I. Nosulenko, M. S. Kazunin, A. O. Kinichenko, O. Antypenko, L. Zhurakhivska, O. Voskoboinik, S. Kovalenko, Інна Степанівна Носуленко, Максим Станіславович Казунін, Анна Олександрівна Кініченко, Олексій Миколайович Антипенко, Олексій Юрійович Воскобойнік, С.И. Коваленко
Aim. To the purposeful search for the DHFR-inhibitors among substituted pteridine-2,4,7-triones and 7-aryl-(hetaryl-)furo[3,2- g ]pteridine-2,4(1 H ,3 H )-diones for further biological re-search. Methods. In vitro methods, molecular docking, SAR-analysis, statistical methods. Results. The DHFR-inhibitory activity of substituted 1-methylpteridine-2,4,7-triones ( 2 , 3 , 4 ) and 7-aryl-(hetaryl-)furo[3,2- g ]pteridine-2,4(1 H ,3 H )-diones ( 5 , 6 ) was studied. It was estab-lished that 6-(2-hydroxy-2-aryl-(hetaryl-)ethyl)-1-methylpteridine-2,4,7(1 H ,3 H ,8 H )-triones ( 3 ) and butyl 2-(7-aryl- (hetaryl-)-1-methyl-2,4-dioxo-1,4-dihydrofuro[3,2- g ]pteridine-3(2 H )-yl)acetates ( 6 ) inhibited DHFR by 14.59–52.11 %, and were less active comparing to methotrexate. It was found that the introduction of aryl moiety with electron-accepting group, naphthyl substituent or electron-accepting heterocycle (furan, thiophene and benzofuran) caused an increase in the DHFR-inhibitory activity. Additionally, it was shown, that annulation of the furan cycle to the pteridine system was reasonable in the scope of new DHFR-inhibitors synthesis. Thereby it may be concluded that the calculated values of affinity are not reliable predictors for the DHFR-inhibiting activity of studied compound. However, the molecular docking study may be used for evaluation of the interactions between the studied inhibitor and active center of DHFR. Conclusions. The conducted primary in vitro screening revealed low or moderate DHFR-inhibiting activity of the synthesized compounds. The visualization of molecular docking showed that despite the structural similarity to methotrexate, the obtained compounds form different ligand-enzyme interactions. The calculated values of affinity cannot be used as predictors of DHFR-inhibiting activity because of the absence of correlation between the abovementioned indicators. The obtained compounds may be of interest for further studies aimed at the search for anti-inflammatory, anti-viral, hypoglycemic, hypotensive, anti-ische mic agents due to the expected low-toxicity associated with the slight DHFR-inhibiting activity.
{"title":"Dihydrofolate reductase inhibitors among pteridine and fu-ro[3,2-g]pteridine derivatives","authors":"I. Nosulenko, M. S. Kazunin, A. O. Kinichenko, O. Antypenko, L. Zhurakhivska, O. Voskoboinik, S. Kovalenko, Інна Степанівна Носуленко, Максим Станіславович Казунін, Анна Олександрівна Кініченко, Олексій Миколайович Антипенко, Олексій Юрійович Воскобойнік, С.И. Коваленко","doi":"10.7124/BC.000A51","DOIUrl":"https://doi.org/10.7124/BC.000A51","url":null,"abstract":"Aim. To the purposeful search for the DHFR-inhibitors among substituted pteridine-2,4,7-triones and 7-aryl-(hetaryl-)furo[3,2- g ]pteridine-2,4(1 H ,3 H )-diones for further biological re-search. Methods. In vitro methods, molecular docking, SAR-analysis, statistical methods. Results. The DHFR-inhibitory activity of substituted 1-methylpteridine-2,4,7-triones ( 2 , 3 , 4 ) and 7-aryl-(hetaryl-)furo[3,2- g ]pteridine-2,4(1 H ,3 H )-diones ( 5 , 6 ) was studied. It was estab-lished that 6-(2-hydroxy-2-aryl-(hetaryl-)ethyl)-1-methylpteridine-2,4,7(1 H ,3 H ,8 H )-triones ( 3 ) and butyl 2-(7-aryl- (hetaryl-)-1-methyl-2,4-dioxo-1,4-dihydrofuro[3,2- g ]pteridine-3(2 H )-yl)acetates ( 6 ) inhibited DHFR by 14.59–52.11 %, and were less active comparing to methotrexate. It was found that