Unsubstituted Analog Research Articles

Combined Experimental and Theoretical Investigation of the Electrochemical Behavior of Hydroxy‐Substituted Anils

AbstractThe present work explored the electrochemical behavior of two organic compounds, o‐hydroxybenzylidene‐orthochloroaniline(Anil‐1) and o‐hydroxynaphthalidene‐orthochloro aniline(Anil‐2) through a series of theoretical and experimental investigations. The vibrational frequencies of two anilswere analyzed experimentally by FTIR and theoretically by DFT studies. A comparison of the frequencies with their unsubstituted analog, o‐hydroxybenzylideneaniline, confirmed the electron‐donating nature of the −Cl and −OH substituents in anils. The hyperconjugative interaction energy obtained from NBO analysis divulged the direction of the electron donation from the donor orbitals to the acceptor orbitals. UV‐visible studies illustrated prominent π→π* electronic transitions with significant oscillator strength(0.10–0.26) and molar extinction coefficient(~104) experimentally. Analysis of the global and local reactive descriptors of anils revealed a lower HOMO‐LUMO energy gap of Anil‐2(4.05 eV) than Anil‐1(4.46 eV), corroborating the order of decreasing reactivity to be Anil‐2>Anil‐1. The Cyclic Voltammetry studies disclosed the involvement of an oxidation process in Anil‐1 and Anil‐2 with a higher oxidation potential of Anil‐1 (1.43 V) than Anil‐2(1.31 V) due to the naphthyl moiety of the latter. However, the absence of a cathodic peak in both cases envisaged the irreversible nature of oxidation. The results demonstrated that both the anils could be suitable optical materials for microelectronics applications.

Proton Activation in the Presence of a Weak Acid Facilitated by Second Coordination Sphere Effects in Iron Porphyrins**

AbstractThe catalytic activity of two iron‐based porphyrin complexes containing pyridine‐functionalized second coordination spheres, referred to as Py2XPFe and CuPy2XPFe, have been investigated for the hydrogen evolution reaction (HER) and compared with the unsubstituted analog TMPFe in acetonitrile. The CuPy2XPFe incorporates a second metal center within the pyridine residues and represents a heterodinuclear system, while the structurally analogous Py2XPFe lacks an additional metal in the second coordination sphere. Both the Py2XFe and CuPy2XPFe complexes are observed to activate the weak acid, acetic acid (AcOH) at the FeII/I couple rather than at the more energy intensive FeI/0 couple observed for the unfunctionalized TMPFe complex at low acid concentrations. The ability of the monometallic Py2XPFe to activate the weak proton source at the FeII/I couple manifests as an ECEC(E)′ type electrochemical mechanism, rather than an EECC(E)′ type mechanism as observed for TMPFe. The CuPy2XPFe displays improved reactivity compared with the Py2XPFe and TMPFe under the same substrate conditions, however the mechanistic nuances into bimetallic CuPy2XPFe system are currently unclear. The concentration of AcOH was incrementally increased and the rate constants of the initial protonation step i. e. formation of a hydridic species (k1,app), as well as of the protonation of the hydridic species to produce dihydrogen (kglobal) were calculated using the Foot‐of‐the‐wave and plateau current rate equation methodologies, respectively. The kinetic analysis indicates that the activation of protons through the ECEC(E)′ type mechanism for the Py2XPFe results in a system in which k1,app< kglobal. As both the monometallic Py2XPFe and bimetallic CuPy2XPFe activate the AcOH at less cathodic potentials than TMPFe under identical conditions, the overpotentials (ηTOF/2) for these complexes are thus dramatically lower. The reactivity difference of the Py2XPFe when compared to non‐substituted iron porphyrin analogs is due to the hanging group's influence, which is believed to either act as hydrogen bond promoters for the active site or aids to stabilize a catalytic intermediate species during catalysis.

Synthesis of 31-aminopyridinio–chlorophyll-a derivatives and their optical properties

Oxidative reactions of isomeric amino-, methylamino-, and dimethylamino-pyridines with the 3-vinyl group of methyl pyropheophorbide-[Formula: see text], a chlorophyll-[Formula: see text] derivative, afforded 3-{1-[[Formula: see text]/[Formula: see text]/[Formula: see text]-(non/mono/di-methyl-amino)pyridinio]ethenyl}chlorins bearing the C31–N+ bond. Although all the [Formula: see text]/[Formula: see text]-substituents gave almost the same visible absorption spectra in acetonitrile, the [Formula: see text]-methylation effect on the Qy maxima was observed in the [Formula: see text]-substituted analogs with blue-shifted absorption bands. The substitution with most of the amino moieties suppressed the intramolecular electron transfer from the photoexcited chlorin core to the relatively electron-rich pyridinio periphery to enhance the fluorescence emission in acetonitrile, compared with the unsubstituted pyridinio analog. By contrast, the [Formula: see text]-NH2 substituted pyridine–chlorin conjugate was less fluorescent than any other aminated analogs as well as the unsubstituted counterpart. The electron-donating ability of the [Formula: see text]-NH2 group was recovered by the addition of alcohols to give highly fluorescent species.

