Константин Кудрявцев | Lomonosov Moscow State University (original) (raw)
Papers by Константин Кудрявцев
Molecules, 2021
Sortase A (SrtA) of Staphylococcus aureus has been identified as a promising target to a new type... more Sortase A (SrtA) of Staphylococcus aureus has been identified as a promising target to a new type of antivirulent drugs, and therefore, the design of lead molecules with a low nanomolar range of activity and suitable drug-like properties is important. In this work, we aimed at identifying new fragment-sized starting points to design new noncovalent S. aureus SrtA inhibitors by making use of the dedicated molecular motif, 5-arylpyrrolidine-2-carboxylate, which has been previously shown to be significant for covalent binding SrtA inhibitors. To this end, an in silico approach combining QSAR and molecular docking studies was used. The known SrtA inhibitors from the ChEMBL database with diverse scaffolds were first employed to derive descriptors and interpret their significance and correlation to activity. Then, the classification and regression QSAR models were built, which were used for rough ranking of the virtual library of the synthetically feasible compounds containing the dedicat...
Химико-фармацевтический журнал, 2021
В обзоре приведены данные о функциях ферментов сортаз и их субстратов — поверхностных белков, и и... more В обзоре приведены данные о функциях ферментов сортаз и их субстратов — поверхностных белков, и их роли в патогенезе таких инфекционных заболеваниях, как пневмония, инфекционный эндокардит, инфекционный артрит, мастит, заболевания кожи и желудочно-кишечного тракта. Значимость сортаз и поверхностных белков в патогенезе данных заболеваний описана на животных моделях. Приведены данные о перспективных ингибиторах сортаз – натуральных и синтетических, как возможных соединений для лечения инфекционных заболеваний.
Экспериментальная и клиническая фармакология, 2019
Сердечно-сосудистые заболевания остаются ведущей причиной смертности и инвалидизации, что диктует... more Сердечно-сосудистые заболевания остаются ведущей причиной смертности и инвалидизации, что диктует необходимость углубленного изучения их патогенеза и разработки мер лечения и профилактики. Основой современной терапии артериальной гипертензии и других сердечно-сосудистых заболеваний является постулат о необходимости коррекции дисфункции эндотелия как показателя адекватности антигипертензивного и других видов лечения. Фактически это означает, что снижение артериального давления (АД) без нормализации функции эндотелия не может считаться успешно решенной клинической задачей. Однако в настоящее время не существует препаратов для специфической фармакологической коррекции метаболического пути L-аргинин — eNOS — оксид азота, нарушения которого являются универсальным и основополагающим триггерным механизмом инициализации каскада метаболических нарушений, ведущих к артериальной гипертензии и другим заболеваниям сердечно-сосудистой системы. Аргиназы 1 и 2, NOX1 и NOX2 оксидазы как изоформы НАД...
Tetrahedron, 2014
ABSTRACT A library of saturated bridged heterocycles based on 3,6-diazabicyclo[3.2.1]octane-2,4-d... more ABSTRACT A library of saturated bridged heterocycles based on 3,6-diazabicyclo[3.2.1]octane-2,4-dione and bispidine scaffolds (mean compound molecular weight is approximately 300 Da) with up to three stereocenters and four diversity points has been synthesized. Synthetic scaffold modifications leading to an increase in molecular complexity were studied. Well-defined stereochemical structures of both compound sets was confirmed by X-ray studies and halogenoaryl substituents were inserted appropriately for the design of novel non-basic serine protease inhibitors. Comprehensive molecular modeling has been performed for all synthesized compounds giving rationales of ligand–enzyme interactions with thrombin and trypsin. Biological testing confirmed moderate inhibitory activity of halogen-substituted saturated diazabicyclic small molecules towards thrombin.
Angewandte Chemie International Edition, 2013
ABSTRACT Rainbow of pyrrolidines: Red, orange, yellow, green, blue (indigo, violet).
