Imidazolyl Groups Research Articles

Crystal structure of 1,2-bis-[(1H-imidazol-2-yl)methylidene]hydrazine and its one-dimensional hydrogen-bonding network.

In the title compound, C8H8N6, two imidazolyl groups are separated by a zigzag -CH=N-N=CH- linkage. An inversion center is located at the mid-point of the N-N single bond and the complete molecule is generated by symmetry. In the crystal, each mol-ecule forms four N-H⋯N hydrogen bonds with two neighbouring mol-ecules to constitute a one-dimensional ladder-like structure propagating along the a-axis direction.

Self-Assembly Syntheses, Structural Characterization, and Luminescent Properties of Lanthanide Coordination Polymers Constructed by Three Triazole-Carboxylate Ligands

Herein, 15 lanthanide coordination complexes based on three di-, tri-, and tetra-carboxylic ligands with imidazolyl groups have been solvothermally designed, synthesized, and characterized. All the complexes exhibit high thermal stabilities and can remain stable in the open air more than 7 days. Luminescent spectra of Eu3+ and Tb3+ complexes at room temperature indicate that the three carboxylic ligands H2L1, H3L2, and H4L3 are promising potential light sensitizers for lanthanide ions based on their suitable triplet energy levels. Luminescent lifetimes and quantum yields of these compounds were further measured and compared. The correlations between their structural features and photophysical properties are discussed in detail.

Copper-Catalyzed Carbamoylation of Terminal Alkynes with Formamides via Cross-Dehydrogenative Coupling

An efficient approach for direct carbamoylation of terminal alkynes with formamides affording propiolamides has been developed by copper-catalyzed oxidative cross coupling of C(sp)-H and C(sp2)-H bonds in the presence of a pincer ligand with two imidazolyl groups. The catalytic reaction is compatible with diverse functional groups but sensitive to the electronic effect of terminal alkyne and the steric effect of formamides. KIE study indicates the cleavage of the carbamoyl C–H bond affording formamide radical is the rate-determining step.

Synthesis, structure and properties of tris(1-ethyl-4-isopropyl-imidazolyl-κN)phosphine copper(II)

In this study we report the synthesis and characterization of [Cu(T1Et4iPrIP)(CH3OH)Cl]Cl (1) (T1Et4iPrIP=tris(1-ethyl-4-isopropyl-imidazolyl)phosphine). T1Et4iPrIP serves as a His3 biomimetic ligand binding metals through the 3-nitrogen of the imidazolyl group. The structure of 1 features copper(II) bonded to three nitrogen ligands from T1Et4iPrIP along with an oxygen ligand from methanol and a chloride ligand to form slightly distorted square pyramidal geometry with an imidazole group occupying the axial position and the methanol and chloride ligands situated in the basal plane. The weak sigma donation of the ligand set results in low energy d–d electronic transitions and small A‖ (131G). Time-dependent DFT calculations (B3LYP, 6-311+G(d,p)) on the optimized structure of 1 in methanol solvent allowed for the assignment of specific electronic transitions in the UV–Vis spectrum. The highest occupied molecular orbital (HOMO) was noted to consist of 65% Cu-d character identified as the dx2-y2 orbital.

ChemInform Abstract: Cyclodehydrations Leading to Indene Products Having N‐Heterocyclic Substituents.

In this Note, we describe superacid-promoted cyclodehydrations leading to functionalized indenes. The product indenes are synthesized having N-heterocyclic substituents, including pyridyl, imidazolyl, pyrimdyl, and other groups. A mechanism is proposed involving dicationic, superelectrophilic intermediates. The protonated N-heterocyclic rings are shown to dramatically lower the LUMO energy level of the carboxonium electrophile (compared to that of a similar uncharged system).

Structural disorder and transformation in crystal growth: direct observation of ring-opening isomerization in a metal-organic solid solution.

A rare example is reported in which discrete Ag2 L 2 ring and (AgL)∞ chain motifs [L = N,N'-bis(3-imidazol-1-yl-propyl)-pyromellitic diimide] co-crystallize in the same crystal lattice with varying ratios and degrees of disorder. Crystal structures obtained from representative crystals reveal compatible packing arrangements of the cyclic and polymeric isomers within the crystal lattice, which enables them to co-exist within a crystalline solid solution. A feasible pathway for transformation between the isomers is suggested via facile rotation of the coordinating imidazolyl groups. This chemical system could provide a chance for direct observation of ring-opening isomerization at the crystal surface. Mass spectrometry and (1)H NMR titration show a dynamic equilibrium between cyclic and oligomeric species in solution, and a potential crystallization process is suggested involving alignment of precursors directed by aromatic stacking interactions between pyromellitic diimide units, followed by ring-opening isomerization at the interface between the solid and the solution. Both cyclic and oligomeric species can act as precursors, with interconversion between them being facile due to a low energy barrier for rotation of the imidazole rings. Thermogravimetric analysis and variable-temperature powder X-ray diffraction indicate a transition to a different crystalline phase around 120°C, which is associated with loss of solvent from the crystal lattice.

