N1 Atom Research Articles

Novel 4-Anilinoquinazoline Derivatives as Potent Anticancer Agents: Design, Synthesis, Cytotoxic Activity, and Docking Study

The simultaneous inhibition of EGFR and VEGFR-2 is a promising method in cancer treatment. In the present work, several 4-anilinoquinazoline derivatives encompassing different substitutions at the C-4 and C-7 positions of a quinazoline core were designed, synthesised, and evaluated for their cytotoxicity on A431, HUVEC, and HU02 cell lines. Docking studies were carried out to test the interactions of all synthesised compounds with EGFR and VEGFR-2. Furthermore, a wound healing assay was done for the investigation of cell migration. The most potent compound was 8l followed by the compounds 8i and 8j which showed better cytotoxic activities on A431 and HUVEC cell lines than the standard (Vandetanib). The compounds 8f and 8a represented the best docking energies of 8.99 and 9.35 kcal mol−1 for EGFR and VEGFR, respectively. Moreover, molecular docking studies exhibited that compound 8l showed efficient binding affinity against both EGFR and VEGFR-2. It can bind to these receptors through the formation of essential hydrogen bonds between the quinazoline N1 atom and the Met796 backbone of EGFR and two hydrogen bonds with Cys919 and Thr916 of VEGFR-2 with energies of –7.99 and –7.85 kcal mol−1, respectively. In addition, this compound displayed the highest activity on cell migration and wound healing. Compound 8l with the highest cytotoxic activity can be considered a candidate for further investigation and structural optimisation as an antiproliferative agent.

Pseudouridine-Free Ribosome Exhibits Distinct Inter-Subunit Movements

Pseudouridine, the most abundant form of RNA modification, is known to play important roles in ribosome function. Mutations in human DKC1, the pseudouridine synthase responsible for catalyzing the ribosome RNA modification, cause translation deficiencies and are associated with a complex cancer predisposition. The structural basis for how pseudouridine impacts ribosome function remains uncharacterized. Here we characterized structures and conformations of a fully modified and a pseudouridine-free ribosome from Saccharomyces cerevisiae in absence of ligands or when bound with translocation inhibitor cycloheximide by electron cryomicroscopy. In the modified ribosome, the rearranged N1 atom of pseudouridine is observed to stabilize key functional motifs by establishing predominately water-mediated close contacts with the phosphate backbone. The pseudouridine-free ribosome, however, is devoid of such interactions and displays conformations reflective of abnormal inter-subunit movements. The erroneous motions of the pseudouridine-free ribosome may explain its observed deficiencies in translation.

Rh(ii)-Catalyzed denitrogenative 1-sulfonyl-1,2,3-triazole-1-alkyl-1,2,3-triazole cross-coupling as a route to 3-sulfonamido-1H-pyrroles and 1,2,3-triazol-3-ium ylides

The reaction of 1-alkyl-1H-1,2,3-triazoles with rhodium(ii) azavinyl carbenes, generated from 1-sulfonyl-1H-1,2,3-triazoles, was utilized to prepare 3-sulfonamido-1H-pyrroles and 1,2,3-triazol-3-ium ylides in good yields.

Bright mechanoluminescence and dramatically different mechanofluorochromic behaviors of tetraarylimidazoles by slight modulation of substituent structure

Three tetraarylimidazoles IMDMA, IMCZ and IMDPA by respective introduction of dimethylaminophenyl, N-carbazoly-phenyl and diphenylaminophenyl at N1 atom on imidazole core are prepared and their photophysical properties in both solution and solid state are investigated. The bright mechanoluminescence can be readily observed on these crystals, and a mechanism that polar molecular couples rather than space groups should be truly responsible for mechanoluminescence is elaborated in this work and it is verified to be effective on these imidazoles and many crystals in other reports. Interestingly, the slight modulation of substituent structures correspondingly results in red-shifted, no-shifted and blue-shifted emission on IMDPA, IMCZ and IMDMA under force stimuli. The reason for such sharply differentiated mechanofluorochrism is revealed to be flexibility difference of substituents in aid of theoretical calculations and crystallography. This work presents a very appropriate system to understand the structure-packing-property relationship.