Химико-фармацевтический журнал, 2021
Уменьшение адгезии золотистого стафилококка предоставляет дополнительные возможности для профилак... more Уменьшение адгезии золотистого стафилококка предоставляет дополнительные возможности для профилактики и терапии инфекционных заболеваний, вызываемых, в том числе, резистентными штаммами. В настоящей работе с использованием оптической микроскопии исследовано взаимодействие штамма S. aureus АТСС 29213 и эпителиальных эукариотических клеток и установлены низкомолекулярные органические соединения класса 5-арилпирролидин-2-карбоксилатов, индуцирующие снижение адгезии бактериальных клеток к клеткам Vero. Рацемический метил (2S*,4S*,5R*)-4-(гидроксиметил)-1-метил-5-(2-фтор-5-метоксифенил)пирролидин-2-карбоксилат вызывает статистически значимое ингибирование адгезии типового штамма S. aureus и характеризуется отсутствием цитотоксичности в отношении как эукариотических клеток линии Vero, так и изученного штамма S. aureus.
Tetrahedron, 2014
A library of saturated bridged heterocycles based on 3,6-diazabicyclo[3.2.1]octane-2,4-dione and ... more A library of saturated bridged heterocycles based on 3,6-diazabicyclo[3.2.1]octane-2,4-dione and bispidine scaffolds (mean compound molecular weight is approximately 300 Da) with up to three stereocenters and four diversity points has been synthesized. Synthetic scaffold modifications leading to an increase in molecular complexity were studied. Well-defined stereochemical structures of both compound sets was confirmed by X-ray studies and halogenoaryl substituents were inserted appropriately for the design of novel non-basic serine protease inhibitors. Comprehensive molecular modeling has been performed for all synthesized compounds giving rationales of ligandeenzyme interactions with thrombin and trypsin. Biological testing confirmed moderate inhibitory activity of halogen-substituted saturated diazabicyclic small molecules towards thrombin.
Chemistry, an Asian journal, 2015
Functionalized oligomeric organic compounds with well-defined β-proline scaffold have been synthe... more Functionalized oligomeric organic compounds with well-defined β-proline scaffold have been synthesized by a cycloadditive oligomerization approach in racemic and enantiopure forms. The structure of the novel β-peptides was investigated by NMR spectroscopic and X-ray methods determining the conformational shapes of the β-proline oligomers in solution and solid states. The main structural elements subject to conformational switches are β-peptide bonds between 5-arylpyrrolidine-2-carboxylic acid units existing in Z/E configurations. The whole library of short β-peptides and intermediate acrylamides has been tested on antiproliferative activity towards the hormone-refractory prostate cancer cell line PC-3 revealing several oligomeric compounds with low micromolar and submicromolar activities. Bromine-substituted dimeric and trimeric acrylamides induced caspase-dependent apoptosis of PC-3 cells through cell-cycle arrest and mitochondrial damage.
A reaction of racemoc methyl 4-oxo-2-phthalimidobutanoate, diethyl aminomalonate, and phenyl viny... more A reaction of racemoc methyl 4-oxo-2-phthalimidobutanoate, diethyl aminomalonate, and phenyl vinyl sulfone in the presence AgOAc occurred stereospecifically to form tetrasubstituted pyrrolidine including structural elements of all three initial compounds. The relative stereochemistry of the asymmetrical carbon atoms in the molecule was established by XRD analysis, and it coincided with two stereogenic centers in the left part of kaitocephalin molecule. Therefore the developed three-component process can be recommended for an effective total synthesis of kaitocephalin.
The Scientific World Journal, 2014
This study was designed to determine novel small-molecule agents influencing the pathogenesis of ... more This study was designed to determine novel small-molecule agents influencing the pathogenesis of gastric lesions induced by stress. To achieve this goal, four novel organic compounds containing structural fragments with known antioxidant activity were synthesized, characterized by physicochemical methods, and evaluated in vivo at water immersion restraint conditions. The levels of lipid peroxidation products and activities of antioxidative system enzymes were measured in gastric mucosa and correlated with the observed gastroprotective activity of the active compounds. Prophylactic single-dose 1 mg/kg treatment with (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline efficiently decreases up to 86% stress-induced stomach ulceration in rats. Discovered small-molecule antiulcer agents modulate activities of gastric mucosa tissue superoxide dismutase, catalase, and xanthine oxidase in concerted directions. Gastroprotective effect of (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline at least partially depends on the correction of gastric mucosa oxidative balance.