Position-specific modification with imidazolyl group on10–23 DNAzyme realized catalytic activity enhancement

Nucleoside analogues with imidazolyl and histidinyl groups were synthesized for site-specific modification on the catalytic core of 10–23 DNAzyme. The distinct position-dependent effect of imidazolyl group was observed. Positive effect at A9 position was always observed. The pH- and Mg2+-dependence of the imidazolyl-modified DNAzymes suggested that imidazolyl group in 10–23 DNAzyme probably plays a dual role, its hydrogen bonding ability and spacial occupation play the favorable influence on the catalytic conformation of the modified DNAzymes. This research demonstrated that the catalytic performance of DNAzymes could be enhanced by incorporation of additional functional groups. Chemical modification is a feasible approach toward more efficient DNAzymes for therapeutic and biotechnological applications.

Cyclodehydrations leading to indene products having N-heterocyclic substituents.

In this Note, we describe superacid-promoted cyclodehydrations leading to functionalized indenes. The product indenes are synthesized having N-heterocyclic substituents, including pyridyl, imidazolyl, pyrimdyl, and other groups. A mechanism is proposed involving dicationic, superelectrophilic intermediates. The protonated N-heterocyclic rings are shown to dramatically lower the LUMO energy level of the carboxonium electrophile (compared to that of a similar uncharged system).

Synthesis, characterization and X-ray structures of N-heterocyclic carbene palladium complexes based on calix[4]arenes: highly efficient catalysts towards Suzuki–Miyaura cross-coupling reactions

A new series of calix[4]arene supported N-heterocyclic carbene palladium complexes were developed and fully characterized. A mono-substituted calix[4]arene was prepared through conventional procedures, following with the attachment of imidazolyl derivative groups to compose the precursors of novel NHCs ligands. Undergoing the alkylation with n-butylbromide and corresponding metallation with palladium and pyridine, original complexes were obtained. After a full characterization in solution and solid state, the evaluation of catalytic activity was taken out in Suzuki–Miyaura cross-coupling reactions, which revealed good performances.

Reversible immobilization of glucoamylase onto magnetic polystyrene beads with multifunctional groups

A novel and simple process for the surface functionalization of micron-sized monodisperse magnetic polystyrene (PS) microbeads was reported. The polystyrene seed particles were prepared prior to the dispersion polymerization method. Afterwards, series of surface chemical modifications on polystyrene microspheres were conducted, and three end-functional microspheres with carboxyl, imidazolyl and sulphydryl groups were obtained. The functional magnetic polystyrene microspheres were prepared by impregnation and subsequent precipitation of ferric and ferrous ions into the polystyrene particles. Finally, the functional magnetic polystyrene was used for the reversible immobilization of glucoamylase via metal-affinity adsorption. The results indicated that the obtained immobilized glucoamylase presented excellent reusability, applicability, magnetic response and regeneration of supports. The magnetic PS microspheres retained >65% of its initial activity at 65°C over 6h; and the lowest residual activity of immobilized glucoamylase prepared by regenerated supports still remained about 50% of the initial activity after the 10th cycles.

Synthesis, Structure and Properties of Lanthanide-Organic Frameworks with Imidazolylmethylisophthalate Ligands

Three new lanthanide-organic frameworks {[Ln(L)(OClO3)(H2O)]·0.5H2O}n [Ln=Sm (1), Eu (2), Er (3)] have been prepared by hydrothermal reactions of the corresponding lanthanide oxide (Ln2O3), silver perchlorate (AgClO4) and 5-(imidazol-1-ylmethyl)isophthalic acid. The complexes have been characterized by single-crystal and powder X-ray diffraction, IR spectroscopy, and elemental analyses. In 1-3, the metal centers are eight-coordinated to show polyhedral coordination geometries with an LnO8 donor set. The imidazolyl groups are free of coordination, and the perchlorate and carboxylate groups bridge the Ln3+ cations leading to the formation of wave-like layer structures containing metal-chains. The fluorescence properties of complex 2 were investigated.

