Thioether Moiety Research Articles

Palladium(II) complexes of hemilabile NNS and NNSe iminophosphorane ligands: Synthesis, characterization, and reactivity

Four terdentate ligands combining (2-indolyl)iminophosphorane with a thioether or selenoether moiety, with general formula 2-C8H6N(Ph2P = NC6H4XR) [X = S, R = CH3 (2), C6H5 (3); X = Se, R = CH3 (4), C6H5 (5)], were synthesized and fully characterized, including the structure of ligand (2) by single-crystal X-ray crystallography. Treatment of ligands 2–5 with PdCl2(CH3CN)2 produces non-symmetrical N,N,X-Pd(II) pincer complexes [PdCl{2-C8H5N(Ph2P = NC6H4XR-κ3-N,N,X)}] [X = S, R = CH3 (6), C6H5 (7); X = Se, R = CH3 (8), C6H5 (9)]. All complexes were fully characterized spectroscopically and by single-crystal X-ray crystallography. In presence of NaPF6 or NaBF4, treatment of 6 with neutral ligands NEt3, Pyridine and PPh3 gives mononuclear cationic complexes 10, 11, 12 where Cl− is replaced by the corresponding ligand. The solid state structure of cationic complexes 10–12 show that κ3-N,N,X pincer coordination is preserved. Reaction of 6 with diphosphane Ph2P(CH2)2PPh2 (dppe) in 1:1 ratio promotes liberation of the sulfur donor atom from Pd(II) and gives the mononuclear cationic complex 13 bearing the ligand in bidentate N,N chelation and the diphosphane in P,P chelation. Solid-state structure of 13 determined by X-ray crystallography confirms the labile character of the thioether group and reveals a strong interaction between the iminic nitrogen and sulfur atom, holding the thioether group very close to the metal center. Reversibility of the process is proven by reformation of the pincer structure upon treatment of 13 with O2 and release of Ph2P(O)(CH2)2P(O)Ph2 (dppeO2). When complexes 7–9 are treated with the same sequence of reactions, 31P NMR monitoring indicates that pincer complexes with selenoether donors undergo the same reversible hemilability.

Design, synthesis and biological evaluation of the thioether-containing lenalidomide analogs with anti-proliferative activities

Lenalidomide and its analogs have exhibited extensive anti-tumor, anti-inflammatory and immunomodulatory properties in pharmaceutical research. In this work, a series of novel thioether-containing lenalidomide analogs were designed and synthesized for biological evaluation. Lenalidomide showed significant anti-proliferative activity against the MM.1S cell line (IC50 = 50 nM) while it displayed no anti-proliferative activity against other treated tumor cell lines. Compared with lenalidomide, compound 3j exhibited preferable anti-proliferative activity against the MM.1S (IC50 = 1.1 nM), Mino (IC50 = 2.3 nM) and RPMI 8226 cell lines (IC50 = 5.5 nM). In addition, compound 3j displayed selective anti-proliferative activity against several tumor cell lines, including various B-NHL, MM and AML cell lines, and showed no cytotoxicity on the normal human cell line PBMC, suggesting a good safety profile. Following oral administration, compound 3j achieved a Cmax of 283 ng/mL at 0.83 h, and had a higher relative oral bioavailability value (F = 39.2%) than that of CC-220 (F = 22.8%), but its oral exposure in vivo was somewhat low (AUC = 755 h ng/mL). Furthermore, it was found that oral administration of compound 3j at dosages of 60 mg/kg could delay RPMI 8226 tumor growth in the female CB-17 SCID mice. The current work confirmed that installing thioether moiety at the 4-position of isoindolinone is an effective strategy for identifying new promising lenalidomide analogs with anti-tumor activities in preclinical study.

