A simple and effective method was proposed for the synthesis of new phosphinic peptides in free form, structural isosteres of the dipeptide components of beta-amyloid (Aβ42), potential inhibitors of zinc-metalloproteinases.

The synthesis of a phosphinic structural analogue of the tetrapeptide Met-Glu-γ-His-Phe by adding the dipeptide component His-Phe to the adamantyl ester of the phosphinic pseudo-Met-[P]-Glu-peptide in the form of cyclic glutamate anhydride is proposed. The conditions for the interaction of phosphinic pseudo-Met-[P]-Glu-anhydride with His-Phe in free form to form phosphinic Met-[P]-Glu-γ-His-Phe tetrapeptide have been found. A chromatographic mass-spectrometry study, including MS2, and NMR of the phosphinic tetrapeptide on 1H, 13C, 31P nuclei was carried out using the methods of two-dimensional 1H–1H COSY, 1H–13C HSQC and 1H–13C HMBC NMR spectroscopy.

The reaction between dialkyl methylenebiscarbamates and phosphonous carboxylic acids affords N-protected phosphinic pseudopeptides incorporating glycine isostere. The compounds obtained are promising building blocks for subsequent peptide modification.

The amidoalkylation of a phosphonous acid containing a structural isostere of diethyl glutamiate, using ethyl carbamate and 3-(methylthio)propionaldehyde, was proposed for the synthesis of NC(O)OEt-protected phosphinic pseudo-Met-Glu-peptide. Subsequent adamantyl protection of the phosphorylic function and hydrolysis of carboxylic groups made it possible to obtain phosphinic Met-[P]-Glu peptide in the form of cyclic glutamate anhydride. It was found that the latter reacts with the third amino acid component histidine to form the phosphinic Met-[P]-Glu-γ-His tripeptide.

A comparative study of samarium-153 complexation with several phosphonate ligands (acyclic and cyclen-based) was carried out. Methods of quality control of the resulting complexes were proposed, and their biological behavior was determined. It is noted that the biological behavior of the radionuclide compound is the principal criterion for choosing it as an active pharmaceutical substance for the development of radiopharmaceuticals.

An unusual greater reactivity of phosphonous propionic acids was found in comparison with phosphonous propionic esters in carbamate version of Kabachnik-Fields reaction. Compounds of tricoordinated phosphorus generated in situ during the amidoalkylation of hydrophosphorylic compounds in acetyl chloride/acetic anhydride mixture were found by 31P NMR analysis. A hypothesis is proposed about the generation of spirophosphoranes in situ to explain the mechanism for the formation of the phosphorus-carbon bond in the reaction under study.

BACKGROUND:Treatment of neurodegenerative diseases, such as Parkinson's disease, Huntington's chorea, Alzheimer's disease, is one of the priority directions in modern medicine. Thus, search and production of new physiologically active substances for the treatment of neurodegenerative disorders is one of the most important tasks for organic chemistry. The approach based on the replacement of a peptide bond in a peptide molecule with a structural isostere, non-hydrolyzable methylene phosphoryl fragment makes it possible to increase the metabolic stability of peptide molecules to the destructive action of peptidases. METHODS:This work is devoted to the approbation of a new synthetic approach to the production of physiologically active substances in a series of peptide-type compounds with activity by replacing the peptide bond with isosteric methylene-phosphoryl fragment with the preservation of the original amino acid sequence. RESULTS:A phosphine analog of the known physiologically active tripeptide proline-glycine-proline was obtained, cytotoxicity and neuroprotective properties of the initial tripeptide and its phosphine analog were studied. CONCLUSION:Preliminary biological tests have shown that the obtained phosphine analog of the proline-glycine-proline tripeptide is involved in modulating the formation of sediments in the cellular system of proteinopathy, which may indicate their potential antiaggregatory properties.

Two new aminodiphosphonic acids derived from salicylic acid and its phosphonic analogue were prepared through a simple and efficient synthesis. 2-[(2-Amino-2,2-diphosphono)ethyloxy]-benzoic acid 8 and 2-[(2-amino-2,2-diphosphono)ethyloxy]-5-ethyl-phenylphosphonic acid 9 were evaluated for their applicability as 68Ga binding bone-seeking agents. Protonation constants of 8 and 9 and stability constants of the Ga3+ complexes with 8 and 9 in water were determined. The stability constant of Ga3+ complex with fully phosphorylated acid 9 (logKGaL = 31.92 ± 0.32) significantly exceeds stability constant of Ga3+ complex with 8 (logKGaL = 26.63 ± 0.24). Ligands 8 and 9 are as effective for Ga3+ cation binding as ethylenediamine-N,N’-diacetic-N,N’-bis(methy1enephosphonic) acid and ethylenediamine-N,N,N’,N’-tetrakis(methylenephosphonic) acid, respectively. The labelling process and stability of [68Ga]Ga-8 and [68Ga]Ga-9 were studied. Both 8 and 9 readily form 68Ga-complexes stable to ten-fold dilution with saline. However, in fetal bovine serum, only [68Ga]Ga-9 was stable enough to be subject to biological evaluation. It was injected into rats with bone pathology and aseptic inflammation of soft tissues. For [68Ga]Ga-9 in animals with a bone pathology model in 60 and 120 min after injection, a slight accumulation in the pathology site, stable blood percentage level, and moderate accumulation in the liver were observed. For animals with an aseptic inflammation, the accumulation of [68Ga]Ga-9 in the pathology site was higher than that in animals with bone pathology. Moreover, the accumulation of [68Ga]Ga-9 in inflammation sites was more stable than that for [68Ga]Ga-citrate. The percentage of [68Ga]Ga-9 in the blood decreased from 3.1% ID/g (60 min) to 1.5% ID/g (120 min). Accumulation in the liver was comparable to that obtained for [68Ga]Ga-citrate.

