A set of 12 abietane diterpene derivatives have been synthesised by the Ugi-four component reaction (Ugi-4CR) and tested for cytotoxicity and activity against influenza virus A/Puerto Rico/8/34 ...(H1N1) and SARS-CoV-2 pseudovirus. Five dipeptide derivatives demonstrated a selectivity index (SI) higher than 10 and IC
50
values from 2 to 32 μM against influenza virus. Compound 11 was found to be a lead with SI of 200, and time-of-addition experiments showed the viral entry into the cell and the binding of the virus to the receptor as a possible target. Compound 7 was the only one showed weak anti-SARS-CoV-2 activity with EC
50
value of 80.96 µM. Taken together, our data suggest the potency of diterpene acids-Ugi products as new effective anti-influenza compounds.
Advances in high-throughput high-resolution mass spectrometry and the development of thermal proteome profiling approach (TPP) have made it possible to accelerate a drug target search. Since its ...introduction in 2014, TPP quickly became a method of choice in chemical proteomics for identifying drug-to-protein interactions on a proteome-wide scale and mapping the pathways of these interactions, thus further elucidating the unknown mechanisms of action of a drug under study. However, the current TPP implementations based on tandem mass spectrometry (MS/MS), associated with employing lengthy peptide separation protocols and expensive labeling techniques for sample multiplexing, limit the scaling of this approach for the ever growing variety of drug-to-proteomes. A variety of ultrafast proteomics methods have been developed in the last couple of years. Among them, DirectMS1 provides MS/MS-free quantitative proteome-wide analysis in 5-min time scale, thus opening the way for sample-hungry applications, such as TPP. In this work, we demonstrate the first implementation of the TPP approach using the ultrafast proteome-wide analysis based on DirectMS1. Using a drug topotecan, which is a known topoisomerase I (TOP1) inhibitor, the feasibility of the method for identifying drug targets at the whole proteome level was demonstrated for an ovarian cancer cell line.
Graphical Abstract
A series of
-cyclodextrin (
-CD)-conjugates were prepared by combining three abietane-type diterpene acids with two azide-functionalized
-CDs via click chemistry, and the antiviral activity against ...wild-type and omicron SARS-CoV-2 spike pseudovirus as well as the antibacterial activity against
were investigated. All the synthesised conjugates exhibited no significant cytotoxicity to BHK-21-hACE2 cells with cell viability over 80% at concentration of 15
M. Among the conjugates, the heptavalent
-CD-dehydroabietic acid conjugate
exhibited higher anti-SARS-CoV-2 activity against the omicron variant compared to the other conjugates. This study suggested that the multivalent diterpene acid derivatives may have potential application against coronaviruses as entry inhibitors.
A chemical library was constructed based on the resin acids (abietic, dehydroabietic, and 12-formylabietic) and its diene adducts (maleopimaric and quinopimaric acid derivatives). The one-pot ...three-component CuCl-catalyzed aminomethylation of the abietane diterpenoid propargyl derivatives was carried out by formaldehyde and secondary amines (diethylamine, pyrrolidine, morpholine, and homopiperazine). All compounds were tested for cytotoxicity and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells and SARS-CoV-2 pseudovirus in BHK-21-hACE2 cells. Among 21 tested compounds, six derivatives demonstrated a selectivity index (SI) higher than 10, and their IC50 values ranged from 0.19 to 5.0 μM. Moreover, two derivatives exhibited potent anti-SARS-CoV-2 infection activity. The antiviral activity and toxicity strongly depended on the nature of the diterpene core and heterocyclic substituent. Compounds 12 and 21 bearing pyrrolidine moieties demonstrated the highest virus-inhibiting activity with SIs of 128.6 and 146.8, respectively, and appeared to be most effective when added at the time points 0–10 and 1–10 h of the viral life cycle. Molecular docking and dynamics modeling were adopted to investigate the binding mode of compound 12 into the binding pocket of influenza A virus M2 protein. Compound 9 with a pyrrolidine group at C20 of 17-formylabietic acid was a promising anti-SARS-CoV-2 agent with an EC50 of 10.97 µM and a good SI value > 18.2. Collectively, our data suggested the potency of diterpenic Mannich bases as effective anti-influenza and anti-COVID-19 compounds.
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•Diterpenic Mannich bases show antiviral activity against influenza and SARS-CoV-2.•Compounds with pyrrolidine fragments are recognized as promising compounds.•Abietic acid derivative 9 was found to be a promising anti-SARS-CoV-2 lead compound.•Formylabietic acid scaffold 12 exhibited potent anti-influenza A inhibitory activity.
Economic and Fiscal Resilience of Russia's Regions Klimanov, Vladimir V.; Kazakova, Sofia M.; Mikhaylova, Anna A.
Regional science policy & practice,
August 2020, 2020-08-00, 20200801, Letnik:
12, Številka:
4
Journal Article
Recenzirano
Nowadays there is an increase of attention from the international organizations to resilience of development, suggesting that the concept of sustainability is gradually being replaced by resilience ...as a development goal. The article explains the need to adapt the theory of regional resilience in Russian researches and determines the prerequisites for the formation that theory. The definitions of the concept of “resilience” from different areas of knowledge, including regional economic and fiscal resilience, are given, and the basic properties and and factors influencing regional resilience are determined. Based on 17 economic, social and financial indicators, an integral resilience index was determined for the Russia's regions, which revealed resilient and non‐resilient regions. According to the study, authors have confirmed the relationship between fiscal and socio‐economic resilience.