Thioether-based 2-aminobenzamide derivatives: Novel HDAC inhibitors with potent in vitro and in vivo antitumor activity

Previously, we focused on a series of 2-aminobenzamide-based histone deacetylase (HDAC) inhibitors, compound 9 of which displayed potent HDAC inhibitory activity against HDAC1 and HDAC2, and moderate anti-proliferative activity against several cancer cell lines. In the current study, we have designed and synthesized a series of novel HDAC inhibitors based on thioether moiety with 9 as a lead compound. Representative compounds12 g and 12 h showed apparently potent anti-proliferative activities against five solid cancer cell lines: A549, HCT116, Hela, A375 and SMMC7721, and low cytotoxicity against NIH 3T3 normal cells. Especially, 12 g and 12 h also revealed potent HDAC inhibitory activity against HDAC1, 2 and 3. In addition, the two compounds could arrest cell cycle in G2/M phase and promote cell apoptosis. Moreover, they showed extended inhibition of colony formation and effectively blocked cell migration towards A549 cancer cells. Furthermore, 12 g and 12 h possessed better pharmacokinetic properties than the lead compound 9. Benefiting from these results, we also explored 12 g and 12 h in the A549 xenografts model for in vivo antitumor activity. The in vivo experiment indicated that 12 g and 12 h could evidently augment antitumor activity (TGI = 56.9% and 62.7% respectively).

Synthesis and Catalytic Properties of Dirhodium Paddlewheel Complexes with Tethered, Axially Coordinating Thioether Ligands

Novel mixed-ligand rhodium(II) paddlewheel complexes incorporating tethered axial thioether ligands have been synthesized and characterized. The thioether moiety is essential for high yields and the suppression of byproducts in cyclopropanation reactions using an electron-deficient diazoacetate. Crystal structures, UV-vis analysis, and cyclic voltammetry experiments shed light on the catalytic performance of the complexes.

Thiol-Cyanobenzothiazole Ligation for the Efficient Preparation of Peptide-PNA Conjugates.

Antisense oligonucleotide (ASO)-based drugs are emerging with great potential as therapeutic compounds for diseases with unmet medical needs. However, for ASOs to be effective as clinical entities, they should reach their intracellular RNA and DNA targets at pharmacologically relevant concentrations. Over the past decades, various covalently attached delivery vehicles have been utilized for intracellular delivery of ASOs. One such approach is the use of biocompatible cell-penetrating peptides (CPPs) covalently conjugated to ASOs. The stability of the linkage is of paramount importance for maximal intracellular delivery to achieve the desired therapeutic effect. In this study, we have investigated the efficiency and stability of four different bioorthogonal and nonreductive linkages including triazole, thioether, thiosuccinimide thioether and thiazole moieties. Here we have shown that thiazole and thiosuccinimide are the two most efficient and facile approaches for the preparation of peptide-ASO conjugates. The thiazole linkage had a higher stability compared to the thiosuccinimide thioether at physiological conditions (pH 7.4, 37 °C) in the presence of a biologically relevant concentration of glutathione. We have also shown that the peptide-ASO conjugate with a thiosuccinimide linkage has a significantly lower antisense activity compared to the peptide-ASO with the thiazole linkage, which maintains its antisense activity after 24 h of exposure to glutathione. In summary, we have demonstrated that the bioorthogonal thiazole linkage offers the benefits of mild reaction conditions, fast reaction kinetics, absence of any byproducts, and higher stability compared to other conjugation approaches. This facile ligation can be used for the synthesis of a variety of bioconjugates where a stable linkage is required.

Physicochemical and Ion-Sensing Properties of Benzofurazan-Appended Calix[4]arene in Solution and on Gold Nanoparticles: Spectroscopy, Microscopy, and DFT Computations in Support of the Species of Recognition.

