Arsenical.

Based on the potential therapeutic value in targeting metabolism for the treatment of cancer, an organic arsenical PDT-BIPA was fabricated, which exerted selective anti-cancer activity in vitro and in vivo via targeting lactate dehydrogenase A (LDHA) to remodel the metabolic pathway. In details, the precursor PDT-BIPA directly inhibited the function of LDHA and converted the glycolysis to oxidative phosphorylation causing ROS burst and mitochondrial dysfunction. PDT-BIPA also altered several gene expression, such as HIF-1α and C-myc, to support the metabolic remodeling. All these changes lead to caspase family-dependent cell apoptosis in vivo and in vitro without obvious side effect. Our results provided this organic arsenical precursor as a promising anticancer candidate and suggested metabolism as a target for cancer therapies.

Mitochondrion-Targeting, Environment-Sensitive Red Fluorescent Probe for Highly Sensitive Detection and Imaging of Vicinal Dithiol-Containing Proteins.

Mitochondrial vicinal dithiol-containing proteins (VDPs) are key regulators in cellular redox homeostasis and useful markers for diagnostics of redox-dependent diseases. Current probes fail to target mitochondrial VDPs and show limited sensitivity and response rate. We develop a novel fluorescent probe using an engineered benzoxadiazole fluorophore that allows selective targeting of mitochondria and exhibits highly sensitive environment responsiveness. This probe is almost nonfluorescent in aqueous media, while delivering intense fluorescence upon binding to VDPs via a cyclic dithiaarsane ligand. The fluorescence probe is shown to have rapid response within 30 s and high sensitivity for detecting reduced bovine serum albumin (rBSA) in the concentration range from 0 to 0.1 µM with a detection limit of 2 nM. To our knowledge, this is the first fluorescence probe for VDPs which exhibits deep red emission, instantaneous response, high turn-on fluorescence ratio, and specific mitochondrial localization. It may provide a new tool for in situ monitoring mitochondrial VDPs.

Dithiol Aryl Arsenic Compounds as Potential Diagnostic and Therapeutic Radiopharmaceuticals.

Arsenic-72 ((72)As) and (77)As have nuclear properties useful for positron emission tomography (PET) and radiotherapy, respectively. The thiophilic nature of arsenic led to the evaluation of dithioarylarsines for potential use in radiopharmaceuticals. Several dithioarylarsines were synthesized from their arylarsonic acids and dithiols and were fully characterized by NMR, ESI-MS, and X-ray crystallography. This chemistry was translated to the no-carrier-added (nca) (77)As level. Because arsenic was available at the nca nanomolar level only as [(77)As]arsenate, this required addition of an aryl group directly to the As to form the [(77)As]arylarsonic acid. The [(77)As]arsenate was reduced from (77)As (V) to (77)As (III), and a modified Bart reaction was used to incorporate the aryl ring onto the (77)As, which was followed by dithiol addition. Various modifications and optimizations resulted in 95% radiochemical yield of nca [(77)As]p-ethoxyphenyl-1,2-ethanedithiolatoarsine.

Synthesis of Arylazide- and Diazirine-Containing CrAsH-EDT2 Photoaffinity Probes.

Two photo-crosslinking biarsenical (CrAsH-EDT2 )-modified probes were synthesized that are expected to be useful tools for tetracysteine-labeled proteins to facilitate the co-affinity purification of their DNA binding sequences and interacting proteins. In addition, improvements for the synthesis of CrAsH-EDT2 and N(1) -(4-azido-2-nitrophenyl)hexane-1,6-diamine are reported. Both photoprobes effectively entered HeLa cells (and the nucleus) and were dependent on the tetracysteine motif in recombinant DMRT1 (doublesex and Mab3-related transcription factor) to induce fluorescence, suggesting that their crosslinking abilities can be exploited for the identification of nucleic acids and proteins associated with a protein of interest.

p-Azidophenylarsenoxide: An Arsenical "Bait" for the In Situ Capture and Identification of Cellular Arsenic-Binding Proteins.

Identification of arsenic-binding proteins is important for understanding arsenic health effects and for developing arsenic-based therapeutics. We report here a strategy for the capture and identification of arsenic-binding proteins in living cells. We designed an azide-labeled arsenical, p-azidophenylarsenoxide (PAzPAO), to serve bio-orthogonal functions: the trivalent arsenical group binds to cellular proteins in situ, and the azide group facilitates click chemistry with dibenzylcyclooctyne. The selective and efficient capture of arsenic-binding proteins enables subsequent enrichment and identification by shotgun proteomics. Applications of the technique are demonstrated using the A549 human lung carcinoma cells and two in vitro model systems. The technique enables the capture and identification of 48 arsenic-binding proteins in A549 cells incubated with PAzPAO. Among the identified proteins are a series of antioxidant proteins (e.g., thioredoxin, peroxiredoxin, peroxide reductase, glutathione reductase, and protein disulfide isomerase) and glyceraldehyde-3-phosphate dehydrogenase. Identification of these functional proteins, along with studies of arsenic binding and enzymatic inhibition, points to these proteins as potential molecular targets that play important roles in arsenic-induced health effects and in cancer treatment.

