Dioxygen-halogen bonding exemplified by crystalline peroxosolvates of N,N'-bis(haloacetyl) bispidines.

The halogen bonding in molecular crystals and supramolecular assemblies has been widely investigated. Special attention is given to the molecular structures capable of simultaneously exhibiting different types of non-covalent interactions, including conventional hydrogen bonds and halogen bonds. This paper systematically analyzes crystalline peroxosolvates of bispidine-based bis-amide derivatives, containing haloacetic acid residues, namely previously reported 1,1'-(1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl)bis(2-iodooethanone) peroxosolvate C13H20I2N2O2·H2O2 (1) and four new crystalline compounds, 1,1'-(1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl)bis(2-bromoethanone) peroxosolvate C13H20Br2N2O2·H2O2 (2), 1,1'-(9-hydroperoxy-9-hydroxy-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl)bis(2-iodoethanone) peroxosolvate C13H20I2N2O5·0.5H2O2 (3), 1,1'-(9-hydroperoxy-9-hydroxy-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl)bis(2-bromoethanone) peroxosolvate C13H20Br2N2O5·H2O2 (4), and 1,1'-(9-hydroperoxy-9-hydroxy-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonane-3,7-diyl)bis(2-chloroethanone) peroxosolvate C13H20Cl2N2O5·H2O2 (5). Compounds 2-5 were synthesized for the first time and their crystal structures were determined by single-crystal X-ray diffractometry (SCXRD). To the best of our knowledge, 3-5 are unprecedented crystalline hydrogen peroxide adducts of organic hydroperoxides (R-OOH). Short intermolecular contacts between halogen and hydroperoxo oxygen atoms were found in 1-3. The halogen bonding of C-I(Br) fragments with dioxygen species in compounds 1-3 as well as in the previously reported cocrystal of diacetone diperoxide with triodotrinitrobenzene (6) was identified through reduced density gradient analysis, Hirshfeld surface analysis, and Bader analysis of crystalline electron density. The interactions were quantified using the electron density topological properties acquired from the periodic DFT calculations and evaluated to lie in the range of 9-19 kJ mol-1. A distinctive spectral feature was revealed for this type of interaction, involving a red shift of the characteristic O-O stretching vibration by about 6 cm-1, which appeared in IR spectra as a narrow low-intensity band in the region 837-872 cm-1.

Synthesis of N,N'-Unsymmetrical 9-Amino-5,7-dimethyl-bispidines.

A new approach to the preparation of N,N'-unsymmetrically substituted 9-aminobispidines through aminal bridge removal reaction has been developed, the principal feature of which is the ability to selectively functionalize all three nitrogen atoms. The intermediates of 1,3-diazaadamantane's aminal bridge removal reaction are characterized, and the mechanism of this reaction is proposed based on the analysis of their structures. Representatives of the previously unknown saturated heterocyclic 1,5,9-triazatricyclo[5.3.1.03,8]undecane system were obtained and structurally characterized. Thus, it was possible for the first time to obtain 3,7,9-trisubstituted bispidines containing acetyl, Boc, and benzyl groups at nitrogen atoms, which can be independently removed (orthogonal protective groups).

"Stereoelectronic Deprotection of Nitrogen": Recovering Nucleophilicity with a Conformational Change.

Ureas are often thought of as "double amides" due to the obvious structural similarity of these functional groups. The main structural feature of an amide is its planarity, which is responsible for the conjugation between the nitrogen atom and carbonyl moiety and the decrease of amide nucleophilicity. Consequently, since amides are poor nucleophiles, ureas are often thought of as poor nucleophiles as well. Herein, we demonstrate that ureas can be distinctly different from amides. These differences can be amplified by rotation around one of the ureas' C-N bonds, which switches off the amide resonance and recovers the nucleophilicity of one of the nitrogen atoms. This conformational change can be further facilitated by the judicious introduction of steric bulk to disfavor the planar conformation. This change in reactivity is an example of "stereoelectronic deprotection," a concept when the desired reactivity of a functional group is produced by a conformational change rather than a chemical modification. This concept may be used complementarily to the traditional protecting groups. We also demonstrate both the viability and the utility of this concept by the synthesis of unusual 2-oxoimidazolium salts possessing quaternary nitrogen atoms at the urea moiety.