A calix[4]arene conjugate (L) functionalized at the lower rim with a benzofurazan fluorophore (NBD) and at the upper rim with a thioether moiety has been synthesized and characterized by 1H NMR, 13C NMR, and mass spectrometry techniques. Both the absorption and emission spectral data for L in different solvents exhibited progressive changes with an increase in polarity. Ion recognition studies were performed by absorption and fluorescence spectroscopy using 10 different metal ions. Among these, Hg2+ exhibited greater changes in these spectra, whereas Cu2+ showed only significant changes and all other ions showed no change in the spectral features. Although the Hg2+ has dominant influence on the spectral features and provides a detection limit of 56.0 ± 0.6 ppb, the selectivity was hampered because of the presence of the derivatizations present on both the rims of L for ion interaction in solution. Therefore, L was immobilized onto gold nanoparticles (AuNPL’s) so that the upper rim derivatizations anchor onto the gold surface through Au–S interactions, and this leaves out only the lower rim NBD derivatization for interaction with ions selectively. The AuNPL’s were characterized by transmission electron microscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy (XPS) analyses. The surface characteristics were analyzed by contact angle measurements. The AuNPL’s exhibit greater selectivity and enhanced sensitivity for Hg2+ ions with a lowest detection limit of 48.0 ± 0.8 ppb. The immobilization of L onto AuNPs was reflected in the corresponding fluorescence lifetime values, and the addition of Hg2+ to either L or AuNPL showed fluorescence quenching. The reversible recognition of Hg2+ by L was demonstrated by titrating L or AuNPL with Hg2+ followed by tetra-butyl ammonium iodide for several cycles. The structural features of Hg2+-bound species were demonstrated by density functional theory computations and were supported by the XPS data. The Hg2+ induces aggregated fibrillar morphology into supramolecular L, as demonstrated by microscopy when Hg2+ was added either to L or to AuNPL, supporting aggregation-caused quenching.

Enzymatic synthesis and chemical inversion provide both enantiomers of bioactive epoxydocosapentaenoic acids

Epoxy PUFAs are endogenous cytochrome P450 (P450) metabolites of dietary PUFAs. Although these metabolites exert numerous biological effects, attempts to study their complex biology have been hampered by difficulty in obtaining the epoxides as pure regioisomers and enantiomers. To remedy this, we synthesized 19,20- and 16,17-epoxydocosapentaenoic acids (EDPs) (the two most abundant EDPs in vivo) by epoxidation of DHA with WT and the mutant (F87V) P450 enzyme BM3 from Bacillus megaterium WT epoxidation yielded a 4:1 mixture of 19,20:16,17-EDP exclusively as (S,R) enantiomers. Epoxidation with the mutant (F87V) yielded a 1.6:1 mixture of 19,20:16,17-EDP; the 19,20-EDP fraction was ∼9:1 (S,R):(R,S), but the 16,17-EDP was exclusively the (S,R) enantiomer. To access the (R,S) enantiomers of these EDPs, we used a short (four-step) chemical inversion sequence, which utilizes 2-(phenylthio)ethanol as the epoxide-opening nucleophile, followed by mesylation of the resulting alcohol, oxidation of the thioether moiety, and base-catalyzed elimination. This short synthesis cleanly converts the (S,R)-epoxide to the (R,S)-epoxide without loss of enantiopurity. This method, also applicable to eicosapentaenoic acid and arachidonic acid, provides a simple, cost-effective procedure for accessing larger amounts of these metabolites.

CO2-Catalyzed Efficient Dehydrogenation of Amines with Detailed Mechanistic and Kinetic Studies

CO2-catalyzed dehydrogenation of amines has been achieved under photocatalytic conditions. With this concept, various amines have been selectively dehydrogenated to the corresponding imines in the presence of different functional groups such as nitrile, nitro, ester, halogen, ether, thioether, and carbonyl or carboxylic acid moieties. At the end, the CO2-catalyzed synthesis of pharmaceutical drugs has been achieved. The CO2 radical has been detected by EPR spectroscopy using DMPO, and the mechanism of this reaction is proposed on the basis of DFT calculations and experimental evidence.