The effect of diphenylethane side-chain substituents on dibenzocyclohexadiene formation and their inhibition of α-synuclein aggregation in vitro

The naturally-occurring di-catechol lignan nordihydroguaiaretic acid (NDGA) and an analog without methyl groups on the butyl linker both undergo intramolecular cyclization at pH 7.4 to form dibenzocyclooctadienes. Both NDGA and these dibenzocyclooctadienes have been shown to prevent in vitro aggregation of α-synuclein, an intrinsically disordered protein associated with Parkinson’s disease. NDGA possesses two vicinal methyl groups on the butyl linker and the presence of these methyl groups attenuates the rate of intramolecular cyclization versus the unsubstituted analog, in opposition to the anticipated Thorpe-Ingold effect, likely due to steric repulsions during cyclization.Numerous 1,2-bis-ethane di-catechols are known to inhibit α-synuclein aggregation in vitro and we hypothesize that these compounds undergo a similar intramolecular cyclization and the cyclized products may be responsible for the activity. To test this hypothesis we prepared a series of 1,2-bis-ethane di-catechols with 0, 2 and 4 methyl substituents on the linker. We have confirmed that these compounds undergo intramolecular cyclization to form dibenzocyclohexadienes and that steric interactions between the methyl substituents leads to an increase in the rate of intramolecular cyclization, which is in contrast to what was observed for lignan di-catechols. The rate of cyclization to form six-membered rings is 10–30 times more rapid than formation of eight membered rings and the dibenzocyclohexadienes also prevent in vitro aggregation of α-synuclein.

Dark and photoinduced cytotoxicity of solubilized hydrophobic octa-and hexadecachloro-substituted lutetium(III) phthalocyanines

Chloro-substituted lutetium(III) phthalocyanines were obtained using fast and effective (yields 75–78%) template synthesis under microwave irradiation. Target compounds possess intense (logε ∼ 5) absorption in the range 680–700 nm, which overlaps with the “therapeutic window” range for photosensitizers in photodynamic therapy. Chloro-substituted complexes demonstrate moderate quantum yields (up to 54% for perchlorinated complex) of singlet oxygen generation. Moreover, chloro-substituted lutetium(III) phthalocyanines showed the ability to generate the superoxide anion radical (O2–•) with higher efficiency compared to unsubstituted analog. Stable colloid suspensions of the water-soluble nanoparticles were obtained by incorporation of the chlorinated lutetium(III) phthalocyanines into mixed polylactide micelles. The dark and photoinduced cytotoxic activity of the obtained nanoparticles was tested using the HeLa cell line. Demonstrated results showed a promising potential of the chlorinated lutetium(III) phthalocyanines as photosensitizers for medical applications.

Design, synthesis and biological evaluation of novel 5-((substituted quinolin-3-yl/1-naphthyl) methylene)-3-substituted imidazolidin-2,4-dione as HIV-1 fusion inhibitors.

A series of novel 5-(substituted quinolin-3-yl or 1-naphthyl)methylene)-3-substituted imidazolidin-2,4-dione 9-26 was designed and synthesized. The prepared compounds were identified using 1H NMR, 13C NMR as well as elemental analyses. The inhibitory activity of 9-26 on HIV-1IIIB replication in MT-2 cells was evaluated. Some derivatives showed good to excellent anti-HIV activities as compounds 13, 18, 19, 20, 22 and 23. They showed EC50 of 0.148, 0.460, 0.332, 0.50, 0.271 and 0.420μM respectively being more potent than compound I (EC50=0.70μM) and II ( EC50=2.40μM) as standards. The inhibitory activity of 9-26 on infected primary HIV-1 domain, 92US657 (clade B, R5) was investigated. All the tested compounds consistently inhibited infection of this virus with EC50 from 0.520 to 11.857μM. Results from SAR studies showed that substitution on ring A with 6/7/8-methyl group resulted in significant increase in the inhibitory activity against HIV-1IIIB infection (5- >300 times) compared to the unsubstituted analog 9. The cytotoxicity of these compounds on MT-2 cells was tested and their CC50 values ranged from 11 to 85μM with selectivity indexes ranged from 0.53 to 166. The docking study revealed nice fitting of the new compounds into the hydrophobic pocket of HIV-1 gp41 and higher affinity than NB-64. Compound 13, the most active in preventing HIV-1IIIB infection, adopted a similar orientation to compound IV. Molecular docking analysis of the new compounds revealed hydrogen bonding interactions between the imidazolidine-2,4-dione ring and LYS574 which were missed in the weakly active derivatives.

