The review summarizes data on the synthesis methods and properties of 4-amino-5-oxoproline derivatives, including those with substituents at the amino and/or carboxyl group, carbon skeleton atoms, as well as peptides incorporating a 4-amino-5-oxoproline fragment. Particular attention is paid to the synthesis methods of the individual stereoisomers of derivatives of this amino acid, which serve as starting materials for constructing more complex structures such as peptidomimetics, etc. 4-Amino-5-oxoproline derivatives exhibit a variety of biological activities: antitumor, immunomodulatory, psychotropic, etc., and are of interest for the development of new therapeutic agents based on them.

A method for the preparation of asymmetric disulfides containing 1,2-dicarba-closo-dodecaborane and (R)-cysteine residues was developed. The approach to creating the S-S bond is based on the interaction of thiols with thiosulfonates and makes possible the targeted synthesis of unsymmetrical disulfides based on natural molecules, starting from readily available reagents that are stable to the action of moisture and atmospheric oxygen. We demonstrated that cysteine and glutathione conjugates containing a (closo-carboranyl)acetic acid moiety attached via a cysteamine residue and a disulfide bridge can be obtained using either a strategy based on the use of acid-labile protecting groups or an approach that involves creating a disulfide bond in an aqueous medium without using protecting groups. The proposed approach opens up broad prospects for chemoselective functionalization of compounds containing thiol groups, which can be used in the design of new agents for boron neutron capture therapy and related modalities.

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis and is one of the most dangerous and socially significant diseases. The growth and expanding spectrum of drug resistance of M. tuberculosis makes it necessary to design new anti-tuberculosis pharmaceuticals with alternative mechanism of action. In this study, original synthetic routes to the novel conjugates of closo- and nido-carboranes and monoterpenes (geraniol, nerol, and citronellol) attached via linkers were proposed. Monoterpene derivatives were obtained starting from closo- and nido-carborane-containing building blocks with carboxyl or chloroethyl groups. The structures of all synthesized molecules were confirmed by 1H, 13C and 11B NMR, and ESI–MS. Antimycobacterial activity of the synthesized compounds against the standard drug-sensitive laboratory strain M. tuberculosis H37Rv using the REMA method was assessed. It has been found that nido-carborane conjugates with monoterpene residues attached via an ethylenediamine linker exhibit weak inhibitory activity against the M. tuberculosis H37Rv strain in in vitro experiments; amides of (closo-carboran-1-yl)acetic acid containing monoterpene residues did not exhibit antimycobacterial activity. The developed method can be applied to obtain various bioactive nido-carborane derivatives.

Derivatives of natural amino acids are selectively absorbed by many types of tumour cells. This makes the use of amino acids, especially polyfunctional ones, attractive as a basis in the design of low-toxicity agents for targeted boron delivery for boron neutron capture therapy (BNCT) of tumours. We synthesized a series of new (S)-ornithine and (S)-lysine derivatives containing a 7,8-dicarba-nido-undecaborane (nido-carborane) residue attached to the amino group in the side chain or alpha position. The MTT assay demonstrated moderate cytotoxicity of the lysine and ornithine derivatives containing a nido-carborane residue in the side chain. It has been found that sodium salt of Nε-(nido-carboran-7-yl)acetyl-(S)-lysine is capable of accumulation by MDA-MB-231 (human breast carcinoma) and SK-Mel 28 (human melanoma) cell lines, providing a boron concentration of up to 0.67 µg/106 cells in in vitro experiments. This (S)-lysine derivative containing a nido-carborane residue in the side chain can be considered as a promising compound for in-depth study in vivo experiments aimed at designing an efficient boron delivery agent for BNCT.

A method for the synthesis of new glycerol esters containing both one or two 1,2-dicarba-closo-dodecaborane (ortho-carborane) clusters and natural fatty acid (stearic and palmitic) fragments has been developed. Carborane moieties were attached to the glycerol hydroxy groups via omega-amino acid residues. Synthesis of carboranecontaining lipid analogues containing up to 19 wt.% boron has been carried out using readily available building blocks. It has been shown that ortho-carborane-containing mono- and diglycerides have a tendency to isomerization as a result of intramolecular migration of the acyl fragment. The isomeric composition was determined by 1H and 13C NMR spectroscopy, as well as by HPLC. The developed preparation method for triglycerides containing 10 or 20 boron atoms per molecule can be used to obtain various carborane-containing lipid analogues. The synthesized compounds are of interest as a potential basis for boron-enriched liposomes and micelles for use in BNCT or PBCT.

