scholarly journals Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

2021 ◽  
Vol 17 ◽  
pp. 2680-2715
Author(s):  
Umesh P Aher ◽  
Dhananjai Srivastava ◽  
Girij P Singh ◽  
Jayashree B S
Keyword(s):  
Scientific Community ◽  
Therapeutic Agents ◽  
Molecular Probes ◽  
Modified Nucleosides ◽  
Nucleoside Analogues ◽  
Comprehensive Overview ◽  
Simple Modification ◽  
The Third ◽  
Effective Synthesis ◽  
Methylene Group

Sugar-modified nucleosides have gained considerable attention in the scientific community, either for use as molecular probes or as therapeutic agents. When the methylene group of the ribose ring is replaced with a sulfur atom at the 3’-position, these compounds have proved to be structurally potent nucleoside analogues, and the best example is BCH-189. The majority of methods traditionally involves the chemical modification of nucleoside structures. It requires the creation of artificial sugars, which is accompanied by coupling nucleobases via N-glycosylation. However, over the last three decades, efforts were made for the synthesis of 1,3-oxathiolane nucleosides by selective N-glycosylation of carbohydrate precursors at C-1, and this approach has emerged as a strong alternative that allows simple modification. This review aims to provide a comprehensive overview on the reported methods in the literature to access 1,3-oxathiolane nucleosides. The first focus of this review is the construction of the 1,3-oxathiolane ring from different starting materials. The second focus involves the coupling of the 1,3-oxathiolane ring with different nucleobases in a way that only one isomer is produced in a stereoselective manner via N-glycosylation. An emphasis has been placed on the C–N-glycosidic bond constructed during the formation of the nucleoside analogue. The third focus is on the separation of enantiomers of 1,3-oxathiolane nucleosides via resolution methods. The chemical as well as enzymatic procedures are reviewed and segregated in this review for effective synthesis of 1,3-oxathiolane nucleoside analogues.

A review of methods to synthesise 4′-substituted nucleosides

2014 ◽  
Vol 12 (46) ◽  
pp. 9291-9306 ◽  
Author(s):  
Mark Betson ◽  
Nigel Allanson ◽  
Philip Wainwright
Keyword(s):  
Scientific Community ◽  
Therapeutic Agents ◽  
Molecular Probes ◽  
Modified Nucleosides ◽  
Diagnostic Tools

Modified nucleosides have received a great deal of attention from the scientific community, either for use as therapeutic agents, diagnostic tools, or as molecular probes.

scholarly journals Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1292 ◽  
Author(s):  
Shirin Hafezi ◽  
Mohamed Rahmani
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Targeted Therapies ◽  
Single Agent ◽  
Therapeutic Agents ◽  
Malignant Cells ◽  
Future Perspectives ◽  
Comprehensive Overview ◽  
Antiapoptotic Proteins ◽  
Preclinical And Clinical Studies

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer.

scholarly journals Modern Approaches in the Discovery and Development of Plant-Based Natural Products and Their Analogues as Potential Therapeutic Agents

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 349
Author(s):  
Asim Najmi ◽  
Sadique A. Javed ◽  
Mohammed Al Bratty ◽  
Hassan A. Alhazmi
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Natural Product ◽  
Therapeutic Agents ◽  
Throughput Capacity ◽  
Scientific Interest ◽  
Comprehensive Overview ◽  
Natural Sources ◽  
Discovery Research ◽  
Drug Discovery Research

Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher’s opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign.

scholarly journals Synthesis of Some New Nucleoside Analogues Containing Seven Membered Ring and Studying Their Biological Activity

2016 ◽  
Vol 13 (3) ◽  
pp. 531-546
Author(s):  
Baghdad Science Journal
Keyword(s):  
Antibacterial Activity ◽  
Membered Ring ◽  
Nucleoside Analogues ◽  
Second Step ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
The Third ◽  
Ft Ir ◽  
Fourth Step ◽  
Propiolic Acid

In this work, a series of new Nucleoside analogues (D-galactopyranose linked to oxepanebenzimidazole moiety) was synthesized via multisteps synthesis. The first step involved preparation of two benzimidazoles 2-styrylbenzimidazole and 2-(phenyl ethynyl) benzimidazole via reaction of phenylenediamine with cinnamic acid or ?-phenyl propiolic acid. Electrophilic addition of the prepared benzimidazoles by three anhydrides in the second step afforded (4-6) and (14-16) which in turn were treated with 1,2,3,4-di-O-isopropylidene galactopyranose in the third step to afford a series of the desirable protected nucleoside analogues (7-9) ,(17-19)which after hydrolysis in methanolic sodium methoxidein the fourth step afforded the free nucleoside analogues (10-12) and (20-22) .The synthesized compounds were identified by FT-IR and some of them by 1H-NMR and13C-NMR. The synthesized oxepane nucleoside analogues were screened for their antibacterial activity against three types of bacteria including Staphylococcusaureus ,Bacillus(gram positive) andE.coli (gram negative) bacteria repectively.