A Formal [5+1] Annulation Reaction of Sulfur Ylides and 2‐(1H‐indol‐2‐yl)phenols: Access to Indole‐Fused 4H‐benzo[e][1,3]oxazines

AbstractThe first sulfur ylides involved formal [5+1]‐annulation reaction was developed between prop‐2‐ynylsulfonium salts and 2‐(1H‐indol‐2‐yl)phenols. Prop‐2‐ynylsulfonium salt participates in the reaction with its β‐carbon atom and acts as a novel C1 synthon. Various indole‐fused 4H‐benzo[e][1,3]oxazines bearing a thioether moiety were constructed in good to high yields under mild conditions.magnified image

Magnetic nanoparticles as a support for a copper (II) complex with nuclease activity

Magnetic nanoparticles have been extensively explored for the development of platforms for drug delivery and imaging probes. In this work, we have used a modular capping strategy to produce magnetic gold-coated Fe3O4 (Fe3O4@Au) nanoparticles, which have been decorated with a copper (II) complex containing a thioether derivative of clip-phen (Fe3O4@Au@Cu), where the complex [Cu(2CP-Bz-SMe)]2+ has affinity to bind DNA and proven nuclease activity (2CP-Bz-SMe=1,3-bis((1,10-phenanthrolin-2-yl)oxy)-N-(4-(methylthio)benzylidene)propan-2-imine). The functionalization of Fe3O4@Au with the copper complex occurs through the sulfur atom of the thioether moiety, as indicated by Raman scattering on surface. The magnetic measurements showed the nanomaterial Fe3O4@Au@Cu is still magnetic although the gold shell and the functionalization with the copper complex have diminished the magnetization due to the dilution of the magnetic core. The nuclease assays performed with Fe3O4@Au@Cu indicate that the nuclease activity of the nanomaterial toward the plasmid DNA involves an oxidative pathway in which H2O2 species is involved as intermediate in a Fenton-like reaction. Based on the electron paramagnetic resonance spectra (aN = 15.07 G, aH = 14.99 G), such nuclease activity is assigned, essentially, to the HO species indicating that the radical production property of [Cu(2CP-Bz-SMe)]2+ is successfully transferred to the core-shell gold-coated Fe3O4 magnetic nanoparticles. To the best of our knowledge, this is the first study reporting nuclease activity due to the reactive oxygen species generated by a copper complex immobilized on a gold-coated magnetic nanoparticle.

Reaction-Based Color-Convertible Fluorescent Probe for Ferroptosis Identification.

Ferroptosis is an iron-mediated, caspase-independent pathway of cell death that is accompanied with the accumulations of reactive oxygen species (ROS) and oxygenases, as well as being involved in many other pathophysiological procedures. However, specific and rapid monitoring of ferroptosis in living cells or tissues has not been achieved so far. Herein, a quinoxalinone-based fluorescent probe (termed as Quinos-4, or QS-4) with a reactive aromatic thioether moiety was designed for ferroptosis identification. Upon exposing it to high levels of ROS and hemeoxygenase-1 (HO-1), which are considered as the biochemical characteristics of ferroptosis, QS-4 could be oxidized into a sulfoxide derivative (QSO-4) and its original aggregation-induced enhanced red fluorescence emission could be converted to green fluorescence emission sharply. On the basis of this unique reaction-induced color conversion, this molecular probe can be employed for identifying the occurrence of ferroptosis both in vitro and in vivo.

Functional Polyethylenes with Precisely Placed Thioethers and Sulfoniums through Thiol–Ene Polymerization

The precise functionalization of polyethylenes, often accomplished through acyclic diene metathesis polymerization (ADMET), is a significant area of research that has improved polyethylene properties and performance. Here, the synthesis of precisely functionalized polyethylenes was accomplished using the thiol–ene step-growth (TES) polymerization. The simplicity and versatility of this technique allowed for the synthesis of a variety of polymers and enabled the study of carbon spacer length between and repeat unit symmetry about the resulting backbone thioether moiety. In addition, the backbone thioethers of some samples were functionalized postpolymerization with methyl triflate to produce polyethylenes containing sulfonium cations. All polymers were then characterized for their thermal stability, crystallinity, and morphology using differential scanning calorimetry (DSC) and X-ray scattering. While the carbon spacer length and repeat unit symmetry had no effect on polymer thermal stability, the incorpor...

OEGylated Cyclodextrins Responsive to Temperature, Redox, and Metal Ions.