Preparation of Ferrocene-Terminated Dendrimers for the Thermal Decomposition of Ammonium Perchlorate.

As a common oxidizer, ammonium perchlorate (AP) is an important component in composite solid propellants (CSPs). Ferrocene (Fc)-based compounds are often selected as burning rate catalysts (BRCs) to catalyze AP decomposition owing to their excellent catalytic behavior. However, one of the drawbacks of Fc-based BRCs is migration in CSPs. In this study, five Fc-terminated dendrimers are designed and synthesized to improve the anti-migration properties, and their chemical structures are confirmed systemically by the related spectra characterization techniques. Moreover, the redox performance, catalytic effect on AP decomposition, combustion performance, and mechanical properties in CSPs are also studied. The shapes of the prepared propellant samples are observed via scanning electron microscopy. The obtained Fc-based BRCs have good redox performance, a positive effect on promoting AP decomposition, excellent combustion catalytic performance, and good mechanical properties. Meanwhile, they have a higher anti-migration ability than catocene (Cat) and Fc. This study demonstrates that Fc-terminated dendrimers have great potential to be applied as anti-migration BRCs in CSPs.

Photoprocesses in Derivatives of 1,4- and 1,3-Diazadistyryldibenzenes.

Photoprocesses in 1,4-diazadistyrylbenzene (1) and 1,3-diazadistyrylbenzene derivative (2) diperchlorates in MeCN were studied by absorption, luminescence, and kinetic laser spectroscopies. For compound 1, trans-cis-photoisomerization and intersystem crossing to a triplet state are observed. For compound 2, photoelectrocyclization is suggested. Quantum chemical calculations of diazadistyrylbenzene structures in the ground and excited states were carried out. The schemes for photoreactions were proposed.

Bispidine Platform as a Tool for Studying Amide Configuration Stability.

In this work, the solution conformations of seventeen 3,7-diacyl bispidines were studied by means of NMR spectroscopy including VT NMR experiments. The acyl groups included alkyl, alkenyl, aryl, hetaryl, and ferrocene moieties. The presence of syn/anti-isomers and their ratios were estimated, and some reasons explaining experimental facts were formulated. In particular, all aliphatic and heterocyclic units in the acylic R(CO) fragments led to an increased content of the syn-form in DMSO-d6 solutions. In contrast, only the anti-form was detected in DMSO-d6 and CDCl3 in the case when R = Ph, ferrocenyl, (R)-myrtenyl. In the case of a chiral compound derived from the natural terpene myrtene, a new dynamic process was found in addition to the expected inversion around the amide N-C(O) bond. Here, rotation around the CO-C=C bond in the acylic R fragment was detected, and its energy was estimated. For this compound, ΔG for amide N-C(O) inversion was found to be equal to 15.0 ± 0.2 kcal/mol, and for the rotation around the N(CO)-C2' bond, it was equal to 15.6 ± 0.3 kcal/mol. NMR analysis of the chiral bispidine-based bis-amide was conducted for the first time. Two X-ray structures are reported. For the first time, the unique syn-form was found in the crystal of an acyclic bispidine-based bis-amide. Quantum chemical calculations revealed the unexpected mechanism for amide bond inversion. It was found that the reaction does not proceed as direct N-C(O) bond inversion in the double-chair (CC) conformation but rather requires the conformational transformation into the chair-boat (CB) form first. The amide bond inversion in the latter requires less energy than in the CC form.

Europium complexes with dinitropyrazole: unusual luminescence thermal behavior and irreversible temperature sensing.

Europium 3,5-dinitropyrazole complexes demonstrate an unusual luminescence behavior upon heating, i.e. there is a noticeable increase of the luminescence intensity beyond a temperature of 200 °C. We propose and successfully demonstrate the possibility of using this phenomenon for sensing overheating above this temperature. An on/off ratio of 37 is reached.