the introduction of aryl moiety with electron-accepting group, naphthyl substituent or electron-accepting heterocycle (furan, thiophene and benzofuran) caused an increase in the DHFR-inhibitory activity. Additionally, it was shown, that annulation of the furan cycle to the pteridine system was reasonable in the scope of new DHFR-inhibitors synthesis. Thereby it may be concluded that the calculated values of affinity are not reliable predictors for the DHFR-inhibiting activity of studied compound. However, the molecular docking study may be used for evaluation of the interactions between the studied inhibitor and active center of DHFR. Conclusions. The conducted primary in vitro screening revealed low or moderate DHFR-inhibiting activity of the synthesized compounds. The visualization of molecular docking showed that despite the structural similarity to methotrexate, the obtained compounds form different ligand-enzyme interactions. The calculated values of affinity cannot be used as predictors of DHFR-inhibiting activity because of the absence of correlation between the abovementioned indicators. The obtained compounds may be of interest for further studies aimed at the search for anti-inflammatory, anti-viral, hypoglycemic, hypotensive, anti-ische mic agents due to the expected low-toxicity associated with the slight DHFR-inhibiting activity.","PeriodicalId":9017,"journal":{"name":"Biopolymers & Cell","volume":"4 1","pages":"143-152"},"PeriodicalIF":0.0,"publicationDate":"2021-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81255141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
O. Kholodniak, V. Stavytskyi, M. S. Kazunin, N. Bukhtiyarova, G. Berest, I. Belenichev, S. Kovalenko, Олена Валеріївна Холодняк, Віктор Валерійович Ставицький, Максим Станіславович Казунін, Ніна Вікторівна Бухтіярова, Галина Григорівна Берест, Ігор Федорович Бєленічев, С.И. Коваленко
Aim. A targeted search for anticonvulsant agents among unknown diacylthiosemicarbazides with the analysis of the structure-activity relationship (SAR-analysis). Methods. Organic synthesis; molecular docking; spectral methods; pentylenetetrazole convulsions, statistical methods. Results. A strategy of search for new anticonvulsant agents among unknown diacylthiosemicarbazides has been developed. It included virtual-oriented screening towards [the] active centers of enzymes and sodium channels that underlie the mechanism of antiepileptic drugs activity. The synthesis of diacylthiosemicarbazides was carried out by the in situ method, namely, accomplishing the interaction of cycloalkanecarbonyl chlorides with ammonium isothiocyanate and the subsequent nucleophilic addition of cycloalkyl- (aralkyl-, aryl-, hetaryl-) carboxylic acid hydrazides. The peculiarities of the structure of the synthesized compounds were confirmed by spectral methods (LCMS and 1 H NMR spectra). Biological screening showed that diacylthiosemicarbazides ( 2 ) in the experimental model of pentylenet-erazole seizures in rats increased the latency period of seizures by 2.77–7.82 times, reduced the duration of tonic-clonic seizures by 1.23–5.59 minutes and prevented mortality by 30–60 %, relative to the control group of animals. It was shown that diacylthiosemicarbazides ( 2.6 , 2.15 , 2.22 , 2.18 ) with cyclopropane- or cyclopentanecarboxamide groups show the anticonvulsant activity that exceeds that of the reference drug Depakine or competes with it. Conclusions. A range of new diacylthiosemicarbazides were obtained and the primary screening of their anticonvulsant activity was performed, the SAR-analysis was provided, and the hit-compound was identified for further in-depth pharmacological studies.