Journal of Biomedical Science, 2015
Background: Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is ... more Background: Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is a major obstacle in clinical treatment. An approach to inhibit HRPC growth and ultimately to kill cancers is highly demanded. Results: KUD773 induced the anti-proliferative effect and subsequent apoptosis in PC-3 and DU-145 (two HRPC cell lines); whereas, it showed less active in normal prostate cells. Further examination showed that KUD773 inhibited tubulin polymerization and induced an increase of mitotic phosphoproteins and polo-like kinase 1 (PLK1) phosphorylation, indicating a mitotic arrest of the cell cycle through an anti-tubulin action. The kinase assay demonstrated that KUD773 inhibited Aurora A activity. KUD773 induced an increase of Cdk1 phosphorylation at Thr 161 (a stimulatory phosphorylation site) and a decrease of phosphorylation at Tyr 15 (an inhibitory phosphorylation site), suggesting the activation of Cdk1. The data were substantiated by an up-regulation of cyclin B1 (a Cdk1 partner). Furthermore, KUD773 induced the phosphorylation and subsequent down-regulation of Bcl-2 and activation of caspase cascades.
![Research paper thumbnail of Synthesis of bridged heterocycles from cis-pyrrolidine-2,4-dicarboxylic acids: I. 3,6-Diazabicyclo[3.2.1]octanes](https://attachments.academia-assets.com/40473041/thumbnails/1.jpg)
](Russian Journal of Organic Chemistry, 2010
cis-5-Arylpyrrolidine-2,4-dicarboxylic acid monoamides undergo thermal intramolecular condensatio... more cis-5-Arylpyrrolidine-2,4-dicarboxylic acid monoamides undergo thermal intramolecular condensation with formation of bicyclic imides having a 3,6-diazabicyclo[3.2.1]octane skeleton. The use of copper(I) cyanide as catalyst ensures high yields of 3,6-diazabicyclo[3.2.1]octane-2,4-diones substituted at the 3-, 5-, 6-, and 7-positions. (1R*,5R*,7S*)-7-(4-Chlorophenyl)-5,6-dimethyl-3,6-diazabicyclo[3.2.1]octane-2,4-dione was found to inhibit thrombin in a buffer solution at a millimolar concentration.
Russian Journal of Organic Chemistry, 2006
Molecules, 2021
Sortase A (SrtA) of Staphylococcus aureus has been identified as a promising target to a new type... more Sortase A (SrtA) of Staphylococcus aureus has been identified as a promising target to a new type of antivirulent drugs, and therefore, the design of lead molecules with a low nanomolar range of activity and suitable drug-like properties is important. In this work, we aimed at identifying new fragment-sized starting points to design new noncovalent S. aureus SrtA inhibitors by making use of the dedicated molecular motif, 5-arylpyrrolidine-2-carboxylate, which has been previously shown to be significant for covalent binding SrtA inhibitors. To this end, an in silico approach combining QSAR and molecular docking studies was used. The known SrtA inhibitors from the ChEMBL database with diverse scaffolds were first employed to derive descriptors and interpret their significance and correlation to activity. Then, the classification and regression QSAR models were built, which were used for rough ranking of the virtual library of the synthetically feasible compounds containing the dedicat...
Химико-фармацевтический журнал, 2021
В обзоре приведены данные о функциях ферментов сортаз и их субстратов — поверхностных белков, и и... more В обзоре приведены данные о функциях ферментов сортаз и их субстратов — поверхностных белков, и их роли в патогенезе таких инфекционных заболеваниях, как пневмония, инфекционный эндокардит, инфекционный артрит, мастит, заболевания кожи и желудочно-кишечного тракта. Значимость сортаз и поверхностных белков в патогенезе данных заболеваний описана на животных моделях. Приведены данные о перспективных ингибиторах сортаз – натуральных и синтетических, как возможных соединений для лечения инфекционных заболеваний.
