Light-induced rearrangement from macrocyclic to bicyclic lactam: A case study of -chlorinated laurolactam.

Converting macrocycle lactams into bicyclic lactams is proposed as an additional way to further increase the metabolic stability of peptide-based drugs. Unfortunately, the synthesis of bicyclic lactams has to start almost from scratch. This study explores the Hofmann-Löffler-Freytag (HLF) reaction mechanism and products as a potential late-stage functionalisation strategy for facile conversion of macrocyclic to bicyclic ring.

Nanoplastics increase oestrogenic activity of neurotherapeutic drugs.

Environmental pollution with plastic nanoparticles (PNPs) has rendered hazard assessment of unintentional human exposure to neurotherapeutic drugs through contaminated water and food ever more complicated. Due to their small size, PNPs can easily enter different cell types and cross different biological barriers, while their high surface-to-volume ratio enables higher adsorption of chemicals. This is how PNPs take the role of a Trojan horse as they enhance bioaccumulation of many different pollutants.

Regioselective Rearrangement of Nitrogen- and Carbon-Centered Radical Intermediates in the Hofmann-Löffler-Freytag Reaction.

The Hofmann-Löffler-Freytag (HLF) reaction serves as a late-stage functionalization technique for generating pyrrolidine heterocyclic ring systems. Contemporary HLF protocols utilize in situ halogenated sulfonamides as precursors in the radical-mediated rearrangement cycle. Despite its well-established reaction mechanism, experiments toward the detection of radical intermediates using EPR techniques have only recently been attempted.

Synthesis and Biological Evaluations of Granulatamide B and its Structural Analogues.

Background: While granulatamides A and B have been previously isolated, their biological activities have been only partially examined. The aim of this study was to synthesize granulatamide B (4b), a tryptamine-derivative naturally occurring in coral species, using the well-known procedure of Sun and Fürstner and its 12 structural analogues by modifying the side chain, which differs in length, degree of saturation as well as number and conjugation of double bonds.

Methods: The prepared library of compounds underwent comprehensive assessment for their biological activities, encompassing antioxidative, antiproliferative, and antibacterial properties, in addition to toxicity evaluation using a Zebrafish model.

Ferrocenoyl-adenines: substituent effects on regioselective acylation.

A series of -substituted adenine-ferrocene conjugates was prepared and the reaction mechanism underlying the synthesis was explored. The S2-like reaction between ferrocenoyl chloride and adenine anions is a regioselective process in which the product ratio (7/9-ferrocenoyl isomers) is governed by the steric property of the substituent at the -position. Steric effects were evaluated by using Charton (empirical) and Sterimol (computational) parameters.

Transformation of L-DOPA and Dopamine on the Surface of Gold Nanoparticles: An NMR and Computational Study.

Gold nanoparticles (AuNPs) have found applications in biomedicine as diagnostic tools, but extensive research efforts have been also directed toward their development as more efficient drug delivery agents. The high specific surface area of AuNPs may provide dense loading of molecules like catechols (L-DOPA and dopamine) on nanosurfaces, enabling functionalization strategies for advancing conventional therapy and diagnostic approaches of neurodegenerative diseases. Despite numerous well-described procedures in the literature for preparation of different AuNPs, possible transformation and structural changes of surface functionalization agents have not been considered thoroughly.

Electronic Coupling in 1,2,3-Triazole Bridged Ferrocenes and Its Impact on Reactive Oxygen Species Generation and Deleterious Activity in Cancer Cells.

Mixed-valence (MV) binuclear ferrocenyl compounds have long been studied as models for testing theories of electron transfer and in attempts to design molecular-scale electronic devices (., molecular wires). In contrary to that, far less attention has been paid to MV binuclear ferrocenes as anticancer agents.

Fate and transformation of silver nanoparticles in different biological conditions.

The exploitation of silver nanoparticles (AgNPs) in biomedicine represents more than one third of their overall application. Despite their wide use and significant amount of scientific data on their effects on biological systems, detailed insight into their in vivo fate is still lacking. This study aimed to elucidate the biotransformation patterns of AgNPs following oral administration.

Combined NMR and Computational Study of Cysteine Oxidation during Nucleation of Metallic Clusters in Biological Systems.