Assembly of 1D and 2D zinc(II) coordination polymers from flexible polyimidazolyl-based ligands

Abstract Reactions of Zn(NO3)2∙ 6H2O with 1,3,5-tris(imidazol-1-ylmethyl)-2,4,6-trimethylbenzene (titmb) in the presence of 1,4-benzenedicarboxylic acid (1,4-H2BDC) or 1,3-benzenedicarboxylic acid (1,3-H2BDC) under hydrothermal conditions afforded one 1D and one 2D coordination polymers [Zn3(titmb)2(1,4-BDC)3(H2O)6] (1) and [Zn2(titmb)(1,3-BDC)2(H2O)] (2), respectively. Similar reactions of Zn(NO3)2∙ 6H2O with 1,3-bis(imidazol-1-ylmethyl)-2,4,6-trimethylbenzene (bitmb) and 1,4-H2BDC gave rise to one 2D coordination polymer [Zn2(bitmb)2(1,4-BDC)2] (3). Compound 1 has a 1D linear chain formed from linking 24-membered [Zn2(titmb)2] metallamacrocycles and [Zn(1,4-BDC)(H2O)2] units via imidazolyl groups of titmb ligands. Compound 2 has a 2D network assembled from connecting spiral [Znn(1,3-BDC)n] chains with titmb linkers, while compound 3 also has a 2D network formed by linking 24-membered [Zn2(bitmb)2] metallamacrocycles via 1,3-BDC bridges. The ligands titmb and bitmb in compounds 1–3 adopt less-common cis–trans–trans and cis–trans conformations, respectively. Their thermal and photoluminescent properties were also investigated.

Determination of acidity constants and ionic mobilities of polyprotic peptide hormones by CZE

CZE has been applied to determination of thermodynamic acidity constants (pKa ) of ionogenic groups and actual ionic mobilities of polyprotic peptides-synthetic human and salmon gonadotropin-releasing hormones and their derivatives and fragments. First, the mixed acidity constants, pKa,imix, of ionogenic groups, and actual ionic mobilities, mi , of gonadotropin-releasing hormone peptides were determined by nonlinear regression analysis of pH dependence of their effective electrophoretic mobilities. The effective mobilities were measured by CZE in a series of BGEs within a broad pH range (1.80-12.10), at constant ionic strength (25 mM) and reference temperature (25°C). Second, the pKa,imix values were recalculated to thermodynamic pKa s using the Debye-Hückel theory. Thermodynamic pKa of carboxyl groups was estimated to be in the range of 2.5-3.3 for C-terminal amino acids of the above peptides, and 5.2 for glutamic acid in the middle of peptide chain; pKa of imidazolyl group of histidine residues was in the range of 5.7-6.8, pKa of N-terminal amino group of the peptide with free N-terminus was equal to 6.2, pKa of phenol group of tyrosine residues was in the range of 9.8-10.8, and pKa of guanidinyl group or arginine residues reached values 11.1-11.3, depending on the position of the residues in the peptide and on the amino acid sequence of the peptide. Absolute values of actual ionic mobilities of peptides with charge number ±2 were in the range (14.6-18.6) × 10(-9) m(2) V(-1) s(-1) , and ionic mobilities of peptides with charge number ±1 reached values (6.5-12.9) × 10(-9) m(2) V(-1) s(-1) .

Human thromboxane synthase: comparative modeling and docking evaluation with the competitive inhibitors Dazoxiben and Ozagrel

Thromboxane synthase (TXAS) is a P450 epoxygenase that synthesizes thromboxane A2 (TXA2), a potent mediator of platelet aggregation, vasoconstriction and bronchoconstriction. This enzyme plays an important role in several human diseases, including myocardial infarction, stroke, septic shock, asthma and cancer. Despite of the increasing interest on developing TXAS inhibitors, the structure and activity of TXAS are still not totally elucidated. In this study, we used a comparative molecular modeling approach to construct a reliable model of TXAS and analyze its interactions with Dazoxiben and Ozagrel, two competitive inhibitors. Our results were compatible with experimental published data, showing feasible cation–π interaction between the iron atom of the heme group of TXAS and the basic nitrogen atom of the imidazolyl group of those inhibitors. In the absence of the experimental structure of thromboxane synthase, this freely available model may be useful for designing new antiplatelet drugs for diseases related with TXA2.