Organic arsenicals as efficient and highly specific linkers for protein/peptide-polymer conjugation.

The entropy-driven affinity of trivalent (in)organic arsenicals for closely spaced dithiols has been exploited to develop a novel route to peptide/protein-polymer conjugation. A trivalent arsenous acid (As(III)) derivative (1) obtained from p-arsanilic acid (As(V)) was shown to readily undergo conjugation to the therapeutic peptide salmon calcitonin (sCT) via bridging of the Cys(1)-Cys(7) disulfide, which was verified by RP-HPLC and MALDI-ToF-MS. Conjugation was shown to proceed rapidly (t < 2 min) in situ and stoichiometrically through sequential reduction-conjugation protocols, therefore exhibiting conjugation efficiencies equivalent to those reported for the current leading disulfide-bond targeting strategies. Furthermore, using bovine serum albumin as a model protein, the trivalent organic arsenical 1 was found to demonstrate enhanced specificity for disulfide-bond bridging in the presence of free cysteine residues relative to established maleimide functional reagents. This specificity represents a shift toward potential orthogonality, by clearly distinguishing between the reactivity of mono- and disulfide-derived (vicinal or neighbors-through-space) dithiols. Finally, p-arsanilic acid was transformed into an initiator for aqueous single electron-transfer living radical polymerization, allowing the synthesis of hydrophilic arsenic-functional polymers which were shown to exhibit negligible cytotoxicity relative to a small molecule organic arsenical, and an unfunctionalized polymer control. Poly(poly[ethylene glycol] methyl ether acrylate) (PPEGA480, DPn = 10, Mn,NMR = 4900 g·mol(-1), D = 1.07) possessing a pentavalent arsenic acid (As(V)) α-chain end was transformed into trivalent As(III) post-polymerization via initial reduction by biological reducing agent glutathione (GSH), followed by binding of GSH. Conjugation of the resulting As(III)-functional polymer to sCT was realized within 35 min as indicated by RP-HPLC and verified later by thermodynamically driven release of sCT, from the conjugate, in the presence of strong chelating reagent ethanedithiol.

An arsenical-maleimide for the generation of new targeted biochemical reagents.

The finding that arsenic trioxide is an effective treatment for acute promyelocytic leukemia has renewed interest in the pharmacological uses of inorganic and organic arsenicals. Here we synthesized and characterized the reactivity of an arsenical-maleimide (As-Mal) that can be efficiently conjugated to exposed cysteine residues in peptides and proteins with the ultimate goal of directing these As(III) species to vicinal thiols in susceptible targets within cells and tissues. As-Mal conjugated to a surface cysteine in thioredoxin provides a more potent inhibitor for Escherichia coli thioredoxin reductase than comparable simple inorganic or organic arsenicals. As-Mal can be coupled to all of the eight cysteine residues of reduced unfolded ribonuclease A or to site-specific locations using appropriate cysteine mutations. We observed particularly strong binding to the two CxxC motifs of protein disulfide isomerase using a mutant RNase in which As-Mal was specifically incorporated at residues 26 and 110. As-Mal will serve as a facile reagent for the incorporation of As(III) species into a wide range of thiol-containing proteins, biomaterials, and surfaces.

III-V nanocrystals capped with molecular metal chalcogenide ligands: high electron mobility and ambipolar photoresponse.

In this work, we synthesized InP and InAs nanocrystals (NCs) capped with different inorganic ligands, including various molecular metal chalcogenide complexes (MCCs) and chalcogenide ions. We found that MCCs and chalcogenide ions can quantitatively displace organic ligands from the surface of III-V NCs and serve as the inorganic capping groups for III-V NC surfaces. These inorganic ligands stabilize colloidal solutions of InP and InAs NCs in polar solvents and greatly facilitate charge transport between individual NCs. Charge transport studies revealed high electron mobility in the films of MCC-capped InP and InAs NCs. For example, we found that bridging InAs NCs with Cu(7)S(4)(-) MCC ligands can lead to very high electron mobility exceeding 15 cm(2)/(V s). In addition, we observed unprecedented ambipolar (positive/negative) photoresponse of MCC-capped InAs NC solids that changed sign depending on the ligand chemistry, illumination wavelength, and doping of the NC solid. For example, the sign of photoconductance of InAs NCs capped with Cu(7)S(4)(-) or Sn(2)S(6)(4-) ions converted from positive at 0.80 and 0.95 eV to negative at 1.27 and 1.91 eV. We propose an explanation of this unusually complex photoconductivity of InAs NC solids.

Versatile probes for the selective detection of vicinal-dithiol-containing proteins: design, synthesis, and application in living cells.