{"title":"Design, synthesis and anticonvulsant activity of new Diacylthiosemicarbazides","authors":"O. Kholodniak, V. Stavytskyi, M. S. Kazunin, N. Bukhtiyarova, G. Berest, I. Belenichev, S. Kovalenko, Олена Валеріївна Холодняк, Віктор Валерійович Ставицький, Максим Станіславович Казунін, Ніна Вікторівна Бухтіярова, Галина Григорівна Берест, Ігор Федорович Бєленічев, С.И. Коваленко","doi":"10.7124/BC.000A46","DOIUrl":"https://doi.org/10.7124/BC.000A46","url":null,"abstract":"Aim. A targeted search for anticonvulsant agents among unknown diacylthiosemicarbazides with the analysis of the structure-activity relationship (SAR-analysis). Methods. Organic synthesis; molecular docking; spectral methods; pentylenetetrazole convulsions, statistical methods. Results. A strategy of search for new anticonvulsant agents among unknown diacylthiosemicarbazides has been developed. It included virtual-oriented screening towards [the] active centers of enzymes and sodium channels that underlie the mechanism of antiepileptic drugs activity. The synthesis of diacylthiosemicarbazides was carried out by the in situ method, namely, accomplishing the interaction of cycloalkanecarbonyl chlorides with ammonium isothiocyanate and the subsequent nucleophilic addition of cycloalkyl- (aralkyl-, aryl-, hetaryl-) carboxylic acid hydrazides. The peculiarities of the structure of the synthesized compounds were confirmed by spectral methods (LCMS and 1 H NMR spectra). Biological screening showed that diacylthiosemicarbazides ( 2 ) in the experimental model of pentylenet-erazole seizures in rats increased the latency period of seizures by 2.77–7.82 times, reduced the duration of tonic-clonic seizures by 1.23–5.59 minutes and prevented mortality by 30–60 %, relative to the control group of animals. It was shown that diacylthiosemicarbazides ( 2.6 , 2.15 , 2.22 , 2.18 ) with cyclopropane- or cyclopentanecarboxamide groups show the anticonvulsant activity that exceeds that of the reference drug Depakine or competes with it. Conclusions. A range of new diacylthiosemicarbazides were obtained and the primary screening of their anticonvulsant activity was performed, the SAR-analysis was provided, and the hit-compound was identified for further in-depth pharmacological studies.","PeriodicalId":9017,"journal":{"name":"Biopolymers & Cell","volume":"161 1","pages":"125-142"},"PeriodicalIF":0.0,"publicationDate":"2021-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86457340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
V. Kashuba, N. Hryshchenko, G. Gerashchenko, N. Melnichuk, T. Marchishak, S. Chernushyn, L. Chernenko, V. K. Liashko, Z. Tkachuk, M. Tukalo
Aim. To identify and characterize the SARS-CoV-2 variants, collected upon the new wave of COVID-19 outbreak in Ivano-Frankivs’k region of Ukraine, using the whole genome genotyping. Methods. The parallel whole genome sequencing was performed on the processed RNA, isolated from nasopharyngeal swabs of 19 patients, using an Ion GeneStudio S5 Plus System. Results. All the identified SARS-CoV-2 genotypes were referred to 20I/501Y.V1 clade, the variant VUI202012/01 GRY (the B.1.1.7 lineage). In the analyzed virus variants forty-seven various mutations were found. Besides the founder 20I/501Y.V1 missense mutations, several unique alterations were detected, including those in the S-and N-proteins of SARS-CoV-2, that might have clinical and epidemiological relevance. Conclusions. The current wave of the COVID-19 outbreak in Ukraine is associated not only with seasonal fluctuations in the virus transmission, but also with the emergence of more aggressive virulent variants, such as B.1.1.7, which basically displaced previous strains and affects the younger population.