The widespread biomedical applications of silver and gold nanoparticles (AgNPs and AuNPs, respectively) prompt the need for mechanistic evaluation of their interaction with biomolecules. In biological media, metallic NPs are known to transform by various pathways, especially in the presence of thiols. The interplay between metallic NPs and thiols may lead to unpredictable consequences for the health status of an organism.

Ionization Energy and Reduction Potential in Ferrocene Derivatives: Comparison of Hybrid and Pure DFT Functionals.

Hybrid density functionals have been regularly applied in state-of-the-art computational models for predicting reduction potentials. Benchmark calculations of the absolute reduction potential of ferricenium/ferrocene couple, the IUPAC-proposed reference in nonaqueous solution, include the B3LYP/6-31G(d)/LanL2TZf protocol. We used this procedure to calculate ionization energies and reduction potentials for a comprehensive set of ferrocene derivatives.

Toxicity and safety study of silver and gold nanoparticles functionalized with cysteine and glutathione.

This study was designed to evaluate the nano-bio interactions between endogenous biothiols (cysteine and glutathione) with biomedically relevant, metallic nanoparticles (silver nanoparticles (AgNPs) and gold nanoparticles (AuNPs)), in order to assess the biocompatibility and fate of nanoparticles in biological systems. A systematic and comprehensive analysis revealed that the preparation of AgNPs and AuNPs in the presence of biothiols leads to nanoparticles stabilized with oxidized forms of biothiols. Their safety was tested by evaluation of cell viability, reactive oxygen species (ROS) production, apoptosis induction and DNA damage in murine fibroblast cells (L929), while ecotoxicity was tested using the aquatic model organism .

Transacylation in Ferrocenoyl-Purines. NMR and Computational Study of the Isomerization Mechanism.

In the reaction of purines with ferrocenoyl chloride in dimethylformamide (DMF), a regioselective acylation occurred. The two products have been isolated and, according to detailed NMR analysis, identified as - and -ferrocenoylated isomers. In a more polar solvent, for example, in dimethylsulfoxide (DMSO), the two isomers interconvert to each other.

Luminescent pyrenyl-GNA nucleosides: synthesis, photophysics and confocal microscopy studies in cancer HeLa cells.

Glycol nucleic acids (GNA) are synthetic genetic-like polymers with an acyclic three-carbon propylene glycol phosphodiester backbone. Here, synthesis, luminescence properties, circular dichroism (CD) spectra, and confocal microscopy speciation studies of (R,S) and (S,R) pyrenyl-GNA (pyr-GNA) nucleosides are reported in HeLa cells. Enantiomerically pure nucleosides were obtained by a Sharpless asymmetric dihydroxylation reaction followed by semi-preparative high-performance liquid chromatography (HPLC) separation using Amylose-2 as the chiral stationary phase.

Chlorination of 5-fluorouracil: Reaction mechanism and ecotoxicity assessment of chlorinated products.

What happens to drugs in the chlorinating environment? Degradation products may vary in pharmacological profiles and in ecotoxicity potentials compared to the parent compound. This study combines synthesis, NMR spectroscopy, quantum chemical calculations, and toxicity experiments on Daphnia magna to investigate chemical fate of antineoplastic drug 5-fluorouracil (5-FU) in chlorinated environment, which is common in waste-water treatment procedures, but also endogenous in activated neutrophils. A reduction of toxicity (EC after 48 h is 50% higher than for the parent 5-FU) was observed after the first chlorination step, in which a chlorohydrin 5-chloro-5-fluoro-6-hydroxy-5,6-dihydrouracil was formed.

Ferrocenyl GNA Nucleosides: A Bridge between Organic and Organometallic Xeno-nucleic Acids.

The enantioselective synthesis and electrochemistry of the first ferrocenyl GNA nucleosides is reported. These compounds were obtained by a Sharpless asymmetric dihydroxylation reaction of [3-(N1-thyminyl)-1-(ferrocenyl)]propene as S,R and R,S enantiomers in about 70 % yield with enantiomeric excesses of >99 % and 71 %, respectively. The absolute configurations of the chiral carbon atoms in the nucleosides were assigned by single-crystal X-ray diffraction analysis of the methyl derivatives in the solid state.

Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M -Lactamase.