The present work provides a versatile access for "smart" cyclodextrins (CDs) that are responsive to temperature, redox, and metal ions. These CDs are modified with oligoethylene glycols through thiol-ene click chemistry, which are inherently thermoresponsive in aqueous solutions. At the same time, their thermoresponsiveness is tunable through oxidation or metal ion chelation of thioether moieties. Significantly, these stimuli-responsive CDs retained strong inclusion abilities to guest dyes, and the inclusion complexation can be tuned by thermally induced phase transitions, oxidation, as well as metal chelation. The stimuli-responsive complexation with dyes allows to fabricate colorimetric/fluorescent sensors for temperature or for soft metal ions, such as Ag+ and Hg2+. With multiple responsiveness integrated in one material, these monodisperse CDs have formed a new class of stimuli-responsive macrocycles, which can reversibly encapsulate and release guest species through multiple switches.

Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2

New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-RafV600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-RafV600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC50 of 21 nM, 27 nM and 17 nM, B-RafV600E with IC50 of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC50 of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay.

Synthesis and properties of novel organosoluble copoly(arylene ether nitriles) containing thioether moiety

In this work, a series of novel organosoluble copoly(arylene ether nitriles) containing thioether moiety (PENS) were synthesized via nucleophilic aromatic substitution polymerization of 2,6-dichlorobenzonitrile with bisphenol A and sodium sulfide nonahydrate, using N-Methyl-2-Pyrrolidone as solvent in the presence of anhydrous potassium carbonate. The chemical structures of PENS were characterized by FTIR and 1H NMR. The derived copolymers showed high glass transition temperatures in the range of 167–178 °C and excellent thermal stability with the 5% weight loss temperatures ranging from 465 °C to 503 °C. Meanwhile, all of the PENS were amorphous and can be readily cast into transparent films with a tensile strength exceeding 77 MPa and a breaking elongation over 4.8%.In addition, the dielectric constant of all the PENS copolymers showed weak frequency dependence, the dielectric loss showed slight decrease with increasing frequency over the range of 100 Hz to 200 kHz. Therefore, this kind of organosoluble copoly(arylene ether nitriles) containing thioether moiety could be a good candidate as matrix resins for high-performance polymeric materials.

Enantioselective, Lewis Base-Catalyzed Sulfenocyclization of Polyenes.

A sulfenium-ion-initiated, catalytic, enantioselective polyene cyclization is described. Homogeranylarenes and ortho-geranylphenols undergo polycyclization in good yield, diastereoselectivity, and enantioselectivity. The stereodetermining step is the generation of an enantiomerically enriched thiiranium ion from a terminal alkene and a sulfenylating agent in the presence of a chiral Lewis basic catalyst. The use of hexafluoroisopropyl alcohol as the solvent is crucial to obtain good yields. The thioether moiety resulting from the reaction can be subsequently transformed into diverse oxygen and carbon functionality postcyclization. The utility of this method is demonstrated by the enantioselective syntheses of (+)-ferruginol and (+)-hinokiol.

Unmasking Dipole Character of Acyl Ketene Dithioacetals via a Cascade Reaction with Arynes: Synthesis of Benzo[b]thiophenes.

An unusual strategy toward novel substituted benzo[b]thiophenes has been developed. The generation of arynes in the presence of acyl ketene dithioacetals resulted in a cascade reaction involving [3 + 2] cycloaddition, and a dealkylative arylation of a thioether moiety to afford 2,3-disubstuted benzo[b]thiophenes. This route represents an expeditious approach to benzothiophenes that employs acyl ketene dithioacetals as dipoles.