的目标。利用全基因组基因分型技术鉴定和表征在乌克兰伊万诺-弗兰基夫斯克地区新一波COVID-19疫情中收集的SARS-CoV-2变异体。方法。使用Ion GeneStudio S5 Plus系统对从19例患者鼻咽拭子中分离的加工RNA进行平行全基因组测序。结果。所有鉴定的SARS-CoV-2基因型均为20I/501Y。V1分支，变种VUI202012/01 GRY (B.1.1.7谱系)。在分析的病毒变异中发现了47种不同的突变。除了创始人20I/501Y。V1错义突变，检测到一些独特的改变，包括SARS-CoV-2的- n蛋白，这些可能具有临床和流行病学相关性。结论。目前在乌克兰爆发的COVID-19疫情不仅与病毒传播的季节性波动有关，而且还与B.1.1.7等更具侵略性的毒性变异的出现有关，这些变异基本上取代了以前的毒株，并影响到年轻人群。
{"title":"Identification and characterization of the sars-cov-2 lineage b.1.1.7 upon the new outbreak of the covid-19 in Ukraine in february 2021","authors":"V. Kashuba, N. Hryshchenko, G. Gerashchenko, N. Melnichuk, T. Marchishak, S. Chernushyn, L. Chernenko, V. K. Liashko, Z. Tkachuk, M. Tukalo","doi":"10.7124/BC.000A52","DOIUrl":"https://doi.org/10.7124/BC.000A52","url":null,"abstract":"Aim. To identify and characterize the SARS-CoV-2 variants, collected upon the new wave of COVID-19 outbreak in Ivano-Frankivs’k region of Ukraine, using the whole genome genotyping. Methods. The parallel whole genome sequencing was performed on the processed RNA, isolated from nasopharyngeal swabs of 19 patients, using an Ion GeneStudio S5 Plus System. Results. All the identified SARS-CoV-2 genotypes were referred to 20I/501Y.V1 clade, the variant VUI202012/01 GRY (the B.1.1.7 lineage). In the analyzed virus variants forty-seven various mutations were found. Besides the founder 20I/501Y.V1 missense mutations, several unique alterations were detected, including those in the S-and N-proteins of SARS-CoV-2, that might have clinical and epidemiological relevance. Conclusions. The current wave of the COVID-19 outbreak in Ukraine is associated not only with seasonal fluctuations in the virus transmission, but also with the emergence of more aggressive virulent variants, such as B.1.1.7, which basically displaced previous strains and affects the younger population.","PeriodicalId":9017,"journal":{"name":"Biopolymers & Cell","volume":"36 1","pages":"117-124"},"PeriodicalIF":0.0,"publicationDate":"2021-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80714820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. Afanasieva, Dmytro E. Duzhyy, P. Belan, N. Voitenko, A. Sivolob
. The loop domain organization of chromatin plays an important role in transcription regulation and is known to be dependent on the cell functional states. The aim of this work was to investigate the possible DNA loop reorganization in dorsal ganglion neurons upon inflammatory pain. Methods. We used single cell gel electrophoresis (the comet assay) to analyze the kinetics of the DNA loop migration from the nucleoids obtained from lysed neurons. Results. Independently of inflammation, the neurons are characterized by relatively low amount of DNA in the comet tails due to a low content of DNA in the loops, which may be resolved by the comet assay (up to ~400 kb). Upon inflammation the contour length of the loops essentially decreases, in parallel with a respective increase of DNA in relatively short (up to ~100 kb) loops. Conclusions. The reorganization of the DNA loops upon inflammation could be suggested to be accompanied by rather significant changes in the transcription regulation.
{"title":"DNA loop organization in dorsal root ganglion neurons: effects of peripheral inflammation","authors":"K. Afanasieva, Dmytro E. Duzhyy, P. Belan, N. Voitenko, A. Sivolob","doi":"10.7124/BC.000A4F","DOIUrl":"https://doi.org/10.7124/BC.000A4F","url":null,"abstract":". The loop domain organization of chromatin plays an important role in transcription regulation and is known to be dependent on the cell functional states. The aim of this work was to investigate the possible DNA loop reorganization in dorsal ganglion neurons upon inflammatory pain. Methods. We used single cell gel electrophoresis (the comet assay) to analyze the kinetics of the DNA loop migration from the nucleoids obtained from lysed neurons. Results. Independently of inflammation, the neurons are characterized by relatively low amount of DNA in the comet tails due to a low content of DNA in the loops, which may be resolved by the comet assay (up to ~400 kb). Upon inflammation the contour length of the loops essentially decreases, in parallel with a respective increase of DNA in relatively short (up to ~100 kb) loops. Conclusions. The reorganization of the DNA loops upon inflammation could be suggested to be accompanied by rather significant changes in the transcription regulation.","PeriodicalId":9017,"journal":{"name":"Biopolymers & Cell","volume":"37 1","pages":"89-104"},"PeriodicalIF":0.0,"publicationDate":"2021-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86999729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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