Novel Bispidine-Monoterpene Conjugates-Synthesis and Application as Ligands for the Catalytic Ethylation of Chalcones.

A number of new chiral bispidines containing monoterpenoid fragments have been obtained. The bispidines were studied as ligands for Ni-catalyzed addition of diethylzinc to chalcones. The conditions for chromatographic analysis by HPLC-UV were developed, in which the peaks of the enantiomers of all synthesized chiral products were separated, which made it possible to determine the enantiomeric excess of the resulting mixture. It was demonstrated that bispidine-monoterpenoid conjugates can be used as the ligands for diethylzinc addition to chalcone C=C double bond but not as inducers of chirality. Besides products of ethylation, formation of products of formal hydrogenation of the chalcone C=C double bond was observed in all cases. Note, that this formation of hydrogenation products in significant amounts in the presence of such catalytic systems was found for the first time. A tentative scheme explaining the formation of all products was proposed.

New approach to increase the sensitivity of Tb-Eu-based luminescent thermometer.

The formation of trimetallic terbium-europium-gadolinium complexes was proposed as an approach to increase the sensitivity of the corresponding terbium-europium complexes for temperature measurement due to the suppression of multiphotonic emission. This approach results in over a 2-fold increase of the sensitivity of Eu-Tb carboxylate, which reached 5.3% K-1 in the physiological range.

Isonitriles as Stereoelectronic Chameleons: The Donor-Acceptor Dichotomy in Radical Additions.

Radical addition to isonitriles (isocyanides) starts and continues all the way to the transition state (TS) mostly as a simple addition to a polarized π-bond. Only after the TS has been passed, the spin density moves to the α-carbon to form the imidoyl radical, the hallmark intermediate of the 1,1-addition-mediated cascades. Addition of alkyl, aryl, heteroatom-substituted, and heteroatom-centered radicals reveals a number of electronic, supramolecular, and conformational effects potentially useful for the practical control of isonitrile-mediated radical cascade transformations. Addition of alkyl radicals reveals two stereoelectronic preferences. First, the radical attack aligns the incipient C···C bond with the aromatic π-system. Second, one of the C-H/C-C bonds at the radical carbon eclipses the isonitrile N-C bond. Combination of these stereoelectronic preferences with entropic penalty explains why the least exergonic reaction (addition of the t-Bu radical) is also the fastest. Heteroatomic radicals reveal further unusual trends. In particular, the Sn radical addition to the PhNC is much faster than addition of the other group IV radicals, despite forming the weakest bond. This combination of kinetic and thermodynamic properties is ideal for applications in control of radical reactivity via dynamic covalent chemistry and may be responsible for the historically broad utility of Sn radicals ("the tyranny of tin"). In addition to polarity and low steric hindrance, radical attack at the relatively strong π-bond of isonitriles is assisted by "chameleonic" supramolecular interactions of the radical center with both the isonitrile π*-system and lone pair. These interactions are yet another manifestation of supramolecular control of radical chemistry.

Stereoelectronic Chameleons: The Donor-Acceptor Dichotomy of Functional Groups.

Stereoelectronic factors account for the apparent reversal of donor-acceptor properties of a variety of functional groups by a simple change of their orientation in space. The new reactivity patterns that arise from spatial anisotropy are associated with chameleonic behavior of common organic functionalities.

A new approach to ferrocene derived alkenes via copper-catalyzed olefination.

A new approach to ferrocenyl haloalkenes and bis-alkenes was elaborated. The key procedure involves copper catalyzed olefination of N-unsubstituted hydrazones, obtained from ferrocene-containing carbonyl compounds and hydrazine, with polyhaloalkanes. The procedure is simple, cheap and could be applied for the utilization of environmentally harmful polyhalocarbons. The cyclic voltammetry study of the representative examples of the synthesized ferrocenyl alkenes shows the strong dependence of the cathodic behavior on the amount of vinyl groups: while for the monoalkene containing molecules no reduction is seen, the divinyl products are reduced in several steps.