Экспериментальная и клиническая фармакология, 2019
Сердечно-сосудистые заболевания остаются ведущей причиной смертности и инвалидизации, что диктует... more Сердечно-сосудистые заболевания остаются ведущей причиной смертности и инвалидизации, что диктует необходимость углубленного изучения их патогенеза и разработки мер лечения и профилактики. Основой современной терапии артериальной гипертензии и других сердечно-сосудистых заболеваний является постулат о необходимости коррекции дисфункции эндотелия как показателя адекватности антигипертензивного и других видов лечения. Фактически это означает, что снижение артериального давления (АД) без нормализации функции эндотелия не может считаться успешно решенной клинической задачей. Однако в настоящее время не существует препаратов для специфической фармакологической коррекции метаболического пути L-аргинин — eNOS — оксид азота, нарушения которого являются универсальным и основополагающим триггерным механизмом инициализации каскада метаболических нарушений, ведущих к артериальной гипертензии и другим заболеваниям сердечно-сосудистой системы. Аргиназы 1 и 2, NOX1 и NOX2 оксидазы как изоформы НАД...
Tetrahedron, 2014
ABSTRACT A library of saturated bridged heterocycles based on 3,6-diazabicyclo[3.2.1]octane-2,4-d... more ABSTRACT A library of saturated bridged heterocycles based on 3,6-diazabicyclo[3.2.1]octane-2,4-dione and bispidine scaffolds (mean compound molecular weight is approximately 300 Da) with up to three stereocenters and four diversity points has been synthesized. Synthetic scaffold modifications leading to an increase in molecular complexity were studied. Well-defined stereochemical structures of both compound sets was confirmed by X-ray studies and halogenoaryl substituents were inserted appropriately for the design of novel non-basic serine protease inhibitors. Comprehensive molecular modeling has been performed for all synthesized compounds giving rationales of ligand–enzyme interactions with thrombin and trypsin. Biological testing confirmed moderate inhibitory activity of halogen-substituted saturated diazabicyclic small molecules towards thrombin.
Angewandte Chemie International Edition, 2013
ABSTRACT Rainbow of pyrrolidines: Red, orange, yellow, green, blue (indigo, violet).
Химико-фармацевтический журнал, 2021
Уменьшение адгезии золотистого стафилококка предоставляет дополнительные возможности для профилак... more Уменьшение адгезии золотистого стафилококка предоставляет дополнительные возможности для профилактики и терапии инфекционных заболеваний, вызываемых, в том числе, резистентными штаммами. В настоящей работе с использованием оптической микроскопии исследовано взаимодействие штамма S. aureus АТСС 29213 и эпителиальных эукариотических клеток и установлены низкомолекулярные органические соединения класса 5-арилпирролидин-2-карбоксилатов, индуцирующие снижение адгезии бактериальных клеток к клеткам Vero. Рацемический метил (2S*,4S*,5R*)-4-(гидроксиметил)-1-метил-5-(2-фтор-5-метоксифенил)пирролидин-2-карбоксилат вызывает статистически значимое ингибирование адгезии типового штамма S. aureus и характеризуется отсутствием цитотоксичности в отношении как эукариотических клеток линии Vero, так и изученного штамма S. aureus.
Tetrahedron, 2014
A library of saturated bridged heterocycles based on 3,6-diazabicyclo[3.2.1]octane-2,4-dione and ... more A library of saturated bridged heterocycles based on 3,6-diazabicyclo[3.2.1]octane-2,4-dione and bispidine scaffolds (mean compound molecular weight is approximately 300 Da) with up to three stereocenters and four diversity points has been synthesized. Synthetic scaffold modifications leading to an increase in molecular complexity were studied. Well-defined stereochemical structures of both compound sets was confirmed by X-ray studies and halogenoaryl substituents were inserted appropriately for the design of novel non-basic serine protease inhibitors. Comprehensive molecular modeling has been performed for all synthesized compounds giving rationales of ligandeenzyme interactions with thrombin and trypsin. Biological testing confirmed moderate inhibitory activity of halogen-substituted saturated diazabicyclic small molecules towards thrombin.