X-ray crystal structural and spectral studies of copper(II) and nickel(II) complexes of functionalized bis(thiosemicarbazone) ligands and investigation of their electrochemical behavior

Neutral bivalent copper and nickel bis(thiosemicarbazone) complexes bearing the methoxy and bromine substituents on the dialdehyde-backbone of the ligand have been synthesized. All of them have been characterized by spectroscopic methods and in two cases by X-ray crystallography. Upon formation of these complexes, the each two bis(thiosemicarbazone) arms is deprotonated, acting as dianionic, tetradentate N2S2 ligands. The geometrical distortion from square planar in the copper complex is very greater than the nickel complex. Cyclic voltammetry studies of Cu(II) and Ni(II) complexes in DMF show that all complexes are able to stabilize low oxidation states of Cu(I) and Ni(I). The introduction of different substitutions on the aromatic ring attached to the imine carbon led to two consequences. First, The E1/2 values for the CuI/CuII and NiI/NiII redox couples were cathodically shifted in comparison with the unsubstituted analog. Second, the copper complexes underwent a quasi-reversible one-electron oxidation (CuII/CuIII).

Ruthenium(ii) complexes of pyridinol and N-heterocyclic carbene derived pincers as robust catalysts for selective carbon dioxide reduction.

A new pincer ligand with N-heterocyclic carbene (NHC) and 4-pyridinol-derived rings supports ruthenium complexes for photocatalytic CO2 reduction. The methoxy group on the pyridine ring offers unique catalysis advantages not seen with the unsubstituted analog. Our best catalyst offers selective CO formation, ∼250 turnover cycles, and a 40 h lifetime.

Synthesis and Structure of New N-Alkoxy-N-(1-pyridinium)urea Chlorides

New N-[1-(4-amino)pyridinium]-N-methoxyurea chloride, N-[1-(2-amino)pyridinium]-N-methoxyurea chloride and their analogs were synthesized by N-alkoxy-N-chloroureas reaction with the proper pyridines in acetonitrile or ether solution by improved procedure. XRD study of N-[1-(4-amino)pyridinium]-N-methoxyurea and N-[1-(2-amino)pyridinium]-N-methoxyurea revealed the elongation of N-N + bonds and some shortening of MeO-N bonds, qunonoid deformation of pyridine rings compare to it unsubstituted analog. The substantial pyramidality of central nitrogen atom in O-N-N + moiety and N-C carbamoyl bonds difference were established too. The structure summary of N-alkoxy-N-(1-pyridinium)ureas salts and other derivatives of 1-(N-alkoxyamino)pyridinium salts has been done.

Influence of the halogen atom on the solid-state fluorescence properties of 2-phenyl-benzoxazole derivatives

Four halogenated derivatives of 2-phenyl-benzoxazole and the unsubstituted analog were studied in solution and as powders by absorption and steady-state fluorescence spectroscopy. In solution, the fluorescence quantum yield was progressively decreased with increasing the size of the halogen atom, as explained by heavy atom effect. In the solid state, an increase in photoluminescence efficiency was observed when passing from the fluorinated to chlorinated derivative, and then the fluorescence efficiency was decreased for the brominated and iodinated derivatives, the latter compound being virtually not emissive. To explain the solid-state behavior, the influence of molecular arrangement on the emission properties was discussed on the basis of X-ray data. Finally, microcrystals were generated using a solvent-exchange method. An evolution from elongated platelets to cubic particles was observed with increasing the size of the halogen atom, providing preliminary information for the use of these compounds as micro- and nano-materials.

Protecting the triplet excited state in sterically congested platinum porphyrin

Platinum tetrakis(2,4,6-triethylphenyl)porphyrin (Pt-1) was synthesized and its structural (X-ray), electrochemical and photophysical properties were fully characterized. Comparative studies of Pt-1 and its unsubstituted analog PtTPP show the effect of sterically congesting ortho-substituents on the dynamics of the triplet excited states. Lowered quenching rates by 3-4 times were observed for Pt-1vs. PtTPP in the presence of oxygen and perylene, and in concentration (self)-quenching experiments.