Solvent-dependent Assembly of Discrete and Continuous CoCl2 Adamantane-based Ligand Complexes: Observations by CSI–Mass Spectrometry and X-ray Crystallography

Discrete and continuous coordination structures were obtained in single crystals of CoCl₂ and an adamantane-based bidentate ligand bearing imidazolyl groups, depending on the methanol concentration in a methanol-chloroform mixture. Single-crystal X-ray structure analysis revealed that the metal centers exhibited a tetrahedral geometry in the discrete complex and an octahedral geometry in the continuous metal complex. Conventional analytical methods, including UV-vis and NMR spectroscopy, could not identify those two complexes in solution. In contrast, cold-spray ionization mass spectrometry could detect differences between the discrete complex and the continuous metal complex, and ion peaks due to continuous ligand adducts were found only in the spectrum of the continuous metal complex.

Abstract 2474: Synthesis and antiproliferative activity of novel 17β-acetyl-testosterone-7α-platinum(II) hybrids designed for the treatment of human prostate cancer.

Abstract Prostate cancer is a major public health problem worldwide. In the United-States, prostate cancer is ranked first of all new cancer cases diagnosed in men and it is the second most lethal cancer. Antiandrogens are normally used in clinic to slow down the progression of androgen-sensitive (AR+) prostate cancer inducing prolonged remission without definite cure. In general, 10 years after the initial treatment of early prostate cancers, 19% of patients will experience local tumor progression, 15% distant metastases and 10% will die. Furthermore, advanced prostate cancers quickly (18 to 24 months) become androgen-insensitive (AR-) and antihormone therapy becomes ineffective. At this point, the median survival of approved drug combination treatments is then under 20 months. Consequently, the search for new, more selective and efficient treatments is still a subject of intense research. To that end, we used the natural tropism of testosterone for prostate tissues to target platinum(II) complexes to prostate cancer cells. The platinum complexes were linked to the 7α position on testosterone as it is located between the 3-carbonyl and 17-hydroxyl groups involved in key hydrogen bonds essential for androgen receptor interactions. L- and D-2-pyridylalanine, L-histidine and L-4-thiazolylalanine derivatives were linked to 17β-acetyl-testosterone selected to chelate platinum(II). Four new amino acid platinum(II) complexes were prepared (compounds 1a-1d), characterized and evaluated for their antiproliferative activity on LNCaP (AR+), PC3 (AR-) and DU145 (AR-) human prostate adenocarcinoma cancer cell lines. The new testosterone-platinum(II) complexes exhibited antiproliferative activities at the micromolar level on all prostate cancer cell lines tested. Structure-activity relationships show that the stereochemistry of amino acids (compounds 1a, b) does not affect the antiproliferative activity. Moreover, the replacement of a pyridinyl moiety by an imidazolyl group (compound 1c) decreased the activity by up to 10 fold whereas the replacement by a thiazolyl group (compound 1d) showed an antiproliferative activity between 2.5 to 8.0 times higher than that of cisplatin. The innovative design and the significant activity of our testosterone-platinum(II) complexes toward AR+ and AR- prostate cancer cells suggest that they might be useful for treatment of advanced prostate cancers. Citation Format: Sébastien Fortin, Kevin Brasseur, Nathalie Morin, Éric Asselin, Gervais Bérubé. Synthesis and antiproliferative activity of novel 17β-acetyl-testosterone-7α-platinum(II) hybrids designed for the treatment of human prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2474. doi:10.1158/1538-7445.AM2013-2474

DNA duplex-supported artificial esterase mimicking by cooperative grafting functional groups

The molecular structures of enzyme mimics may be modified to optimize their catalytic properties. In this study, to generate artificial enzyme mimics, Watson–Crick base paired DNA duplexes were designed as scaffolds which were assembled by nucleotides modified with specific functional groups. This process allowed various functional groups to be precisely assembled at different sites on the duplexes. By using this strategy, the 5-[2-(1H-imidazolyl-4)-(E)-ethylene]-2′-deoxythymidine (1) analog with the 5-substituted imidazolyl group was incorporated into single strands of DNA. Upon DNA duplex formation, several combinations of the imidazolyl group were formed. Using p-nitrophenyl acetate as the substrate of the catalytic reaction, we evaluated the hydrolysis capabilities of the imidazolyl assemblies. The catalytic ability was closely related to the distribution of imidazolyl groups in the DNA duplex. The most effective catalytic center was that of the duplex O5–O6 construct with three imidazolyl groups. This construct displayed bell-shaped pH-dependent and Mg2+-independent kinetic curves, which are typical characteristics of imidazolyl-mediated catalytic reactions.

