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.

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.

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.

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.

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.

Herpes simplex virus type 1 (HSV-1) is an extremely widespread pathogen characterized by recurrent infections. HSV-1 most commonly causes painful blisters or sores around the mouth or on the genitals, but it can also cause keratitis or, rarely, encephalitis. First-line and second-line antiviral drugs used to treat HSV infections, acyclovir and related compounds, as well as foscarnet and cidofovir, selectively inhibit herpesvirus DNA polymerase (DNA-pol). It has been previously found that (S)-4-[6-(purin-6-yl)aminohexanoyl]-7,8-difluoro-3,4-dihydro-3-methyl-2H-[1,4]benzoxazine (compound 1) exhibits selective anti-herpesvirus activity against HSV-1 in cell culture, including acyclovir-resistant mutants, so we consider it as a lead compound. In this work, the selection of HSV-1 clones resistant to the lead compound was carried out. High-throughput sequencing of resistant clones and reference HSV-1/L2 parent strain was performed to identify the genetic determinants of the virus’s resistance to the lead compound. We identified a candidate mutation presumably associated with resistance to the virus, namely the T321I mutation in the UL15 gene encoding the large terminase subunit. Molecular modeling was used to evaluate the affinity and dynamics of the lead compound binding to the putative terminase binding site. The results obtained suggest that the lead compound, by binding to pUL15, affects the terminase complex. pUL15, which is directly involved in the processing and packaging of viral DNA, is one of the crucial components of the HSV terminase complex. The loss of its functional activity leads to disruption of the formation of mature virions, so it represents a promising drug target. The discovery of anti-herpesvirus agents that affect biotargets other than DNA polymerase will expand our possibilities of targeting HSV infections, including those resistant to baseline drugs.

A new group of charge-compensated nido-carboranyl derivatives of sulfur-containing amino acids and biotin has been synthesized in which the boron atom in position 9 or 10 of carborane is attached to a positively charged sulfur atom. The possibilities of obtaining symmetrical B(10)-substituted and asymmetric B(9)-substituted nido-carboranes were studied. Using the example of (S)-methionine and D-biotin derivatives, water-soluble S-substituted charge-compensated nido-carboranes with free functional groups were prepared. The results obtained open up prospects for the development of potential boron delivery agents for BNCT as well as new bioactive compounds containing a negatively charged nido-carboranyl fragment bearing a positive charge on the sulfur atom associated with the boron cluster.

A series of (2S,4S)-4-amino-N-arylpyroglutamic acids was first obtained by the nucleophilic substitution of bromine atom in dimethyl (2S,4RS)-4-bromo-N-phthaloylglutamate under the action of primary arylamines, followed by the separation of diastereomers and removal of protecting groups by acidic hydrolysis. These compounds were studied for anti-platelet and antithrombotic activity in experiments in vitro and in vivo. Some compounds were identified as exhibiting a significant effect on platelet function, which was manifested in slowing down the process of thrombus formation in the model of arterial and deep vein thrombosis. It was established that the most efficient compound is (2S,4S)-4-amino-N-(4-fluoro-phenyl)pyroglutamic acid, with its effect being comparable to that of acetylsalicylic acid.

Short peptides containing the Arg-Gly-Asp (RGD) fragment can selectively bind to integrins on the surface of tumor cells and are attractive transport molecules for the targeted delivery of therapeutic and diagnostic agents to tumors (for example, glioblastoma). We have demonstrated the possibility of obtaining the N- and C-protected RGD peptide containing 3-amino-closo-carborane and a glutaric acid residue as a linker fragment. The resulting carboranyl derivatives of the protected RGD peptide are of interest as starting compounds in the synthesis of unprotected or selectively protected peptides, as well as building blocks for preparation of boron-containing derivatives of the RGD peptide of a more complex structure.

The dipeptide glycyl-( S )-5-hydroxynorvaline was obtained from 1- tert -butyl 5-methyl N -Boc-glycyl-( S )-glutamate via saponification, reduction of the activated 5-carboxy group with sodium borohydride, removal of the N -Boc and OBu t protecting groups by refluxing in aqueous dioxane. Using the example of the synthesis of ( S )-5-hydroxynorvaline, it was shown that the used sequence of chemical transformations is not accompanied by racemization.