Chemistry, an Asian journal, 2015
Functionalized oligomeric organic compounds with well-defined β-proline scaffold have been synthe... more Functionalized oligomeric organic compounds with well-defined β-proline scaffold have been synthesized by a cycloadditive oligomerization approach in racemic and enantiopure forms. The structure of the novel β-peptides was investigated by NMR spectroscopic and X-ray methods determining the conformational shapes of the β-proline oligomers in solution and solid states. The main structural elements subject to conformational switches are β-peptide bonds between 5-arylpyrrolidine-2-carboxylic acid units existing in Z/E configurations. The whole library of short β-peptides and intermediate acrylamides has been tested on antiproliferative activity towards the hormone-refractory prostate cancer cell line PC-3 revealing several oligomeric compounds with low micromolar and submicromolar activities. Bromine-substituted dimeric and trimeric acrylamides induced caspase-dependent apoptosis of PC-3 cells through cell-cycle arrest and mitochondrial damage.
A reaction of racemoc methyl 4-oxo-2-phthalimidobutanoate, diethyl aminomalonate, and phenyl viny... more A reaction of racemoc methyl 4-oxo-2-phthalimidobutanoate, diethyl aminomalonate, and phenyl vinyl sulfone in the presence AgOAc occurred stereospecifically to form tetrasubstituted pyrrolidine including structural elements of all three initial compounds. The relative stereochemistry of the asymmetrical carbon atoms in the molecule was established by XRD analysis, and it coincided with two stereogenic centers in the left part of kaitocephalin molecule. Therefore the developed three-component process can be recommended for an effective total synthesis of kaitocephalin.
The Scientific World Journal, 2014
This study was designed to determine novel small-molecule agents influencing the pathogenesis of ... more This study was designed to determine novel small-molecule agents influencing the pathogenesis of gastric lesions induced by stress. To achieve this goal, four novel organic compounds containing structural fragments with known antioxidant activity were synthesized, characterized by physicochemical methods, and evaluated in vivo at water immersion restraint conditions. The levels of lipid peroxidation products and activities of antioxidative system enzymes were measured in gastric mucosa and correlated with the observed gastroprotective activity of the active compounds. Prophylactic single-dose 1 mg/kg treatment with (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline efficiently decreases up to 86% stress-induced stomach ulceration in rats. Discovered small-molecule antiulcer agents modulate activities of gastric mucosa tissue superoxide dismutase, catalase, and xanthine oxidase in concerted directions. Gastroprotective effect of (2-hydroxyphenyl)thioacetyl derivatives of L-lysine and L-proline at least partially depends on the correction of gastric mucosa oxidative balance.
Journal of Biomedical Science, 2015
Background: Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is ... more Background: Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is a major obstacle in clinical treatment. An approach to inhibit HRPC growth and ultimately to kill cancers is highly demanded. Results: KUD773 induced the anti-proliferative effect and subsequent apoptosis in PC-3 and DU-145 (two HRPC cell lines); whereas, it showed less active in normal prostate cells. Further examination showed that KUD773 inhibited tubulin polymerization and induced an increase of mitotic phosphoproteins and polo-like kinase 1 (PLK1) phosphorylation, indicating a mitotic arrest of the cell cycle through an anti-tubulin action. The kinase assay demonstrated that KUD773 inhibited Aurora A activity. KUD773 induced an increase of Cdk1 phosphorylation at Thr 161 (a stimulatory phosphorylation site) and a decrease of phosphorylation at Tyr 15 (an inhibitory phosphorylation site), suggesting the activation of Cdk1. The data were substantiated by an up-regulation of cyclin B1 (a Cdk1 partner). Furthermore, KUD773 induced the phosphorylation and subsequent down-regulation of Bcl-2 and activation of caspase cascades.
Russian Journal of Organic Chemistry, 2010
cis-5-Arylpyrrolidine-2,4-dicarboxylic acid monoamides undergo thermal intramolecular condensatio... more cis-5-Arylpyrrolidine-2,4-dicarboxylic acid monoamides undergo thermal intramolecular condensation with formation of bicyclic imides having a 3,6-diazabicyclo[3.2.1]octane skeleton. The use of copper(I) cyanide as catalyst ensures high yields of 3,6-diazabicyclo[3.2.1]octane-2,4-diones substituted at the 3-, 5-, 6-, and 7-positions. (1R*,5R*,7S*)-7-(4-Chlorophenyl)-5,6-dimethyl-3,6-diazabicyclo[3.2.1]octane-2,4-dione was found to inhibit thrombin in a buffer solution at a millimolar concentration.
Russian Journal of Organic Chemistry, 2006