Polymeric chain complexes of copper(II) chloride with 1,5-disubstituted tetrazoles: Structure and magnetic properties

The complex [Cu(5-(N,N-dimethylaminomethyl)-1-(pyridin-2-yl)tetrazole)Cl2]n (1) was prepared by the reaction of 5-(N,N-dimethylaminomethyl)-1-(pyridin-2-yl)tetrazole with copper(II) chloride in solution. According to the single crystal X-ray analysis, complex 1 presents a 1D coordination polymer, formed at the expense of single chlorido bridges between neighboring pentacoordinated copper(II) cations. The tetrazole acts as a chelating ligand, coordinated via the heteroring N4 atoms and the nitrogen atom of the amino group. The temperature-dependent magnetic susceptibility measurements of complex 1, as well as previously described chain coordination polymers [Cu(1-methyl-5-vinyltetrazole)Cl2]n (2) and [Cu2(1-methyl-5-methylsulfonyltetrazole)2(H2O)2Cl4]n (3), revealed that the copper(II) ions are antiferromagnetically coupled in all the complexes. A superexchange pathway between the metal cations in complex 2 is provided at the expense of double chlorido bridges and the tetrazole ring N3,N4-bridges. In complex 3, this pathway is provided by double chlorido bridges which link alternating Cu(1-methyl-5-methylsulfonyltetrazole)2 and Cu(H2O)2 fragments.

Mechanism of Naphthoquinone Selectivity of Thymidylate Synthase ThyX

Naphthoquinones (NQs) are natural and synthetic compounds with a wide range of biological activities commonly attributed to their redox activity and/or chemical reactivity. However, genetic and biochemical experiments have recently demonstrated that 2-hydroxy-NQs (2-OH-NQs) act as highly specific noncovalent inhibitors of the essential bacterial thymidylate synthase ThyX in a cellular context. We used biochemical experiments and molecular dynamics simulations to elucidate the selective inhibition mechanism of NQ inhibitors of ThyX from Mycobacterium tuberculosis (Mtb). Free energy simulations rationalized how ThyX recognizes the natural substrate dUMP in the N3-ionized form using an arginine, Arg199, in Mtb. The results further demonstrated that 2-OH-NQ, similar to dUMP, binds to ThyX in the ionized form, and the strong and selective binding of 2-OH-NQ to ThyX is also explained by electrostatic interactions with Arg199. The stronger binding of the close analog 5F-dUMP to ThyX and its inhibitory properties compared with dUMP were explained by the stronger acidity of the uracil N3 atom. Our results, therefore, revealed that the ionization of 2-OH-NQs drives their biological activities by mimicking the interactions with the natural substrate. Our observations encourage the rational design of optimized ThyX inhibitors that ultimately may serve as antibiotics.

Adsorption mechanism of methylene blue on oxygen-containing functional groups modified graphitic carbon spheres: Experiment and DFT study

Graphitic carbon spheres (GCSs) were prepared using glucose as the starting material. The adsorption performance of as-prepared GCSs, ammonium persulfate (AP-GCSs) and sodium dodecyl sulfate (SDS-GCSs) modified graphitic carbon spheres were investigated. More COOH, COH and SO functional groups attached on the surface of the modified GCSs compared to original counterparts, and the adsorption capacities of AP-GCSs and SDS-GCSs were 295.5 mg/g and 681.4 mg/g, respectively, which was about 1.6 and 3.7 times of that original GCSs. During the adsorption process, the adsorption sites of methylene blue (MB) (the S, N1 and N2 atoms) formed chemical bonds with S and O atoms in the oxygen-containing functional groups (COOH, COH, COOH/COH and SO4). Density functional theory (DFT) calculations revealed that the adsorption energy between MB adsorption sites (S, N1, N2) and SO4 decreased from about −4.30 to −6.38 eV for S, −3.90 to −4.67 eV for N1 and −4.74 to −6.30 eV for N2, demonstrating stronger electronic charge transferring compared with that of COOH and COH. This could be the driving force for the improved adsorption performance of the modified samples.