Hypervalent Sulfur Derivatives as Sulfenylating Reagents: Visible-Light-Mediated Direct Thiolation of Activated C(sp2)-H Bonds with Dihalosulfuranes.

In contrast to hypervalent iodine compounds, the chemistry of their sulfur analogues has been considerably less explored. Herein, we report the direct C-H bond thiolation of electron-rich heterocycles, arenes, and 1,3-dicarbonyls by dichlorosulfuranes under mild conditions. Mechanistic studies and density functional theory calculations suggest the radical chain mechanism of the disclosed transformation. The key to success is attributed to a strikingly low S-Cl bond dissociation energy, which enables the generation of radical species upon exposure to daylight.

A first-in-class ß-glucuronidase responsive conjugate for selective dual targeted and photodynamic therapy of bladder cancer.

In this report, we present a novel prodrug strategy that can significantly improve the efficiency and selectivity of combined therapy for bladder cancer. Our approach involved the synthesis of a conjugate based on a chlorin-e6 photosensitizer and a derivative of the tyrosine kinase inhibitor cabozantinib, linked by a ß-glucuronidase-responsive linker. Upon activation by ß-glucuronidase, which is overproduced in various tumors and localized in lysosomes, this conjugate released both therapeutic modules within targeted cells. This activation was accompanied by the recovery of its fluorescence and the generation of reactive oxygen species. Investigation of photodynamic and dark toxicity in vitro revealed that the novel conjugate had an excellent safety profile and was able to inhibit tumor cells proliferation at submicromolar concentrations. Additionally, combined therapy effects were also observed in 3D models of tumor growth, demonstrating synergistic suppression through the activation of both photodynamic and targeted therapy.

Plier Ligands for Trapping Neurotransmitters into Complexes for Sensitive Analysis by SERS Spectroscopy.

Catecholamines-dopamine, noradrenaline and adrenaline are important biomarkers of neurotransmitter metabolism, indicating neuroendocrine tumors and neurodegenerative diseases. Surface-enhanced Raman spectroscopy (SERS) is a promising analytical technique with unprecedented multiplexing capabilities. However, not all important analytes exhibit strong SERS signals on stable and robust nanostructured substrates. In this work, we propose a novel indicator system based on the formation of mixed ligand complexes with bispidine-based bis-azole ligands which can serve as pliers to trap Cu(II) ions and stabilize its complexes with catecholamines. Four synthesized ligands with different functional groups: carboxyl, amino, benzyl, and methoxybenzyl, were applied for forming stable complexes to shift maximum absorbance of catecholamines from the ultraviolet region to 570-600 nm. A new absorbance band in the visible range resonates with the local surface plasmon resonance (LSPR) band of metal nanoparticles and most used laser wavelengths. This match allowed use of Molecular Immobilization and Resonant Raman Amplification by Complex-Loaded Enhancers (MIRRACLE) methodology to measure intense Raman signals on a nanostructured silver-based SERS-active substrate. The synthesized plier-like ligands fixed and stabilized catecholamine complexes with Cu(II) on the SERS sensor surface, which facilitated the determination of dopamine in a 3.2 × 10-12-1 × 10-8 M concentration range.

The main protease 3CLpro of the SARS-CoV-2 virus: how to turn an enemy into a helper.

Despite the long history of use and the knowledge of the genetics and biochemistry of E. coli, problems are still possible in obtaining a soluble form of recombinant proteins in this system. Although, soluble protein can be obtained both in the cytoplasm and in the periplasm of the bacterial cell. The latter is a priority strategy for obtaining soluble proteins. The fusion protein technology followed by detachment of the fusion protein with proteases is used to transfer the target protein into the periplasmic space of E. coli. We have continued for the first time to use the main viral protease 3CL of the SARS-CoV-2 virus for this purpose. We obtained a recombinant 3CL protease and studied its complex catalytic properties. The authenticity of the resulting recombinant enzyme, were confirmed by specific activity analysis and activity suppression by the known low-molecular-weight inhibitors. The catalytic efficiency of 3CL (0.17 ± 0.02 µM-1-s-1) was shown to be one order of magnitude higher than that of the widely used tobacco etch virus protease (0.013 ± 0.003 µM-1-s-1). The application of the 3CL gene in genetically engineered constructs provided efficient specific proteolysis of fusion proteins, which we demonstrated using the receptor-binding domain of SARS-CoV-2 spike protein and GST fusion protein. The solubility and immunochemical properties of RBD were preserved. It is very important that in work we have shown that 3CL protease works effectively directly in E. coli cells when co-expressed with the target fusion protein, as well as when expressed as part of a chimeric protein containing the target protein, fusion partner, and 3CL itself. The results obtained in the work allow expanding the repertoire of specific proteases for researchers and biotechnologists.

