Ligands 1a Research Articles

Tuning the electronic effects in designing ligands for the inhibition of rotamase activity of FK506 binding protein

FK506-binding protein (FKBP) is a cytosolic enzyme, which catalyzes the cis–trans isomerization of prolyl peptides. The twisted amide geometries assist the isomerization process and inhibit the rotamase activity of FKBP. This work reveals the role of electronic effects in ligands to facilitate the twisted amide geometries for efficient inhibition of the rotamase activity of FKBP12. The azirine ligand (5A) lowered the rotation barrier of –C–N amide bond by ~ 14.0 kcal/mol compared to the reference ligand molecule (1A) using M062X/cc-pVDZ//M062X/6-31G(d) level of theory. A significant lowering in rotation barrier has been achieved in (5A) due to the ring's anti-aromatic nature. The ring strain in the 1H-azirine ring pyramidalizes the amide bond's nitrogen center by 78° in the ground state compared to 1A. The natural bond orbital (NBO) analysis confirmed the lowering in the delocalization of electron density from nitrogen lone pair to π*C = O orbital in amide bonds. The designed models (1A-5A) were developed into ligands to mimic the binding domain of FK506 (1B-5B). The binding of these ligands (1B-5B) was examined with the quantum mechanics and molecular mechanics (QM/MM) ONIOM approach in the presence of FKBP12 binding site residues. The calculated results reveal the preferential binding of twisted amide forms with FKBP12 over their planar analogous. The hydrophobic interactions augment the binding affinity of the twisted forms with the FKBP12 binding site in agreement with the experimental observations. These studied ligands could act as potential inhibitors of FKBP12 for their therapeutic application.

Syntheses and photophysical properties of natural dehydroabietic acid-based ligands and their zinc complexes

Two Schiff base ligands (2a and 2b) and their zinc complexes (3a and 3b) have been designed and facilely synthesized through simple condensation reactions using compound 1 derived from natural dehydroabietic acid as the precursor. The larger dihedral angles of the ligands shown by the single crystal X-ray diffraction analysis indicate their stronger molecular motion, which is in consistence with their low fluorescence efficiency that is verified by the photophysical measurements. After coordination with zinc ions, the fluorescence intensity of the zinc complexes is larger, which might be explained by the structural rigidification via coordination, thereby reducing the energy loss from molecular motion. Furthermore, complex 3b exhibits a specific negative solvatochromic effect, and the absorption of its maximum wavelength shows a hypsochromic shift with increased polarity. Such solvatochromic phenomena can be explained by the synergy of intramolecular charge transfer and the proximity effect that may increase the energy difference between the ground state and the excited state in polar solvents. This work not only discusses their relationship between photophysical properties and structures, but also provides a new natural source for further research in fluorescent materials.

Spleen is not required for therapeutic effects of 4OH-GTS-21, a selective α7 nAChR agonist, in the sub-acute phase of ischemic stroke in rats

Acute ischemic stroke (AIS) causes both central and peripheral inflammation, while activation of α7 nicotinic acetylcholine receptors (nAChRs) provides both central and peripheral anti-inflammatory and anti-apoptotic effects. Here, we provide evidence that 4OH-GTS-21, a selective α7 agonist, produces its therapeutic effects via primarily central sites of action because 4OH-GTS-21 was found equally effective in splenectomized and non-spenectomized rats in the sub-acute phase of ischemic stroke (≤1 week). However, the spleen may boost the therapeutic efficacy of 4OH-GTS-21 in certain behavioral tasks as our data also indicated. In our tests, AIS was modeled by transient middle cerebral artery occlusion (tMCAO). Splenectomy was done 2 weeks before tMCAO. We determined that: 1) Daily 4OH-GTS-21 treatments for 7 days after tMCAO significantly reduced neurological deficits and brain injury in both splenectomized and non-spelenectomized rats demonstrating that the spleen is not required for therapeutic benefits of 4OH-GTS-21; 2) The effects of 4OH-GTS-21 in the adhesive sticker removal test were significantly weaker in splenectomized animals suggesting that the spleen boosts the efficacy of 4OH-GTS-21 in the first week after tMCAO; and 3) Ischemic brain injury was not significantly affected by splenectomy in both vehicle-treated and 4OH-GTS-21-treated animals. These data support the hypothesis that the therapeutic efficacy of sub-chronic (≤1 week) 4OH-GTS-21 primarily originates from central sites of action. These results validate brain availability as a critical factor for developing novel α7 ligands for AIS.