Reaction mechanism catalyzed by the dissimilatory adenosine 5′-phosphosulfate reductase. Adenosine 5′-monophosphate inhibitor and key role of arginine 317 in switching the course of catalysis

The present research is a continuation of our work on dissimilatory reduction pathway of sulfate - involved in biogeochemical sulfur turnover. Adenosine 5′-phosphosulfate reductase (APSR) is the second enzyme in the dissimilatory pathway of the sulfate to sulfide reduction. It reversibly catalyzes formation of the sulfite anion (HSO3−) from adenosine 5′-phosphosulfate (APS) - the activated form of sulfate provided by ATP sulfurylase (ATPS). Two electrons required for this redox reaction derive from reduced FAD cofactor, which is suggested to be involved directly in the catalysis by formation of FADH-SO3− intermediate. The present work covers quantum-mechanical (QM) studies on APSR reaction performed for eight models of APSR active site. The cluster models were constructed based on two crystal structures (PDB codes: 2FJA and 2FJB), differing in conformation of Arg317 active site residue. The described results indicated the most feasible mechanism of APSR forward reaction, including formation of FADHN-SO3− adduct (with proton on N5 atom of isoalloxazine), tautomerization of FADHN-SO3− to FADHO-SO3− (with proton on CO moiety of isoalloxazine), and its reductive cleavage to oxidized FAD and sulfite anion. The reverse reaction proceeds in the backward direction. It is suggested that it requires two AMP molecules, one acting as a substrate and another as an inhibitor of forward reaction, which forces change of Arg317 conformation from “arginine in” (2FJA) to “arginine out” (2FJB). Important role of Arg317 in switching the course of the APSR catalytic reaction is revealed by changing the direction of thermodynamic driving force. The presented research also shows the importance of the protonation pattern of the reduced FAD cofactor and protein residues within the active site.

On the Interaction between Deprotonated Cytosine [C(−H)]− and Ba2+: Infrared Multiphoton Spectroscopy and Dynamics

Gas-phase interactions between Ba2+ and deprotonated cytosine (C(-H) ) were studied in [C(-H) Ba]+ and [C(-H) BaC]+ complexes by IRMPD spectroscopy coupled to tandem mass-spectrometry in combination with DFT calculations. For the [C(-H) BaC]+ complex only one [C(-H) KAN1O-Ba-Canti ]+ isomer was found, although the presence of another structure cannot be excluded. This isomer features a central tetracoordinated Ba2+ that simultaneously interacts with keto-amino [C(-H) ]- deprotonated on N1 and neutral keto-amino C. Both moieties are in different planes as a consequence of an additional NH…O=C hydrogen bond between C and [C(-H) ]- . A sequential IRMPD dynamics is observed in this complex. For the [C(-H) Ba]+ complex produced by electrospray ionization two isomers ([C(-H) KAN1OBa]+ and [C(-H) KAN3OBa]+ ) were identified, in which Ba2+ interacts simultaneously with the C=O group and the N1 or N3 atom of the keto-amino [C(-H) ]- , respectively. A comparison with the related [C(-H) Pb]+ complex (J. Y. Salpin et al., Chem. Phys. Chem. 2014, 15, 2959-2971) is also presented.

Synthesis and biological evaluation of indolylglyoxylamide bisphosphonates, antimitotic microtubule-targeting derivatives of indibulin with improved aqueous solubility

Indibulin (D-24851) derivatives with bisphosphonate fragment connected to the N1 atom of imidazole ring were synthesized by alkylation of (indolyl-3)methylglyoxylates with ethylenebisphosphonate. Biological evaluation of targeted compounds 4a–d using the phenotypic sea urchin embryo assay provided evidence that replacing of p-chlorobenzene ring in indibulin by bisphosphonate group did not eliminate antimitotic microtubule destabilizing activity. The most active molecule, tetraacid 5a, at physiological pH formed tetrasodium salt 6a with aqueous solubility value of at least 10 mg/mL. Molecule 5a was more potent in the sea urchin embryo assay than the parent indibulin. This compound also exhibited pronounced cytotoxicity against A549 lung carcinoma and A375 melanoma cell lines.