Development of an LC-MS/MS-based method for quantification and pharmacokinetics study on SCID mice of a dehydroabietylamine-adamantylamine conjugate, a promising inhibitor of the DNA repair enzyme.

Earlier, it was found that the agent KS-389, a conjugate of dehydroabietylamine and 1-aminoadamantane, possess inhibiting activity with regard to Tdp1. It this study, LC-MS/MS-based methods of quantification of KS-389 in mice blood and several organs (brain, liver and kidney) were developed and validated. Validation of the methods was performed according to the guidelines of U.S. Food and Drug Administration and European Medicines Agency in terms of selectivity, linearity, accuracy, precision, recovery, matrix effect, stability and carry-over. Dried blood spots (DBS) method was used for blood sample preparation. HPLC separation was performed on a reversed-phase column; the total analysis time was 12 min. Mass spectral detection was performed on a 6500 QTRAP mass spectrometer in multiple reaction monitoring mode. Transitions 463.5→135.1/107.2 and 336.2→332.2/176.2 were scanned for KS-389 and 2,5-bis(4-diethylaminophenyl)-1,3,4-oxadiazole used as the internal standard, respectively. Pharmacokinetics of the compound as well as its distribution in the organs were studied on SCID mice after intraperitoneal administration of the substance at a dose of 5 mg/kg, and it was found that its maximum concentration in blood is reached in 1-1.5 h and was 80 ng/mL. The maximum concentration in all organs is reached after the same time and is approximately 1500 ng/g and 1100 ng/g in liver and kidney, respectively. This is the first report on the pharmacokinetics of Tdp1 inhibitor based on dehydroabietylamine and 1-aminoadamantane after a single administration to mice. Also, the substance was found to be able to penetrate the blood-brain barrier which is important for, and its maximum concentration was c.a. 25-30 ng/g. These results are important for glioma treatment and make it promising for this purpose.

Corrigendum: The main protease 3CLpro of the SARS-CoV-2 virus: how to turn an enemy into a helper.

[This corrects the article DOI: 10.3389/fbioe.2023.1187761.].

syn-3-(4-Chloro-benz-yl)-1,5-dimethyl-3,7-diaza-bicyclo-[3.3.1]nonan-9-ol.

In the title compound, C(16)H(23)ClN(2)O, both six-membered rings adopt chair conformations, thus allowing the formation of an intra-molecular N-H⋯N hydrogen bond. In the crystal, adjacent mol-ecules are combined into chains running along the ac diagonal via O-H⋯N hydrogen bonds.

Structure-Property Relationships of Dibenzylidenecyclohexanones.

A series of symmetrical dibenzylidene derivatives of cyclohexanone were synthesized with the goal of studying the physicochemical properties of cross-conjugated dienones (ketocyanine dyes). The structures of the products were established and studied by X-ray diffraction, NMR spectroscopy, and electronic spectroscopy. All products had the E,E-geometry. The oxidation and reduction potentials of the dienones were determined by cyclic voltammetry. The potentials were shown to depend on the nature, position, and number of substituents in the benzene rings. A linear correlation was found between the difference of the electrochemical oxidation and reduction potentials and the energy of the long-wavelength absorption maximum. This correlation can be employed to analyze the properties of other compounds of this type. The frontier orbital energies and the vertical absorption and emission transitions were calculated using quantum chemistry. The results are in good agreement with experimental redox potentials and spectroscopic data.