The synthesis and SAR of calcitonin gene-related peptide (CGRP) receptor antagonists derived from tyrosine surrogates. Part 2

Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03mg/kg SC, compound 2 (a racemic mixture of 3 and its (S)-enantiomer) demonstrated robust inhibition of CGRP-induced increases in mamoset facial blood flow up to 105min. The compound possesses a favorable predictive in vitro toxicology profile, and good aqueous solubility. When dosed as a nasal spray in rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42%).

Unusual transformations of phosphoryl compounds in the Kishner reduction

Aiming to obtain the similar unsubstituted hydrazone analog of the same phosphonium salt we studied the reaction of salt I with an aqueous hydrazine in the presence of sodium carbonate in chloroform at 30°C. Unexpectedly, propyldiphenylphosphine oxide II was obtained in 50% yield as the reaction product along with the doubly N-alkylated adduct. Probably the formation of II occurs through an intermediate diphenyl-2-methyl-2hydrazinoethylphosphine oxide III. The latter undergoes successive dehydrogenation and denitrogenation as follows: DOI: 10.1134/S107036321301026X

4-Aryl-4H-naphthopyrans derivatives: one-pot synthesis, evaluation of Src kinase inhibitory and anti-proliferative activities

BackgroundA series of 2-amino-4-aryl-4H-benzo[h or f]chromene-3-carbonitrile derivatives were synthesized and evaluated for inhibition of Src kinase and cell proliferation in breast carcinoma (BT-20) cell lines.MethodsThe one-pot, three-component reaction of α or β-naphthol, malonitrile and an aromatic aldehyde in the presence of diammonium hydrogen phosphate was afforded the corresponding 2-amino-4-aryl-4H-benzo[h or f]chromene-3-carbonitrile derivatives, All target compounds were evaluated for inhibition of Src kinase and cell proliferation in breast carcinoma (BT-20) cell lines.ResultsAmong all tested compounds, unsubstituted 4-phenyl analog 4a showed Src kinas inhibitory effect with IC50 value of 28.1 μM and was the most potent compound in this series. In general, the compounds were moderately active against BT-20. 3-Nitro-phenyl 4e and 3-pyridinyl 4h derivatives inhibited the cell proliferation of BT-20 cells by 33% and 31.5%, respectively, and found to be more potent compared to doxorubicin (25% inhibition of cell growth).ConclusionThe data indicate that 4-aryl-4H-naphthopyrans scaffold has the potential to be optimized further for designing more potent Src kinase inhibitors and/or anticancer lead compounds.

A Small Molecule Inhibitor of Ubiquitin-Specific Protease-7 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Bortezomib Resistance

Bortezomib therapy has proven successful for the treatment of relapsed/refractory, relapsed, and newly diagnosed multiple myeloma (MM); however, dose-limiting toxicities and the development of resistance limit its long-term utility. Here, we show that P5091 is an inhibitor of deubiquitylating enzyme USP7, which induces apoptosis in MM cells resistant to conventional and bortezomib therapies. Biochemical and genetic studies show that blockade of HDM2 and p21 abrogates P5091-induced cytotoxicity. In animal tumor model studies, P5091 is well tolerated, inhibits tumor growth, and prolongs survival. Combining P5091 with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic anti-MM activity. Our preclinical study therefore supports clinical evaluation of USP7 inhibitor, alone or in combination, as a potential MM therapy.

The investigation of the intermediates of spiropyran retinal analogs by laser flash photolysis techniques with different excitation wavelengths

Spectral-kinetic properties of intermediates of spiropyran retinal analogs (SRA), which molecules contain spiropyran and retinoid (with different polyenic chain length and aldehyde terminal group) fragments, have been investigated by nanosecond laser flash photolysis techniques using excitation wavelengths 337 and 380–450 nm in toluene. Relative quantum yields of different SRA intermediates formation relative to those of model compounds, namely triplet excited state and merocyanine form generated upon pyran cycle cleavage have been measured. It has been found that merocyanine form does not form upon photolysis of SRA with polyenic chain length of 5 and 9 using excitation wavelengths of 380–450 nm, the triplet state of retinoid fragment is observed exclusively. The yield of merocyanine (MC) form is the largest one upon SRA photolysis with excitation wavelength of 337 nm for 6′-formylsubstituted spiropyran (it exceeds that of unsubstituted analog in 8 times and forms mainly from the triplet state). The yields of MC for SRA with polyenic chain length of 3, 5 and 9 carbon atoms are 5–10 times smaller than that for unsubstituted spiropyran.