In vitro reactions of a cyanocobalamin-cisplatin conjugate with nucleoside monophosphates.

Cisplatin (CP) is a widely used anticancer drug characterized by toxic side effects that could be alleviated using novel delivery systems including CP prodrugs. The in vitro incubation of a putative prodrug, obtained from cyanocobalamin (CNCbl) and cis-diamminemonochloroplatinum(II) (mCP), with nucleoside monophosphates (NMPs) was investigated. The in vitro reactions between the putative prodrug CNCbl-mCP and the NMPs of adenosine (AMP), guanosine (GMP), cytidine (CMP) and uridine (UMP) were carried out in slightly acidic water-methanol solutions at 37°C for 24 h. Each sample was examined using reversed-phase liquid chromatography coupled with electrospray ionization in positive ion mode and tandem mass spectrometry (RPLC/ESI-MS/MS) by collision-induced dissociation in a linear ion-trap mass spectrometer. Seven adducts were recognized as formed by substitution reactions of the chloride ligand in planar CP. Comparison between observed and theoretical isotopic patterns together with MS/MS fragmentation pathways revealed the presence of single or multiple binding sites depending on the NMP involved. The CNCbl-mCP conjugate was found to interact with N7 or O4 atoms of GMP and UMP, respectively, generating single adducts, while two isomeric adducts were observed for CMP. Finally, AMP gave rise to three isomeric adducts. In agreement with literature data relevant to the interaction between CP and NMPs, the most reactive nucleotides were AMP and GMP. The present RPLC/ESI-MS/MS approach is very promising for investigation of the reactions of CP conjugates with ribonucleotides not only in vitro but also in vivo.

Self‐catalytic mechanism of prebiotic reactions: II. From urea and glycinamide to hypoxanthine

AbstractMechanisms of reactions for formylation of urea, leading to N,N′‐diformylurea, and for the dehydration of glycinamide and N,N′‐diformylurea, yielding hypoxanthine, are suggested. It is shown that these reactions are self‐catalyzed. The first is catalyzed by formic acid, while the second is catalyzed by N,N′‐diformylurea. The suggested reaction mechanism shows that the N3 and N9 atoms of hypoxanthine originate from urea in agreement with available 1H NMR experimental data by Lagoja and Herdewijn (Lagoja & Herdewijn, Chem. Biodiv. 2004, 1, 106). A complete reaction pathway of prebiotic reactions for formation of the hypoxanthine from urea, formic acid, and glycinamide in formamide, where formamide/formimidic acid plays the role of a proton‐carrying catalyst, is also suggested.

Synthesis of 3-Alkoxy-4-Pyrrolin-2-ones via Rhodium(II)-Catalyzed Denitrogenative Transannulation of 1H-1,2,3-Triazoles with Diazo Esters.

A method for the synthesis of densely substituted 4-pyrrolin-2-ones by Rh(II)-catalyzed denitrogenative transannulation of 1-alkyl-4-aryl-1H-1,2,3-triazoles with diazo esters has been developed. The reaction proceeds via an attack of the rhodium-bound carbene at the N2 atom of the triazole and the formation of unstable 3,4-dihydro-1,2,4-triazine, which further undergoes ring contraction to a 4-pyrrolin-2-one under rhodium catalysis. The method is inapplicable to 1,2,3-triazoles with primary alkyl substituent at C4, which afford stable 1,2,3-triazol-3-ium ylides as the main products.

Mononuclear Perfluoroalkyl-Heterocyclic Complexes of Pd(II): Synthesis, Structural Characterization and Antimicrobial Activity.