Discovery of Novel Nonpeptidic PAR2 Ligands.

Proteinase-activated receptor 2 (PAR2) is a class A G protein-coupled receptor whose activation has been associated with inflammatory diseases and cancer, thus representing a valuable therapeutic target. Pathophysiological roles of PAR2 are often characterized using peptidic PAR2 agonists. Peptidic ligands are frequently unstable in vivo and show poor bioavailability, and only a few approaches toward drug-like nonpeptidic PAR2 ligands have been described. The herein-described ligand 5a (IK187) is a nonpeptidic PAR2 agonist with submicromolar potency in a functional assay reflecting G protein activation. The ligand also showed substantial β-arrestin recruitment. The development of the compound was guided by the crystal structure of PAR2, when the C-terminal end of peptidic agonists was replaced by a small molecule based on a disubstituted phenylene scaffold. IK187 shows preferable metabolic stability and may serve as a lead compound for the development of nonpeptidic drugs addressing PAR2.

The Influence of Various N-Heterocyclic Carbene Ligands on Activity of Nitro-Activated Olefin Metathesis Catalysts.

A set of nitro-activated ruthenium-based Hoveyda-Grubbs type olefin metathesis catalysts bearing sterically modified N-hetero-cyclic carbene (NHC) ligands have been obtained, characterised and studied in a set of model metathesis reactions. It was found that catalysts bearing standard SIMes and SIPr ligands (4a and 4b) gave the best results in metathesis of substrates with more accessible C–C double bonds. At the same time, catalysts bearing engineered naphthyl-substituted NHC ligands (4d–e) exhibited high activity towards formation of tetrasubstituted C–C double bonds, the reaction which was traditionally Achilles’ heel of the nitro-activated Hoveyda–Grubbs catalyst.

Tetraphenylethene-Based Supramolecular Coordination Frameworks with Aggregation-Induced Emission for an Artificial Light-Harvesting System.

Supramolecular coordination is an efficient strategy to construct supramolecular coordination frameworks with predesigned structures, assembled shapes, and specific function. In this work, we report the synthesis, structural characterization, and photophysical property of two tetraphenylethene-based supramolecular coordination frameworks 1a and 1b formed from 1,1,2,2-tetrakis(4-(pyridin-4-yl)phenyl)ethene (2a) or 1,1,2,2-tetrakis(4-((E)-2-(pyridin-4-yl)vinyl)phenyl)ethene (2b) and a linear difunctional platinum(II) ligand (3a) via coordination-driven self-assembly. Controlled by the specific angularity and geometry of tetraphenylethene (with 60° and 120°) and difunctional Pt(II) linker (with 180°), these supramolecular coordination frameworks possess a well-defined and two-dimensional (2D) rhombic network-type topology with good periodicity and porosity. Given the aggregation-induced emission (AIE) property of tetraphenylethene units and the porosity of frameworks, 1a and 1b have been successfully used as fluorescent platforms and energy donors to fabricate efficient artificial light-harvesting materials with two fluorescent acceptors (Nile Red and Sulforhodamine 101) via noncovalent interactions in aqueous solution. Furthermore, these light-harvesting materials have been applied for promoting cancer cell imaging with a full shift of imaging channels from blue/green channels to the red channel. Thus, this study provides an effective approach to fabricate functional frameworks as fluorescent platforms for developing more fluorescent materials.

Novel palladium(II) complexes of N-(5-nitro-salicylidene)-Schiff bases: Synthesis, spectroscopic characterization and cytotoxicity investigation

A series of palladium(II) complexes (1e–3e) with the general formulae [Pd(L)(H2O)]·xH2O were newly synthesized by the interaction of palladium(II) chloride and the monosodium salts of N-(5-nitro-salicylidene)-Schiff base ligands (1a–3a) in aqueous DMF solution. The identities of all the complexes were proven by elemental analysis, FTIR, 1H, 13C NMR, LC–MS, UV–vis, XPS, powder XRD spectra, thermal analysis, conductivity and magnetic susceptibility measurements. The obtained analytical and physicochemical results exhibited a square-planar coordination of the palladium(II) ion having a double deprotonated ligand and a coordinated water molecule. In vitro cytotoxicity of these Pd(II) complexes was screened against tumor cell lines (HeLa and MCF-7), and a normal human cell line (HEK-293). The complexes 1e and 2e exhibited a moderate antitumor activity against HeLa cell lines, while 3e had better activity than standard anticancer drug, doxorubicin. All three complexes showed the best active cytotoxicity than doxorubicin against MCF-7 cancer lines. For HEK-293 lines, a decrease in concentration of the complexes significantly decreased their toxicity.

Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)-N-phenylpiperidine-1-carboxamide as novel potent analgesic

Management of moderate to severe pain by clinically used opioid analgesics is associated with a plethora of side effects. Despite many efforts have been dedicated to reduce undesirable side effects, moderate progress has been made. In this work, starting from Tramadol, a series of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)piperidine-1-carboxamide derivatives were designed and synthesized, and their in vitro and in vivo activities were evaluated. Our campaign afforded selective μ opioid receptor (MOR) ligand 2a (KiMOR: 7.3 ± 0.5 nM; KiDOR: 849.4 ± 96.6 nM; KiKOR: 49.1 ± 6.9 nM) as potent analgesic with ED50 of 3.1 mg/kg in 55 °C hot plate model. Its antinociception effect was blocked by opioid antagonist naloxone. High binding affinity toward MOR of compound 2a was associated with water bridge, salt bridge, hydrogen bond and hydrophobic interaction with MOR. The high selectivity of compound 2a for MOR over δ opioid receptor (DOR) and κ opioid receptor (KOR) was due to steric hindrance of compound 2a with DOR and KOR. 2a, a compound with novel scaffold, could serve as a lead for the development of novel opioid ligands.

Crystal formation of 1D coordination polymers based on chiral, achiral and racemic 1,2-cyclohexane scaffolds

Enantiomerically pure ligands (1a and 1b) and meso1c based on trans-1,2-cyclohexanediol and cis-1,2-cyclohexanediol, respectively, were used for the formation of zigzag 1D coordination polymers, when combined with bent HgCl2.

TSPO Ligands Boost Mitochondrial Function and Pregnenolone Synthesis.

Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer’s disease (AD). Previously, we demonstrated that two new TSPO ligands based on an imidazoquinazolinone termed 2a and 2b, stimulated pregnenolone synthesis and ATP production in vitro. In the present study, we compared their effects to those of TSPO ligands described in the literature (XBD173, SSR-180,575, and Ro5-4864) by profiling the mitochondrial bioenergetic phenotype before and after treatment and investigating the protective effects of these ligands after oxidative injury in a cellular model of AD overexpressing amyloid-β (Aβ). Of note, ATP levels increased with rising pregnenolone levels suggesting that the energetic performance of mitochondria is linked to an increased production of this neurosteroid via TSPO modulation. Our results further demonstrate that the TSPO ligands 2a and 2b exerted neuroprotective effects by improving mitochondrial respiration, reducing reactive oxygen species and thereby decreasing oxidative stress-induced cell death as well as lowering Aβ levels. The compounds 2a and 2b show similar or even better functional effects than those obtained with the reference TSPO ligands XBD173 and SSR-180.575. These findings indicate that the new TSPO ligands modulate mitochondrial bioenergetic phenotype and protect against oxidative injury probably through the de novo synthesis of neurosteroids, suggesting that these compounds could be potential new therapeutic tools for the treatment of neurodegenerative disease.

Wnts control membrane potential in mammalian cancer cells.

Wnt ligands belonging to both canonical and non-canonical Wnt pathways regulate membrane potential signifying a very early event in the signal transduction. Wnts activate K+ currents by elevating intracellular Ca2+ and trigger Ca2+ release from intracellular stores. Control of potential by Wnt ligands has significant implications for gene transcriptionand opens up a novel avenue to interfere with this critical pathway. The Wnt signalling network determines gene transcription with free intracellular Ca2+ ( ) and β-catenin as major intracellular signal transducers. Despite its critical importance during development and disease, many of the basic mechanisms of Wnt signal activation remain unclear. Here we show by single cell recording and simultaneous imaging in mammalian prostate cancer cells that an early step in the signal cascade is direct action on the cell membrane potential. We show that Wnt ligands 5A, 9B and 10B rapidly hyperpolarized the cells by activating K+ current by Ca2+ release from intracellular stores. Medium-throughput multi-well recordings showed responses to Wnts at concentrations of 2nm. We identify a putative target for early events as a TRPM channel. Wnts thus act as ligands for ion channel activation in mammalian cells and membrane potential is an early indicator of control of transcription.

Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies.

Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up‐regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing β‐amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD‐related tauopathy (human neuroblastoma cells SH‐SY5Y stably overexpressing the P301L‐mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR‐180,575 and Ro5‐4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD‐related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD.

Synthesis, characterization, structure and redox property of azo-amido and orthometallated azo-imine platinum(II) complexes

The reaction of the ligands bis-2,2′-(N-alkylamino)azobenzene, 1a–c, with K2[PtCl4] in a 1:1 ratio in methanol afforded two types of Pt(II) complexes, 2a–b and 2c. Ligands 1a–b give new Pt(II) amido azo complexes, whereas 1c forms an unexpected orthoplatinated azo imine complex through the unusual oxidative dehydrogenation of one secondary amine (–CH2–NH–) group of the ligand into an imine (–CHN–) function. All three complexes were characterized by 1H NMR and IR spectroscopy, together with elemental analysis. Furthermore, the solid-state structures of two complexes (2a and 2c) were determined using single crystal X-ray diffraction analysis. The diffraction analysis revealed that the ligand 1a binds with the Pt(II) ion in a monoanionic terdentate (N,N,N) fashion, offering a distorted square planar geometry where the fourth coordination site is satisfied by one chloride ligand. In contrast, the 1c ligand binds with the Pt(II) ion in a bi-anionic tetradentate (C,N,N,N) fashion, offering a distorted square planar geometry. Several weaker non-covalent forces are responsible for altering the molecular packing in the lattice. The redox properties of the new complexes were also examined.

Fluorescence and Absorption Titrations of Bio-relevant Imidazole Based Organometallic Pd(II) Complexes with DNA: Synthesis, Characterization, DNA Interaction, Antimicrobial, Cytotoxic and Molecular Docking Studies

Organometallic Pd(II) complexes(4a–4f) of type Na[Pd(3n)Cl2]; where 3n = imidazole ligands (3a–3f), were synthesized. The complexes have been characterized by elemental analysis, thermogravimetric analysis, conductance measurement, mass spectrometry, UV–visible absorption spectroscopy, IR, 1H NMR, 13C APT NMR and Energy-dispersive X-ray spectroscopy. The compounds were screened for various biological activities such as nucleolytic, DNA binding, bacteriostatic (MIC) and cytotoxicity. DNA binding aptitude has been studied by UV–visible absorption titration, fluorescence spectroscopy, molecular modelling and viscosity measurement, which suggests Pd(II) complexes as DNA intercalating agents. Gibb’s free energy, enthalpy and entropy change parameters were evaluated for DNA–complex interaction by UV–visible absorption titration at different temperature, in which negative value of all the thermodynamic parameters suggests that the ligand–DNA complex is stabilized by hydrogen bonding and van der Waals forces. The gel electrophoresis of pUC19 DNA in presence of Pd(II) complexes showed the conversion of supercoiled DNA into open circular and linear form of DNA. Compounds were screened against different pathogens for evaluating their bacteriostatic activity in terms of MIC. In vitro cytotoxicity on Artemia cysts and in vivo cytotoxicity on S. pombe cells propose potent cytotoxic nature of Pd(II) complexes.

Synthesis, structure, spectral and luminescence properties of the tetracoordinated diphenylboron and zinc complexes with 1,3,4-oxadiazole and 1,2,4-triazole ligands

The new diphenylboron 1c, 2c and zinc 1d, 2d complexes with 2-(2-hydroxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazole 1a and 1-phenyl-3-methyl-1,2,4-triazole 2a as the chelating ligands and O-ethyl derivatives 1b, 2b of these ligands have been synthesized and their UV–Vis and photoluminescence studied. Molecular structures of the chelate diphenylboron complexes 1c and 2c were determined by X-ray single-crystal diffraction. Spectroscopic properties of all the compounds, including excited state intramolecular proton transfer (ESIPT) rearrangements observed in ligands 1a and 2a were analyzed using DFT and TD DFT calculations. The emission spectra of ligands 1a, 2a contain a moderate intensity band (φ 0.07, 0.19) in DMSO and two low intensity bands (φ 0.002–0.012) in other solvents. 2-(2-Ethoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazole 1b and all the complexes exhibit significant fluorescence both in polar and non-polar solvents in the blue region of the spectrum, 1b: φ 0.84–0.96, λflmax 363–406 nm; 1c,d, 2c,d: φ 0.43–0.65, λflmax 429–457 nm. The displayed spectral characteristics make these complexes promising for the use as blue emitters in the design of light-emitting organic diodes.