Synthesis and photoisomerization of mesogenic 4-alkoxystyrylpyridines

Introduction of long-chain alkoxy substituents into molecules of styrylpyridines as potential ligands for photosensitive metal complexes endows them with liquid crystalline properties over a wide temperature range. trans-cis Photoisomerization of 4-alkoxystyrylpyridines in solution was revealed by NMR and electronic absorption spectroscopy, and the kinetics of transformations of their molecular forms after irradiation were estimated. Photoinduced trans→cis isomerization of 4-alkoxystyrylpyridines is characterized by a higher rate, and intramolecular cyclization of their cis isomers after irradiation is slower, as compared to unsubstituted analog.

Fluorescent Fe(II) metallo-supramolecular polymers: metal-ion-directed self-assembly of new bisterpyridines containing triethylene glycol chains

We synthesized new ditopic bisterpyridine (BTPY) ligands (L2 and L4) containing triethylene glycol (TEG) chains at the ortho-position of the peripheral pyridine ring and succeeded in obtaining fluorescent Fe(II) metallo-supramolecular polyelectrolytes (FeL2-MEPE and FeL4-MEPE) through complexation of Fe(II) ions with L2 and L4, respectively. The Fe(II) ion is known to quench fluorescence, but FeL2-MEPE shows a retention of quantum yield that is nearly threefold higher than that of the unsubstituted analog (FeL3-MEPE). We investigated the substituent effects of TEG chains on metallo-supramolecular polymers and their fluorescent and electrochemical properties in detail. Fluorescent Fe(II) metallo-supramolecular polymers (Fe(II)-MEPEs) are synthesized through complexation of Fe(II) ions with new bisterpyridine ligands bearing triethylene glycol (TEG) chains at the ortho-position of pyridine rings. Although Fe(II) ion is known as a quencher of fluorescence, Fe(II)-MEPE containing TEG chains shows nearly a threefold higher retention of fluorescent properties compared with unsubstituted analogs.

Rearrangements of cyclopentadienyl cyanates, isocyanates and their thio-,seleno-, and telluro-analogs

Dynamic NMR spectroscopy revealed that pentaphenylcyclopentadienyl isoselenocyanate undergoes reversible hetero-Cope rearrangement (ΔG ≠ 408 K ∼ 22 kcal mol−1, C6D5CD3) giving isomeric selenocyanate in which 1,5-sigmatropic shifts of the SeCN group along the perimeter of the cyclopentadiene ring occur (ΔG ≠ 298 K = 16.7 kcal mol−1, C6D5CD3). On the contrary, pentaphenylcyclopentadienyl iso(thio)cyanates Ph5C5NCO and Ph5C5NCS are structurally rigid compounds on the NMR time scale. The energy barrier to the 3,3-shift of the isoselenocyanate group in pentaphenylcyclopentadienyl derivative Ph5C5NCSe (ΔG 298 K ≠ = 17.9 kcal mol−1) caclulated using the B3LYP/6-31G** method is 7.6 kcal mol−1 lower than for the unsubstituted analog H5C5NCSe.

Analogs of MK-499 are differentially affected by a mutation in the S6 domain of the hERG K+ channel

Drug-induced long QT syndrome has been principally ascribed to block of the cardiac hERG K + channel. Methanesulfonanilides, such as MK-499, E-4031 and dofetilide, are potent hERG antagonists that likely bind along the S6 helix within the inner vestibule of the pore. To further investigate these interactions, we broadly explored the structure–activity relationships of closely related analogs of MK-499 using a high-throughput ion flux assay, and evaluated in greater detail using patch-clamp electrophysiology. We observed that substitutions at the 4-position on the benzopyran ring significantly affected the potency of these analogs with the rank order of unsubstituted ≈ ketone > amine > hydroxyl, implicating an important interaction at this position. We also evaluated the potency of these analogs on an S6 mutant of hERG (F656A) previously shown to significantly reduce the affinity for MK-499 and other known hERG antagonists (e.g. cisapride, terfenadine). In contrast to MK-499 (4-hydroxyl) and either the amine or unsubstituted analogs, the potency of the ketone analog was unaffected by this mutation suggesting that a compensatory interaction may be unveiled with the aromatic to apolar substitution, possibly through hydrogen bonding with Ser624 based on molecular modeling. More significantly, we found that this mutation rendered hERG susceptible to block in the closed-state by the smaller, unsubstituted analog, but not by MK-499 or larger analogs. Together these data suggest that interaction with Phe656 is not an absolute requirement for the binding of all methanesulfonanilide compounds, and that this residue may play a broader role in regulating access to the inner vestibule.