The mechanism of the reaction of 7,8-dicarba-nido-undecaborane potassium salt with thioethers was studied for the first time within the framework of the electron density functional theory. The regiospecifity of the reactions involving dimethyl sulfide and methyl S-methyl-N-trifluoroacetyl-(R)-cysteinate at position B(10) of nido-carborane was substantiated by quantum chemical calculations. Evidence was obtained that the reaction of 7,8-dicarba-nido-undecaborane potassium salt with S-nucleophiles proceeded more actively in the presence of mercury(ii) chloride. The structure was optimized and the energies of intermediates were calculated at the final Toluene-CPCM-B3LYP-D3-gCP/def2-TZVP (Hg LANL2TZ) level of the theory. It was found that the key step of the reaction is the synchronous process of the B(10)—S bond formation and the hydrogen abstraction from the B(10) vertex proceeding with the participation of the mercury atom from the nido-carborane-based intermediate π-complex.

A benefit of biomedical application of nanosystems is implementation of a precise effect at the level of an individual cell, and magnetic nanoparticles (MNPs) are some of the best candidates for the development of an intelligent nanosystem with remote control. To develop a nanosystem for precise therapy, a deep understanding of the nanosystem's in vivo behavior is required. Here, we studied penetration and distribution of PEGylated iron oxide MNPs unmodified or modified with the pH low insertion peptide (a ligand for smart targeting of the tumor acidic microenvironment) in vivo in a 4T1 mouse tumor. We revealed that MNPs penetrate into the tumor via both vascular burst and endothelial transcytosis. By implementing an approach based on single-cell high-throughput RNA sequencing, we identified the populations of the cells that took up MNPs in the 4T1 tumor and revealed preferential accumulation of MNPs in regulatory Trem2+ tumor-associated macrophages.

The purpose of this research is to design nanocomposite materials for biomedical applications. New conjugates of PEG derivatives of RGD peptides and magnetic nanoparticles, based on Fe3O4 (MNPs) with silica coating covalently labelled with fluorescent dye Cyanine5, were obtained. It was shown that a higher loading level of RGD peptides occurred in the case of MNPs with SiO2/aminopropylsilane coating, synthesised using N-(phosphonomethyl)iminodiacetic acid (PMIDA) as a surfactant. To confirm the structure and chemical purity of the new RGD-PEG conjugate, a number of methods were used, including 1H NMR, HRMS, and RP-HPLC. The characterisation of MNPs was carried out using the following physical methods: TEM, FTIR, EDX, CHN analysis, DLS, fluorescence spectrometry, vibration magnetometry, and relaxometry. Samples obtained from PMIDA-stabilised MNPs contained a greater amount of the peptide and possessed better hydrodynamic characteristics than samples obtained from non-stabilised MNPs. A comparative study of the MNP cytotoxicity was carried out towards 4T1 and MDA-MB231 cell lines (MTT test), and the possibility of cell labelling was assessed. The cellular uptake was more efficient for nanoconjugates obtained without PMIDA. The data obtained can be used for the design of materials for cell labelling and visualisation.

Amino acids with unusual types of chirality and their derivatives have recently attracted attention as precursors in the synthesis of chiral catalysts and peptide analogues with unique properties. In this study, we have synthesized a new nido-carborane-based planar-chiral amino acid, in the molecule of which the amino group is directly bonded to the B(3) atom, and the carboxyl group is attached to the B(9) atom through the CH2S+(Me) fragment. 3-Amino-9-dimethylsulfonio-nido-carborane, prepared in three steps from 3-amino-closo-carborane in a high yield, was a key intermediate in the synthesis of the target planar-chiral amino acid. The carboxymethyl group at the sulfur atom was introduced by the demethylation reaction of the dimethylsulfonio derivative, followed by S-alkylation. The structure of new 3,9-disubstituted nido-carboranes was studied for the first time using NMR spectroscopy. The resonances of all boron atoms in the 11B NMR spectrum of 3-amino-9-dimethylsulfonio-nido-carborane were assigned based on the 2D NMR correlation experiments. The nido-carborane-based planar-chiral amino acid and related compounds are of interest as a basis for peptide-like compounds and chiral ligands.