Synthesis and structure-activity relationship studies of derivatives of the dual aromatase-sulfatase inhibitor 4-{[(4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate.

4-{[(4-Cyanophenyl)(4H-1,2,4-triazol-4-yl)amino]methyl}phenyl sulfamate and its ortho-halogenated (F, Cl, Br) derivatives are first-generation dual aromatase and sulfatase inhibitors (DASIs). Structure–activity relationship studies were performed on these compounds, and various modifications were made to their structures involving relocation of the halogen atom, introduction of more halogen atoms, replacement of the halogen with another group, replacement of the methylene linker with a difluoromethylene linker, replacement of the para-cyanophenyl ring with other ring structures, and replacement of the triazolyl group with an imidazolyl group. The most potent in vitro DASI discovered is an imidazole derivative with IC50 values against aromatase and steroid sulfatase in a JEG-3 cell preparation of 0.2 and 2.5 nm, respectively. The parent phenol of this compound inhibits aromatase with an IC50 value of 0.028 nm in the same assay.

Self-assembly of amphiphilic peptides into bio-functionalized nanotubes: a novel hydrolase model.

Herein, we report the construction of a novel hydrolase model via self-assembly of a synthetic amphiphilic short peptide (Fmoc-FFH-CONH2) into nanotubes. The peptide-based self-assembled nanotubes (PepNTs-His) with imidazolyl groups as the catalytic centers exhibit high catalytic activity for p-nitrophenyl acetate (PNPA) hydrolysis. By replacement of the histidine of Fmoc-FFH-CONH2 with arginine to produce a structurally similar peptide Fmoc-FFR-CONH2, guanidyl groups can be presented in the nanotubes through the co-assembly of these two molecules to stabilize the transition state of the hydrolytic reaction. Therefore significantly improved catalytic activity has been achieved by the reasonable distribution of three dominating catalytic factors: catalytic center, binding site and transition state stabilization to the co-assembled peptide nanotubes (PepNTs-His-Argmax). The resulting hydrolase model shows typical saturation kinetics behaviour to that of natural enzymes and the catalytic efficiency of a single catalytic center is 519-fold higher than that without catalysts. As for a nanotube with multi-catalytic centers, a remarkable catalytic efficiency could be achieved with the increase of building blocks. This model suggests that the well ordered and dynamic supramolecular structure is an attractive platform to develop new artificial enzymes to enhance the catalytic activity. Besides, this novel peptide-based material has excellent biocompatibility with human cells and is expected to be applied to organisms as a substitute for natural hydrolases.

π-Excess σ2P ligands: synthesis of biaryl-type 1,3-benzazaphosphole hybrid ligands and formation of P^P′–M(CO)4 chelate complexes

Acid-catalyzed cyclocondensations of 2-phosphanylanilines 1 with substituted benzaldehydes or heteroaryl aldehydes open a convenient route to new biaryl-type 1H-1,3-benzazaphosphole hybrid ligands 2a-f with o-phosphanylphenyl, pyridyl, imidazolyl, thienyl or o-methoxyphenyl donor groups (in addition to the σ(2)P donor) and to bromophenyl substituted benzazaphospholes 2g,h. Excess aldehyde leads to concomitant reductive N-alkylation, as shown by formation of 3h besides 2h. The reactions proceed via dihydrobenzazaphospholes 4, which can be detected under mild conditions. The aromaticity-driven dehydrogenation does not liberate dihydrogen but is accomplished by transfer hydrogenations, mainly by reduction of some of the aldehyde. N-Secondary 2-phosphanylanilines 5 also react with aldehydes to form the corresponding N-substituted benzazaphospholes 6. The formation of (P^P')M(CO)4-chelate complexes 8a (M = Cr) and 9a,b (M = Mo) was demonstrated by reaction with M(CO)4(norbornadiene). The crystal structure of 9a, determined in addition to the solution structure elucidation by multinuclear NMR spectra, confirms the chelate formation and reveals a trigonal environment for the low coordinated phosphorus, with the P-Mo(0) vector bent out of the benzazaphosphole ring plane by 14.4° (0.57 Å), together with axial chirality of the molecules in the racemic crystals by twisting of the benzazaphosphole and phenyl π-planes around the common C(2)-C(21) bond.