Endogenous vicinal-dithiol-containing proteins (VDPs) that have two thiol groups close to each other in space play a significant importance in maintaining the cellular redox microenvironment. Approaches to identify VDPs mainly rely on monitoring the different concentration of monothiol and total thiol groups or on indirect labeling of vicinal thiols by using p-aminophenylarsenoxide (PAO). Our previous work has reported the direct labeling of VDPs with a highly selective receptor PAO analogue, which could realize fluorescence detection of VDPs directly in living cells. Herein, we developed a conjugated approach to expand detectable tags to nitrobenzoxadiazole (NBD), fluorescein, naphthalimide, and biotin for the synthesis of a series of probes. Different linkers have also been introduced toward conjugation of VTA2 with these functional tags. These synthesized flexible probes with various features will offer new tools for the potential identification and visualization of vicinal dithiols existing in different regions of VDPs in living cells. These probes are convenient tools for proteomics studies of various disease-related VDPs and for the discovery of new drug targets.

Improved precursor chemistry for the synthesis of III-V quantum dots.

The synthesis of III-V quantum dots has been long known to be more challenging than the synthesis of other types of inorganic quantum dots. This is attributed to highly reactive group-V precursors. We synthesized molecules that are suitable for use as group-V precursors and characterized their reactivity using multiple complementary techniques. We show that the size distribution of indium arsenide quantum dots indeed improves with decreased precursor reactivity.

Ion exchange synthesis of III-V nanocrystals.

III-V nanocrystals displaying high crystallinity and low size dispersity are difficult to access by direct synthesis from molecular precursors. Here, we demonstrate that cation exchange of cadmium pnictide nanocrystals with group 13 ions yields monodisperse, crystalline III-V nanocrystals, including GaAs, InAs, GaP, and InP. This report highlights the versatility of cation exchange for accessing nanocrystals with covalent lattices.

History of arsenic ethers: who was Felix D'Arcet?

Williamson serendipitously discovered (1851) a new and efficient way to produce esters using ethyl iodide and potassium salts and in doing so elucidated the molecular mechanism behind ether formation. Lassaigne (1820) made the analogy between sulphovinic and phosphovinic acids and demonstrated the existence of phosphovinic acid, while Pelouze (1833) synthesised monoethyl phosphovinic acid. Finally 1848 Voegeli produced diethyl phosphovinic acid and the first neutral ester of phosphoric acid, the triethyl phosphate (TEP). The successes of Lassaigne and Pelouze in producing phosphovinic acids and Mitscherlich's theory of isomorphism fuelled the search for the vinic acids of arsenic, phosphorus neighbor in the periodic system. This short report attempts to identify the (less known) pharmacists and chemists involved in the quest for both arsenovinic acids and the neutral esters of arsenic and pyroarsenic acids.

Synthesis of cadmium arsenide quantum dots luminescent in the infrared.

We present the synthesis of Cd(3)As(2) colloidal quantum dots luminescent from 530 to 2000 nm. Previous reports on quantum dots emitting in the infrared are primarily limited to the lead chalcogenides and indium arsenide. This work expands the availability of high quality infrared emitters.

Purification of tetracysteine-tagged proteins by affinity chromatography using a non-fluorescent, photochemically stable bisarsenical affinity ligand.

The use of genetically encoded small peptide tags such as polyhistidine and tetracysteine tags has become important for protein purification and enrichment. An improved affinity purification of tetracysteine (CCXXCC) tagged proteins has been achieved using a nonfluorescent, photochemically stable bisarsenical affinity ligand SplAsH. The photochemical stability of the SplAsH-biotin, shown in compound 5, is superior to FlAsH-EDT(2) and ReAsH-EDT(2). An application of the SplAsH tag for affinity purification of tetracysteine-tagged proteins is reported.

Fast growth synthesis of GaAs nanowires with exceptional length.

We report the first synthesis of GaAs nanowires (NWs) by Au-assisted vapor-liquid-solid (VLS) growth in the novel hydride vapor phase epitaxy (HVPE) environment. Forty micrometer long rodlike <111> monocrystalline GaAs nanowires exhibiting a cubic zinc blende structure were grown in 15 min with a mean density of 10(6) cm(-2). The synthesis of such long figures in such a short duration could be explained by the growth physics of near-equilibrium HVPE. VLS-HVPE is mainly based on solidification after direct and continuous feeding of the arsenious and GaCl growth precursors through the Au-Ga liquid catalyst. Fast solidification (170 microm/h) is then assisted by the high decomposition frequency of GaCl. This predominant feeding through the liquid-solid interface with no mass and kinetic hindrance favors axial rather than radial growth, leading to twin-free nanowires with a constant cylinder shape over unusual length. The achievement of GaAs NWs several tens of micrometers long showing a high surface to volume ratio may open the field of III-V wires, as already addressed with ultralong Si nanowires.

Four-coordinate As(III)-N,S complexes: synthesis, structure, properties, and biological relevance.

Air-stable four-coordinate As(III) complexes, [As(L4)Cl] (1) and [As(L4)I] (2), were prepared using a rearranged form of the deprotonated benzothiazoline ligand, 2-(pyridin-2-yl)-2,3-dihydrobenzo[d]thiazole. Complexes 1 and 2 have been characterized by FTIR, (1)H NMR, UV-vis, and elemental microanalysis. The solid-state structure of 2 was also solved. The unusual and rare four-coordinate geometry of 2 elucidates possible binding modes and properties of N,S-ligated As(III) that may be encountered in biology.