Synthesis of new nido-carborane-containing 6-thiopurines and thioguanines based on nucleophilic substitution of the chlorine atom in the specially synthesized chloroacetyl derivative of 3-amino-nido-carborane by the action of 6-thiopurine or thioguanine in the presence of sodium hydride in ethanol was developed. The resulting 6-thiopurine derivatives containing a nido-carborane moiety and unsubstituted at the position 9 are of interest as potential biologically active compounds, boron delivery agents to tumor cells, and as the basis for nido-carborane-containing nucleosides.

Peptides of the RGD family are of significant interest as vectors for targeted delivery of various therapeutic and diagnostic groups to tumor cells. Their application can be especially useful in the implementation of boron neutron capture therapy (BNCT) of malignant tumors. We have developed a method for obtaining derivatives of the lysine–arginine–glycine–aspartic acid (KRGD) peptide containing two closo‑ or nido‑carborane fragments linked to a lysine residue. It has been shown that to obtain bis(closo‑carboranyl) KRGD peptide with free functional groups, it is preferable to use protecting groups that can be removed under mild acidic conditions. Deboronation of the peptide containing closo‑carborane residues made it possible to obtain a bis(nido‑carboranyl) tetrapeptide containing 20 wt.% boron and having high solubility in water (up to 5 mg/mL). In vitro experiments demonstrated the low cytotoxicity of the KRGD peptide containing two nido‑carborane residues (CC50 > 100 μmol/L). The developed synthetic approach to KRGD derivatives containing 18–20 boron atoms per molecule opens the way to potential boron delivery agents for BNCT.

Abstract—Carriers of herpes simplex virus type 1 (HSV-1) account for more than 90

A comparative study of the kinetic resolution of racemic 6-methoxy-, 6-nitro-, and 6-chloro-3-methyl-3,4-dihydro-2H-[1,4]benzoxazines with (S)-naproxen acyl chloride, N-phthaloyl-(S)-leucyl chloride, and O-phenyl-(R)-lactyl chloride was carried out. The selectivity factors in the kinetic resolution of racemic amines with (S)-naproxen acyl chloride and O-phenyl-(R)-lactyl chloride were higher compared to N-phthaloyl-(S)-leucyl chloride. The factors responsible for the stereodifferentiation in the kinetic resolution of racemic dihydrobenzoxazines containing groups with different electronic properties were explained based on DFT calculations. Stacking interactions between aromatic moieties in the transition state were demonstrated to play a key role in the stereodifferentiation.

Sorption of doxorubicin (Dox) on Fe3O4 magnetic nanoparticles coated with iron and silicon glycerolates (ISG-MNPs) was studied. The Dox sorption experiments were carried out in water at different concentrations of ISG-MNPs and Dox. The loading efficiency was assessed by UV spectroscopy. It was demonstrated that at an ISG-MNPs concentration of 0.2 wt.

Alkylation of 9-methylthio-nido-carborane under the action of the corresponding iodo derivatives of alanine and homoalanine furnished new (nido-carboran-9-yl) derivatives of (R)-cysteine and (S)-methionine. The synthesized chiral nido-carborane derivatives contain asymmetric carbon and sulfur atoms, as well as a chiral plane. The developed approach to the synthesis of sulfur-containing B(9)-substituted nido-carborane derivatives can be used in the preparation of bioactive compounds, including potential boron delivery agents for boron neutron capture therapy of oncological diseases.