Resumen
En la actualidad, las organizaciones internacionales prestan cada vez más atención a la resiliencia del desarrollo, lo que sugiere que el concepto de sostenibilidad está siendo sustituido gradualmente por la resiliencia como objetivo de desarrollo. Este artículo explica la necesidad de adaptar la teoría de la resiliencia regional en la investigación en Rusia y determina los requisitos previos para la formación de esa teoría. Se dan definiciones del concepto de “resiliencia” de diferentes áreas del conocimiento, incluida la resiliencia económica y fiscal regional, y se determinan las propiedades y factores básicos que influyen en la resiliencia regional. Se emplearon 17 indicadores económicos, sociales y financieros para determinar un índice de resiliencia integral para las regiones de Rusia, que reveló las regiones resilientes y no resilientes. Según el estudio, se confirma la relación entre la resiliencia fiscal y la socioeconómica.
抄録
近年、開発のレジリエンスに対する国際組織の関心が高まっており、開発の目標としての持続可能性の概念が徐々にレジリエンスに置き換えられつつあることがうかがえる。本稿では、地域レジリエンスの理論をロシア研究に適用することの必要性を説明し、その理論形成の前提条件を決定した。地域経済や財政的レジリエンスなどの様々な知識分野における「レジリエンス」の概念の定義が示され、基本的な特性と地域のレジリエンスに影響を与える要因を決定する。17の経済・社会・金融指標に基づいて、ロシアの各地域の総合的なレジリエンス指数を決定し、レジリエントな能力のある地域とない地域を明らかにした。本研究から、著者らは財政的レジリエンスと社会経済的レジリエンスに関連性があることを確認した。
The copper catalyzed reaction of N-monosubstituted hydrazones with carbon tetrabromide leads to formation of expected dibromodiazadienes and unexpected dibromostyrenes. The experimental and ...theoretical study of the reaction revealed a key role of N-centered radicals, which can eliminate aryl radicals to form the corresponding dibromostyrenes. Alternatively, the oxidation of intermediate N-centered radicals by Cu(II) results in the corresponding diazadienes. These two reaction pathways are competitive directions of the reaction. Consequently, the reaction can be useful for the synthesis of both dibromostyrenes and rare dibromodiazadienes.
Aim. To evaluate the effectiveness of inulin for the adjustment of intestinal microflora in patients with recurrent vulvovaginal candidiasis (VVC).
Materials and methods. A prospective cohort ...comparative study included 79 women aged 18 to 50 years. They were divided into three groups: the main group included 32 patients receiving complex treatment with a dietary supplement containing inulin derived from the "Extra" variety of Jerusalem artichoke root in combination with fluconazole; the comparison group included 27 patients receiving fluconazole only; and the control group included 20 healthy women. The patients were followed up for 12 months. Examination included stool culture for dysbiosis, complete blood count, urinalysis, blood chemistry (glucose, bilirubin, alanine aminotransferase, aspartate aminotransferase, total protein, urea, creatinine), examination of the vulva and vaginal mucosa, vaginal smear microscopy for microflora, Gram staining, real-time polymerase chain reaction for Mycoplasma hominis, Ureaplasma parvum, Trihomonas vaginalis, Chlamydia traсhomatis, Candida albicans. Subsequently, all subjects every three months underwent a bimanual examination, speculum examination of the cervical mucosa and vagina, Gram staining of vaginal mucosa and cervix swabs, a thorough interview, and history taking. At 12 months, stool was cultured for dysbiosis again, and the data were analyzed.
Results. The VVC therapy in the group of inulin-containing dietary supplement was more effective: the recurrence rate was 3 times lower than with the standard treatment regimen.
Conclusion. The use of dietary supplement containing inulin derived from the "Extra" variety of Jerusalem artichoke root in complex therapy for recurrent VVC can significantly improve the gut and vagina microflora condition and prevent the recurrence and normalization of stool in patients.
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•Acid-promoted transformations of 1,1-dichloro-2-vinylcyclopropane.•Synthesis of 1,1-dichloropent-1-enes.•Reaction mechanisms.
The reaction of 1,1-dichloro-2-vinylcyclopropane with ...arenes under the action of the superacid TfOH afforded 3-aryl-1,1-dichloropent-1-enes (25–43% yield), as the products of cyclopropane ring opening. The reaction of 1,1-dichloro-2-methyl-2-vinylcyclopropane was realized as a two-step procedure, including initial in situ generation of the corresponding triflate, 5,5-dichloro-4-methylpent-4-en-2-yl trifluoromethanesulfonate, from the cyclopropane and TfOH, followed by reaction with arenes and TfOH to give 1,1-dichloro-2-methyl-4-arylpent-1-enes (30–68% yield).
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The azido-Ugi reaction of methyl maleopimarate N-(2- aminoethyl) imide with isocyanides, paraformaldehyde and trimethylsilyl azide in one step leads to 1,5-disubstituted diterpene ...bis-tetrazoles. The compounds demonstrate selective cytotoxicity against NCI-60 cancer cell panel.