Racemic phosphinic tripeptide 1 pyrrolidin-2-yl-{3-[(2-hydroxycarbonyl)-pyrrolidin-1-yl]-3-oxo-propyl}-phosphinic acid has been synthesized, its high resistance toward leucine aminopeptidase, carboxypeptidase Y, and the enzyme system of rat brain membranes has been shown. In vitro experiments with using Semax synthetic peptide have shown that the effect of tripeptide 1 on the hydrolysis rate of Semax in the case of leucine aminopeptidase and carboxypeptidase Y is minimal. In experiments using the enzyme system of rat brain membranes, the decrease of the rate of Semax hydrolysis has been more evident.

В данной работе представлены результаты исследования биоактивных наночастиц силиката магния. Сами наночастицы получали методом химического осаждения в водной среде. Размер и форму образцов исследовали на ПЭМ-микроскопе. Установлено, что поверхность образцов представлена крупными агрегатами. В свою очередь, агрегаты состоят из сферических наночастиц силиката магния с размерами от 10 до 20 нм. На следующем этапе, с помощью нейросетевой обработки экспериментальных данных проводили оптимизацию синтеза наночастиц. Анализ полученной тернарной поверхности показал, что для получения образцов с наименьшим размером агрегатов (700 нм) параметрами синтеза являются: температура – 50 °С, скорость перемешивания – 600 об/мин, концентрация прекурсора – 0,5 моль/л. Определив оптимальные параметры синтеза силиката магния, проводили компьютерное квантово-химическое моделирование. В результате расчетов обнаружено, что энергия конфигурации составила E = –709,302 ккал/моль, величина химической жесткости η = 0,191 эВ, а мягкости – S = 2,62 эВ–1. На основе полученных данных можно заключить, что MgSiO3 обладает высокой стабильностью и характеризуется, как относительно мягкая молекула. На заключительном этапе работы образцы исследовали на ИК-спектрометре. Анализ ИК-спектра показал наличие характерных полос поглощения, которые соответствуют колебаниям связей в молекуле MgSiO3.

Phosphinic isosteres of leucylglycine and isoleucylglycine were obtained by amidoalkylation of (3-benzyloxy-3-oxopropyl)phosphonous acid bearing the structural isostere fragment of glycine benzyl ester in acetyl chloride. A three-component amide version of the Kabachnik–Fields reaction involving methyl (benzyl) carbamates and 2(3)-methylbutanals was studied. The reaction proceeded under the conditions of acylation of the starting (3-benzyloxy-3-oxopropyl)phosphonous acid and in situ generation of a bisacetyl derivative of the three-coordinated phosphorus, the formation of which was detected using NMR 31Р.

The amidoalkylation reactions of a phosphonous acid containing a structural isostere of leucine in acetyl chloride and(or) acetic anhydride were studied under conditions of acid catalysis. A two-component method for the synthesis of a phosphinic analogue of alanylleucine using ethylidenebis(benzylcarbamate) was proposed.

The binding of 68 Ga to two organic ligands containing aminodiphosphonic groups (1,7-diamino-4-oxaheptane-1,1,7,7-tetraphosphonic and 1,7-diamino-4-hydroxycarbonylheptane-1,1,7,7-tetraphosphonic acids) has been examined. The stability and osteotropic potential of the labeled compounds have been evaluated.

A general method for the synthesis of symmetric bis(ω-cyanoalkyl)phosphinic acids from ammonium hypophosphite was proposed. The reaction of bis(trimethylsilyl)hypophosphite generated in situ with the ω-bromoalkylnitrile molecule according to the Arbuzov reaction and the subsequent silylation of the hydrophosphoryl intermediate leads to the formation of bis(trimethylsilyl)phosphonite. The latter reacts with the second ω-haloalkylnitrile molecule by the Arbuzov reaction with the formation of the second phosphorus-carbon bond.

An acid-catalyzed three-component reaction between hypophosphorous acid, aldehydes and alkyl carbamates under mild conditions afforded bis(α-aminoalkyl)phosphinic acids. The proposed facile single-stage protocol is prospective for expansion of a range of phosphinic analogues of HIV protease inhibitors.

A general method for the synthesis of phosphonic aminocarboxylic acids combining aminodiphosphonic and amino acid functions in one molecule was developed. Amino acids of a new type are AP-acids analogs, which are ligands of glutamate receptors that determine the processes of information transmission and processing in the central nervous system, and can also be promising compounds as new components of radiopharmaceuticals.

Methods of synthesis of phosphonic aminocarboxylic acids, ω-phosphonic analogs of monoaminodicarboxylic acids, are reviewed. Many of such compounds are ligands of ionotropic and metabotropic glutamate receptors determining the phenomenon of information processing and communication in central nervous system, important in view of prevention and treatment of Alzheimer, Huntington, and Parkinson diseases and other socially important neurodegenerative and psychoneurological diseases as well as learning and memory processes.