Two mononuclear Pd(II) complexes [PdCl2(pfptp)] (1) and [PdCl2(pfhtp)] (2), with ligands 2-(3-perfluoropropyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfptp) and 2-(3-perfluoroheptyl-1-methyl-1,2,4-triazole-5yl)-pyridine (pfhtp), were synthesized and structurally characterized. The two complexes showed a bidentate coordination of the ligand occurring through N atom of pyridine ring and N4 atom of 1,2,4-triazole. Both complexes showed antimicrobial activity when tested against both Gram-negative and Gram-positive bacterial strains.

An Efficient Synthesis of Functionalized 2H-1,3,5-Oxadiazines via Metal-Carbenoid-Induced 1,2,4-Oxadiazole Ring Cleavage

AbstractA high-yielding method for the synthesis of 2H-1,3,5-oxadiazines by rhodium(II)- or copper(II)-catalyzed reaction of 1,2,4-oxadiazoles with α-diazo esters has been developed. The reaction proceeds via attack of the metallocarbenoid on the oxadiazole N2 atom followed by ring opening/1,6-electrocyclization and enables the introduction of alkyl, aryl, oxy, and amino substituents into the 6-position and electron-withdrawing groups into the 2-position of 1,3,5-oxadiazine. The N2-attack and the N4-attack of the carbenoid cause different oxadiazole ring openings, which are controlled by the substitution at C5. The presence of a substituent at this position is a prerequisite for the N2-attack to occur, leading to the formation of 1,3,5-oxadiazines.

Synthesis of 1-aroyl-3-methylsulfanyl-5-amino-1,2,4-triazoles and their analysis by spectroscopy, X-ray crystallography and theoretical calculations

N-Aroyl-1,2,4-triazoles TAM and TACl were regioselectively synthesized in excellent yields through an efficient N-acylation reaction of 3-amino-5-methylsulfanyl-1H-1,2,4-triazole with aroyl chlorides. Structures of N-aroyl-1,2,4-triazoles were studied by single-crystal X-ray diffraction, observing that their crystal structures are characterized by the formation of dimers through N‒H‧‧‧N bonds. The supramolecular assembly depends on the sort of connections between dimers, which notably change with the para-substituent on the aroyl group. The directly calculated ionization potential (IP), electron affinity (EA), electronegativity (χ), electrophilicity index (ω), hardness (η), and chemical potential (μ) are correlated with the HOMO and LUMO orbital energies. Moreover, molecular electrostatic potential maps of both molecules have been calculated showing a negative region at N2 atom of the 1,2,4-triazole ring instead of exocyclic amino group. The vibrational spectral analysis was carried out using infrared spectroscopy in the range 4000–400 cm−1 for N-aroyl-1,2,4-triazoles TAM and TACl. The experimental spectra were recorded in the solid state. The fundamental vibrational frequencies and intensity of vibrational bands were evaluated using density functional theory (DFT) with the standard B3LYP/6–31G(d,p) method and basis set yielding fairly good agreement between observed and calculated frequencies. Simulation of infrared spectra utilizing the results of these calculations led to an excellent overall agreement with the observed spectral patterns.

Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity.

Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N1 (or N5) atom and azido 2,3,5-tri-O-acetyl-D-β-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC50 (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC50 = 30 μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC50 = 15 μM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRP).Graphic abstract Electronic supplementary materialThe online version of this article (10.1007/s11030-020-10141-y) contains supplementary material, which is available to authorized users.