A series of six novel metallocenyl-7-ADCA (metallocenyl = ferrocenyl or ruthenocenyl; 7-ADCA = 7-aminodesacetoxycephalosporanic acid) conjugates were synthesized and their antibacterial properties evaluated by biochemical and microbiological assays. The ruthenocene derivatives showed a higher level of inhibition of DD-carboxypeptidase 64-575, a Penicillin Binding Protein (PBP), than the ferrocene derivatives and the reference compound penicillin G. Protein X-ray crystallographic analysis revealed a covalent acyl-enzyme complex of a ruthenocenyl compound with CTX-M β-lactamase E166A mutant, corresponding to a similar complex with PBPs responsible for the bactericidal activities of these compounds.

1,1'-Bis(thymine)ferrocene Nucleoside: Synthesis and Study of Its Stereoselective Formation.

The synthesis of 1,1'-bis(thymine)ferrocene nucleoside is reported. This nucleoside was obtained in a two-step synthetic methodology including a Michael addition reaction of 1,1'-bis(3-chloropropionyl)ferrocene with thymine to afford the bis(thymine) adduct in 44 % yield. In the second step, the two prochiral carbonyl functionalities in the Michael adduct were reduced to hydroxyl groups with sodium borohydride.

Cymantrene, Cyrhetrene and Ferrocene Nucleobase Conjugates: Synthesis, Structure, Computational Study, Electrochemistry and Antitrypanosomal Activity.

A series of 11 cymantrene and cyrhetrene nucleobase conjugates, together with the hitherto unreported N7 isomer of a ferrocene-adenine conjugate were synthesised and characterised. The synthetic approach involved a Michael addition reaction of in-situ-generated acryloylcymantrene, acryloylcyrhetrene and acryloylferrocene with the canonical nucleobases thymine, uracil and adenine. The mechanism of these reactions was investigated by means of density functional theory calculations.

A quantum chemical study of HOCl-induced transformations of carbamazepine.

The antiepileptic drug carbamazepine (CBZ) is one of the most persistent pharmaceuticals in the environment. Its chemical fate is influenced by the type of wastewater treatment. This study sets out to determine the degradation mechanism and products in the reaction between CBZ and hypochlorous acid (HOCl), which is the main chlorinating species in water.

A computational study of the chlorination and hydroxylation of amines by hypochlorous acid.

The reactions of hypochlorous acid (HOCl) with ammonia, (di)methylamine, and heterocyclic amines have been studied computationally using double-hybrid DFT methods (B2PLYP-D and BK-PLYP) and a G3B3 composite scheme. In the gas phase the calculated energy barriers for N- and/or C-hydroxylation are ca. 100 kJ mol(-1) lower than the barrier for N-chlorination of amines.

The stability of nitrogen-centered radicals.

Radical stabilization energies (RSEs) for a wide variety of nitrogen-centered radicals and their protonated counterparts have been calculated at G3(MP2)-RAD and G3B3 level. The calculated RSE values can be rationalized through the combined effects of resonance delocalization of the unpaired spin, electron donation through adjacent alkyl groups or lone pairs, and through inductive electron donation/electron withdrawal. The influence of ring strain effects as well as the synergistic combination of individual substituent effects (captodatively stabilized N-radicals) have also been explored.

Chlorination of N-methylacetamide and amide-containing pharmaceuticals. Quantum-chemical study of the reaction mechanism.

Chlorination of amides is of utmost importance in biochemistry and environmental chemistry. Despite the huge body of data, the mechanism of reaction between amides and hypochlorous acid in aqueous environment remains unclear. In this work, the three different reaction pathways for chlorination of N-methylacetamide by HOCl have been considered: the one-step N-chlorination of the amide, the chlorination via O-chlorinated intermediate, and the N-chlorination of the iminol intermediate.

The chemical fate of paroxetine metabolites. Dehydration of radicals derived from 4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine.

Quantum chemical calculations have been used to model reactions which are important for understanding the chemical fate of paroxetine-derived radicals in the environment. In order to explain the experimental observation that the loss of water occurs along the (photo)degradation pathway, four different mechanisms of radical-induced dehydrations have been considered. The elimination of water from the N-centered radical cation, which results in the formation of an imine intermediate, has been calculated as the most feasible process.

Prereactive complexes in chlorination of benzene, triazine, and tetrazine: a quantum chemical study.

In order to perform a complete search for prereactive complexes between arenes and chlorine, the stochastic search method was employed. Stationary points are optimized at B3LYP, M05-2X, and MP2 levels, while improved energetics are calculated using the B2PLYP-D method, which includes corrections important for accurate description of dispersion forces. New intermediates were located and their mechanistic relevance has been discussed.