Design, synthesis, and biological evaluation of novel amide and hydrazide based thioether analogs targeting Histone deacteylase (HDAC) enzymes

Development of HDAC inhibitors have become an ultimate need targeting different types of cancer. In silico virtual screening was applied to screen novel scaffolds via scaffold hopping strategy to develop different acrylamide and aryl/heteroaryl hydrazide based analogs merged with thioether moiety. The acrylamide based analogs showed significant hydrophobic interaction within binding pocket in addition to co-ordination with Zn+2 via carbonyl group, however the aryl/heteroaryl hydrazide based analogs showed binding towards Zn+2 via thiol moiety. Two classes (acrylamide and aryl/heteroaryl hydrazide based analogs) were synthesized to be screened along with 60 cancer cell lines panel to reveal that both of AHM-4 and AHM-5 showed significant inhibitory growth against HL-60 (Leukemia cell lines) at GI50 2.87 μM and 3.20 μM, respectively and MDA-MB-435 (Melanoma cell lines) cell lines at GI50 of 0.37 μM and 0.42 μM, respectively. AHM-4 and AHM-5 showed general inhibitory profile against class I HDAC enzymes with differential inhibitory activity towards HDAC 2 at IC50 32 nM and 20 nM, respectively via ELISA enzymatic assay, in addition to inhibiting activity for the expression of class I HDAC enzymes via real time PCR with differential selective inhibition against HDAC 2 up to 10 folds, compared to control. AHM4 and AHM5 showed cell cycle arrest action at G2/M phase along with induction of apoptosis via assessment of apoptotic parameters such as Caspase 3, 9, and γ- H2AX. The synthesized analogs offer novel scaffold to be further optimized for development of HDAC inhibitors.

Molecular cage-bridged plasmonic structures with well-defined nanogaps as well as the capability of reversible and selective guest trapping.

Creating well-defined plasmonic hotspots with enormous field enhancements as well as the capability of selectively trapping targeted molecules into hotspots is of critical importance and a prerequisite for numerous plasmon-assisted applications, but it represents a great challenge. In this work, a robust molecular cage decorated with thioether moieties at the periphery was designed and synthesized. By using the synthesized cage as a linker, a series of molecular cage-bridged plasmonic structures with well-defined nanogaps (hotspots) were fabricated in an efficient and controllable fashion. It was found both experimentally and theoretically that the nanogaps of about 1.2 nm created by the molecular cage in the resultant plasmonic structures led to a strong plasmon coupling, thus inducing great field enhancement inside the nanogaps. More importantly, the embedded molecular cages endowed the formed hotspots with the capability of selectively trapping targeted molecules, offering huge opportunities for many emergent applications. As a demonstration, the hotspots constructed were used as a unique nanoreactor, and under mild conditions two types of plasmon-driven chemical transformation were successfully performed. All the results clearly indicate that the integration of the host-guest chemistry of the molecular cage with the plasmon-coupling effect of metal particles afforded a new class of plasmonic structures, showing great potential for facilitating a broad variety of plasmon-based applications.

Photoactive rhenium carbonyl complexes of N,N,S-donor ligands: Contrast in binding modes based on flexibility of ligand frames and nature of ancillary ligands

A set of two potentially tridentate ligands with N,N,S donor centers has been employed to isolate Re(I) carbonyl complexes of the type [Re(ligand)(CO)3]X (X=Cl, ClO4). The first ligand 2-quinoline-N-(2′-methylthiophenyl)methyleneimine (qmtpm) contains an imine-N junction between a quinoline (offering N center) and an aryl thioether (offering S center) moiety. In case of the second ligand 2-quinoline-N-(2′-methylthiophenyl)methyleneamine (qmtpa), the imine junction is replaced with a more flexible secondary amine-N junction. The rigidity of the conjugated qmtpm ligand (can only bind in meridional mode) does not afford a Re(I) carbonyl complex with qmtpm ligand binding in a tridentate fashion due to the presence of a strongly bound CO ligand in the equatorial plane of the metal. Although this rigidity is removed in qmtpa, the expected facial binding of the ligand to afford fac-[Re(qmtpa)(CO)3]Cl does not occur unless the σ-binding Cl− ligand is removed from the axial position of the starting [ReCl(CO)5] complex. Taken together the results suggest that both ligand flexibility and presence of easily replaceable ligand dictate the binding mode of tridentate ligands in carbonyl complexes of the type [MI(ligand)(CO)3]X.