Individual ( S )-enantiomers of 6-methoxy-, 6-chloro-, and 6-nitro-3-methyl-3,4-di-hydro-2 H -[1,4]benzoxazines were synthesized via an acylative kinetic resolution of race-mates using ( S )-naproxen acyl chloride as a diastereoselective chiral resolving agent. The acylation of racemic benzoxazines with ( S )-naproxen acyl chloride afforded ( S,S )-dia-stereomers of amides as the major products, which were isolated in diastereomerically pure form (>99% de ) by the recrystallization or flash column chromatography on silica gel. The acidic hydrolysis of ( S,S )-amides gave ( S )-enantiomers (>99% ee according to chiral HPLC) of 6-substituted 3-methyl-3,4-dihydro-2 H -[1,4]benzoxazines. The ( R )-enantiomer of 3-methyl-6-nitro-3,4-dihydro-2 H -[1,4]benzoxazine (>99% ee ) was prepared by the stoichiometric acylation of a scalemic sample with ( S )-naproxen acyl chloride followed by the recrystallization of the ( R , S )-amide and subsequent acidic hydrolysis. The configuration assignment of the chiral centers in the synthesized benzoxazines was made based on the X-ray diffraction analysis of the corresponding amides. The synthesized enantio-merically pure 6-substituted 3-methylbenzoxazines can be used in the synthesis of biologically active compounds.

The architecture of a nanoparticles' surface formed due to a modification with a ligand and protein corona formation in biofluids is critical for interactions with cells in vivo. Here we studied interactions of immune cells with magnetic nanoparticles (MNPs) covalently modified with polyethylene glycol (PEG) and their counterparts conjugated with peptides: a pH (low) insertion peptide (pHLIP) and cycloRGD as a targeting ligand in human serum. The conjugation of MNPs-PEG with pHLIP, but not with cycloRGD, enhanced the association of these particles with mononuclear phagocytic cells in vitro and in vivo. We did not find a clear difference in protein corona composition between the pHLIP-modified and parental PEGylated nanoparticles. Analysis of the effect of autologous human serum on MNP uptake by monocytes showed that the efficiency of endocytosis varies among healthy donors and depends on intrinsic properties of serum. Nevertheless, using classic blood, coagulation, biochemical tests, and anti-PEG IgG serum level, we failed to identify the cause of the observed interdonor variation. These individual differences should be taken into consideration during testing of nanotherapeutics.

A series of novel derivatives of d -biotin containing closo - and nido -carborane residues bound to the biotin carbonyl group either directly or via a linker were synthesized. The possibility of synthesizing a d -biotin conjugate containing two closo -carborane moieties and a glutamic acid residue was shown. The obtained compounds are of interest for biological testing as potential boron delivery agents for the boron neutron capture therapy of tumors.

Stereospecific reactions of dimethyl (2 S ,4 RS )-4-bromo- N -phthaloylglutamate with KOH, triethylamine, and piperidine affording dimethyl ( Z )-1-phthalimidocyclopropane-1,2-dicarboxylate were studied in terms of the density functional theory. The two-stage E1cB mechanism of HBr elimination involving the formation of an intermediate carban-ion upon deprotonation at the C(2) atom was established by the nudged elastic band method. Calculations of the reactions with all bases, carried out with inclusion of the solvent effect using ethanol as the model solvent, demonstrated that the E1cB mechanism of 1,3-elimination of HBr is more preferable than the S N 2 mechanism of nucleophilic substitution of bromine at the C(4) atom. Contrary to this, calculations of the reaction with piperidine using benzene as the model solvent revealed that the S N 2 mechanism is slightly more preferable than the ElcB one. High stereoselectivity of the 1,3-elimination of bromine with respect to the ( Z )-isomer is due to noncovalent repulsive interactions between the methoxycarbonyl groups in the transition state leading from the carbanion to the minor ( E )-diastereomer of 1-phthalimidocyclopropane-1,2-dicarboxylic acid.

Testing a number of N-[omega-(purin-6-yl)aminoalkanoyl] derivatives of 7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine in a panel of nine tumor cell lines has shown that the studied compounds exhibit high cytotoxic activity, especially against 4T1 murine mammary carcinoma, COLO201 human colorectal adenocarcinoma, SNU-1 human gastric carcinoma, and HepG2 human hepatocellular carcinoma cells. Synthesis and study of structural analogs of these compounds made it possible to find that the presence of both a difluorobenzoxazine fragment and a purine residue bound via a linker of a certain length is crucial for the manifestation of the cytotoxic activity of this group of compounds. The study of the effect of the most promising compound on the cell cycle of the human tumor cell lines, the most sensitive and least sensitive to cytotoxic action (MDA-MB-231 breast adenocarcinoma and COLO201 colorectal adenocarcinoma, respectively), allows us to conclude that this compound is an inhibitor of DNA biosynthesis. The found group of purine conjugates may be of interest in the design of new antitumor agents.