In vitro evaluation of arylsubstituted imidazoles derivatives as antiprotozoal agents and docking studies on sterol 14α-demethylase (CYP51) from Trypanosoma cruzi, Leishmania infantum, and Trypanosoma brucei.

There is an urgent need to discover and develop new drugs to combat parasitic diseases as Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei), and leishmaniasis (Leishmania ssp.). These diseases are considered among the 13 most unattended diseases worldwide according to the WHO. In the present work, the synthesis of 14 arylsubstituted imidazoles and its molecular docking onto sterol 14α-demethylase (CYP51) was executed. In addition, the compounds, antiprotozoal activity against T. brucei, T. cruzi, Trypanosoma brucei rhodesiense, and Leishmania infantum was evaluated. In vitro antiparasitic results of the arylsubstituted imidazoles against T. brucei, T. cruzi, T.b. rhodesiense, and L. infantum indicated that all samples from arylsubstituted imidazole compounds presented interesting antiparasitic activity to various extent. The ligands 5a, 5c, 5e, 5f, 5g, 5i, and 5j exhibited strong activity against T. brucei, T. cruzi, T.b. rhodesiense, and L. infantum with IC50 values ranging from 0.86 to 10.23μM. Most samples were cytotoxic against MRC-5 cell lines (1.12 < CC50 < 51.09μM) and only ligand 5c showed a good selectivity against all tested parasites. According to the results of the molecular docking, the aromatic substituents in positions 1, 4, and 5 have mainly stabilizing hydrophobic interactions with the enzyme matrix, while the oxygen from NO2, SO3H, and OH groups interacts with the Fe2+ ion of the Heme group.

Bis(N,N′-substituted oxamate) Zincate(II) complexes: Synthesis, spectroscopy, solid state structure and DFT calculations

Treatment of two equivalents of N,N′-bis(X-phenyl)oxamides (1) with one equivalent of [Zn(OAc)2(H2O)2] (2) in the presence of four equivalents of [nBu4N]OH produce the corresponding bis(N,N′-substituted oxamate) zincate(II) complexes with the general formula (nBu4N)2[Zn(X-phenyloxamide)2] (3) (a, X = 3-NO2; b, X = 4-NO2; c, X = 2,6 CH3; d, X = 3,4-CH3; e, X = 2-Br; f, X = 4-Br; g, X = 2-F; h, X = 4-F; i, X = 2-Cl; j, X = H). Complexes 3a–j have been characterized by elemental analysis, NMR (1H, 13C{1H}) and IR spectroscopy. In addition, 3a and 3f have been characterized by single crystal X-ray crystallography. The zinc (II) ion in the later complexes is four-coordinate with two ethanediamide-nitrogen atoms from two bidentate N,N′-disubstituted oxamate ligands at each metal center. In addition, the calculated electrostatic potentials of 3f rationalize the formation of chain structures via the Br…Br interaction. Complexes 3a–j showed a characteristic LLCT (π → π*) band in the UV-Vis spectra, which was confirmed by TD-DFT calculations. DFT calculations show that the Zn(II) orbitals are neither contributing to the HOMO nor to the LUMO, i.e. the HOMO and LUMO are mainly located on the ligands. The emission spectra analyses for Zn(II) complexes 3a–j show enhanced intensity and blue shifted emission compared to ligands 1a−j. The cyclic voltammetry measurements of complexes 3a–j showed reversible electrochemical processes for the (N,N′-substituted oxamate−2/−3) between −1.52 and −1.77 V using [NnBu4][B(C6F5)4] as the supporting electrolyte. It was found that the 3-nitro- (3a) and 4-nitro-functionalized (3b) derivatives resulted in a significantly higher Fc/Fc+ redox potential (E0′) compared to the more electron-rich 3, 4-dimethyl (3c) and 2,6-dimethyl (3d) derivatives.