1,3-Bis(1-methyl-1H-tetrazol-5-yl)propane and its coordination polymers with Cu2Cl4 and Cu3Cl6 units

1,3-Bis(1-methyl-1H-tetrazol-5-yl)propane (bmtp) was prepared by a procedure including regioselective tert-butylation of 1,3-bis(1H-tetrazol-5-yl)propane and exhaustive methylation of the obtained 1,3-bis(2-tert-butyl-1H-tetrazol-5-yl)propane, followed by removal of the tert-butyl group from the tetrazolium salt under acidic conditions. The ligand bmtp reacts with CuCl2·2H2O in ethanol to give the complexes [Cu3(bmtp)2Cl6(H2O)2]n and [Cu(bmtp)Cl2]n. The transformation of [Cu(bmtp)Cl2]n into [Cu3(bmtp)2Cl6(H2O)2]n is observed in ethanol. According to single crystal X-ray analysis, [Cu(bmtp)Cl2]n was obtained as a mixture of polymorphic forms. They are all 1D coordination polymers, in which polymeric chains include Cu2Cl4 units linked to each other by two bridging ligands via the tetrazole ring N4 atoms. [Cu3(bmtp)2Cl6(H2O)2]n presents a 2D coordination polymer, including Cu3Cl6 units bonded to four others by ligand molecules. In this complex, the tetrazole ligands show monodentate N4 and bridging N3,N4 coordination. The temperature-dependent magnetic susceptibility measurements of this complex revealed that the copper(II) ions are antiferromagnetically coupled, showing a coupling constant J of −4.0 cm−1.

Triboluminescence of trans-stilbene, p-terphenyl and polycyclic aromatic hydrocarbons

Abstract The luminescence of trans-stilbene, p-terphenyl and polycyclic aromatic hydrocarbons (PAHs) during the mechanical grinding of microcrystals in a working cell is studied. The triboluminescence of trans-stilbene, p-terphenyl, naphthalene, anthracene, pyrene, and coronene was detected. No triboluminescence spectrum of tetracene was recorded because of low intensity. No gas component of a triboluminescence spectrum (the lines of N2 molecules and atoms of inert gases) was recorded for all polyaromatic hydrocarbons in air and inert gases (Ne, Ar, and Kr). The bands coinciding with fluorescence spectra of trans-stilbene, p-terphenyl, naphthalene, and anthracene are observed in their triboluminescence spectra during the mechanical grinding of their crystals. High-intensity luminescence of excimers is observed in the triboluminescence spectrum of pyrene and coronene, and there is no luminescence of their monomers. Stable triboluminescence of a pyrene monomer, however, is observed during the grinding of a 200:1 naphthalene/pyrene microcrystal mixture, and it appeared due to the transfer of excitation energy from a naphthalene molecule to pyrene one. The triboluminescence of tetracene was also detected in an anthracene/tetracene mixture. A mechanism of triboluminescence of trans-stilbene, p-terphenyl and PAHs is proposed as electroluminescence arising due to recombination of charge carriers in the electric field of a crystalline layer electrified during the grinding.

Ultrafast excited state dynamics of silver ion-mediated cytosine-cytosine base pairs in metallo-DNA.

To better understand the nexus between structure and photophysics in metallo-DNA assemblies, the parallel-stranded duplex formed by the all-cytosine oligonucleotide, dC20, and silver nitrate was studied by circular dichroism (CD), femtosecond transient absorption spectroscopy, and time-dependent-density functional theory calculations. Silver(I) ions mediate Cytosine-Cytosine (CC) base pairs by coordinating to the N3 atoms of two cytosines. Although these silver(I) mediated CC base pairs resemble the proton-mediated CC base pairs found in i-motif DNA at first glance, a comparison of experimental and calculated CD spectra reveals that silver ion-mediated i-motif structures do not form. Instead, the parallel-stranded duplex formed between dC20 and silver ions is proposed to contain consecutive silver-mediated base pairs with high propeller twist-like ones seen in a recent crystal structure of an emissive, DNA-templated silver cluster. Femtosecond transient absorption measurements with broadband probing from the near UV to the near IR reveal an unusually long-lived (>10 ns) excited state in the dC20 silver ion complex that is not seen in dC20 in single-stranded or i-motif forms. This state is also absent in a concentrated solution of cytosine-silver ion complexes that are thought to assemble into planar ribbons or sheets that lack stacked silver(I) mediated CC base pairs. The large propeller twist angle present in metal-mediated base pairs may promote the formation of long-lived charged separated or triplet states in this metallo-DNA.