Novel Re(I) tricarbonyl coordination compounds based on 2-pyridyl-1,2,3-triazole derivatives bearing a 4-amino-substituted benzenesulfonamide arm: synthesis, crystal structure, computational studies and inhibitory activity against carbonic anhydrase I, II, and IX isoforms†

In this work, two bidentate 2-pyridyl-1,2,3-triazole ligands (3a and 3b) containing a 4-substituted benzenesulfonamide pharmacophore prepared by classical click chemistry procedures, as well as their corresponding rhenium complexes, 4a and 4b of general formula [ReCl(CO)3(L)] (L = 3a or 3b) were prepared and fully characterised by spectroscopic methods (IR, NMR, MS, UV-Vis), elemental analysis, X-ray diffraction, and theoretical studies using DFT and TD-DFT methods. In particular, we showed that, in the solid state, the pyridine and the triazole rings of 3b adopted an uncommon cis configuration which stems from intermolecular hydrogen bonds. Preliminary assays demonstrated a promising nanomolar inhibitory activity against carbonic anhydrase isoform IX for both ligands and complexes with a strong affinity Ki of 2.8 nM for ligand 3a. More interestingly, complex 4b exhibited a pronounced selectivity against hCA IX over the off-targets hCA I and hCA II which makes this compound a promising potential anticancer drug candidate.

Rs12904 polymorphism in the 3'-untranslated region of ephrin A1 ligand and the risk of sporadic colorectal cancer in the Iranian population.

Colorectal cancer (CRC) is rated as the second cause of cancer death. Genetic determinants are considered as driving forces in the development of sporadic CRC. Single-nucleotide polymorphisms (SNPs), due to their abundance in the human genome with collectively huge effect on cellular signaling pathways, are attributed as the main genetic factor in disease susceptibility including cancers. MicroRNAs are contributing to posttranslational gene regulation. They exert their regulatory function by binding to their specific recognition sequences located at 3'-untranslated region (UTR) of mRNAs. In the present study, we have elucidated the role of rs12904, a naturally occurring SNP, in the recognition site of miR200c in the 3'UTR of ephrin A1 ligand gene, in the development of sporadic CRC in the Iranian population. A case-control study using 152 CRC patients and 160 noncancerous counterparts was conducted to determine the rs12904 genotypes using polymerase chain reaction-restriction fragment length polymorphism method. The results revealed no significant association between the rs12904 and sporadic CRC (odds ratio = 0.97, 95% confidence interval = 0.70-1.34). The frequency of genotypes and also alleles of the mentioned polymorphism were not significantly different between case and control groups (P = 0.765 and P = 0.847, respectively). The results suggest that this polymorphism probably has not a crucial role in the Iranian CRC risk and is not an important potential risk factor in molecular diagnostics of mentioned disease among the Iranian population.

Double stereoselective coordination of chiral N,S ligands: Synthesis, coordination chemistry and utilization in Pd‐catalyzed allylic alkylation

A series of chiral pentane‐2,4‐diyl‐based thioether‐amine ligands [4 and 5; (R,S)‐ and (S,S)‐R1SCH(CH3)CH2CH(CH3)NHR2, respectively, where 4a R1 = iPr, R2 = Ph; 4b R1 = tBu, R2 = Ph; 4c R1 = 1‐Ad, R2 = Ph; 5a R1 = iPr, R2 = Ph; 5b R1 = tBu, R2 = Ph; 5c R1 = 1‐Ad, R2 = Ph; 5d R1 = iPr, R2 = 4‐MeOC6H4; 5e R1 = iPr, R2 = 4‐MeC6H4; 5f R1 = iPr, R2 = 3,5‐Me2C6H3] with stereogenic S‐ and N‐donor atoms has been prepared starting from cyclic sulfates via optically pure γ‐aminoalcohol or 2,4‐dimethylazetidine intermediates. The synthesis of the novel diastereomerically related ligand sets 4 and 5 was accomplished starting from the same source of chirality. The modular ligand structure and the novel synthetic strategies developed for their synthesis allowed the easy modification of the ligands’ (i) S‐ and (ii) N‐substituents, as well as (iii) the relative stereochemistry within the ligand backbone. Six‐membered [Pd(N,S)Cl2]‐type chelate complexes of the diastereomerically related ligands 4a and 5a were synthesized and characterized by X‐ray crystallography in the solid phase, by density functional theory calculations and in solution by NMR spectroscopy. The coordination of 5a resulted in the formation of a single chair conformation by the stereospecific locking of both stereolabile (N and S) donor atoms. In contrast, compound 4a forms rapidly equilibrating palladium species due to the fast inversion of the sulfur donor. Ligands with stereochemically fixed donor atoms provided robust and efficient catalytic systems that can be effectively applied in alkylene carbonates as green reaction media. Remarkably, the phosphine‐free catalysts are air‐stable, and at room temperature in the presence of moisture gave excellent ee’s (up to 93%) in asymmetric allylation processes thanks to the double stereoselective coordination.