Building a global scientific community

2020 ◽  
Vol 35 (2) ◽  
pp. 115-122
Author(s):  
Stefan Bargheer
Keyword(s):  
Social Sciences ◽  
Latin America ◽  
Eastern Europe ◽  
North Africa ◽  
Scientific Community ◽  
European Research ◽  
Research Perspective ◽  
Social Sciences And Humanities ◽  
The Third ◽  
The Social

The three volumes reviewed in this essay assemble over 40 case studies written by more than 50 contributors that trace the development of the social sciences and humanities in Europe (East and West) and a number of countries in Latin America, North Africa, and East Asia. Two of these volumes grew out of the European research project ‘International Cooperation in the Social Sciences and Humanities’ (INTERCO-SSH); the third volume extends the focus of this project to Eastern Europe. A particularly innovative aspect shared by all contributions is the application of a transnational research perspective.

scholarly journals Martyrs made in the sky: the Zénith balloon tragedy and the construction of the French Third Republic's first scientific heroes

2019 ◽  
Vol 74 (3) ◽  
pp. 365-386
Author(s):  
Patrick Luiz Sullivan De Oliveira
Keyword(s):  
Twentieth Century ◽  
High Altitude ◽  
Scientific Community ◽  
Central Position ◽  
Practical Applications ◽  
The Third ◽  
Early Twentieth Century ◽  
Claude Bernard ◽  
Made In

Following the balloon's invention in 1783, the French greeted the technology with enthusiasm, speculating extensively about its potential scientific and practical applications. However, the lack of progress in navigating against the winds discredited ballooning, and in the following decades it became the domain of spectacular forms of entertainment and of swindlers trying to defraud public subscriptions. All of this changed after the 1870–1871 Franco-Prussian War, during which balloons were used to breach the siege of Paris. This essay explores how the aeronautical community, led by the recently established Société Française de Navigation Aérienne, mobilized the memory of the war to transform the balloon into a symbol of a heroic republican science. Paramount in that process was the Zénith 's 1875 high-altitude ascent that killed two aeronauts—Joseph Crocé-Spinelli and Théodore Sivel. The tragedy reverberated beyond France's scientific community, and through popular acclaim the two aeronauts became the Third Republic's first scientific martyrs, anticipating the eventual apotheoses of figures like Claude Bernard and Louis Pasteur. The ballooning revival in the last third of the century helped strengthen the association between France and aeronautics, thus setting the stage for the country to acquire a central position in the field by the early twentieth century.

scholarly journals Broad-Spectrum Antiviral Activity of 3’-Deoxy-3’-Fluoroadenosine against Emerging Flaviviruses

2020 ◽  
Author(s):  
Luděk Eyer ◽  
Pavel Svoboda ◽  
Jan Balvan ◽  
Tomáš Vičar ◽  
Matina Raudenská ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Broad Spectrum ◽  
Nucleotide Metabolism ◽  
Modified Nucleosides ◽  
Bioactive Molecules ◽  
Nucleoside Analogues ◽  
Phase Imaging ◽  
Structural And Functional Properties

Emerging flaviviruses are causative agents of severe and life-threatening diseases, against which no approved therapies are available. Among the nucleoside analogues, which represent a promising group of potentially therapeutic compounds, fluorine-substituted nucleosides are characterized by unique structural and functional properties. Despite having been first synthesized almost 5 decades ago, they still offer new therapeutic opportunities as inhibitors of essential viral or cellular enzymes active in nucleic acid replication/transcription or nucleoside/nucleotide metabolism. Here we report evaluation of the anti-flaviviral activity of 28 nucleoside analogues, each modified with a fluoro substituent at different positions of the ribose ring and/or heterocyclic nucleobase. Our antiviral screening revealed that 3′-deoxy-3′-fluoroadenosine exerted a low-micromolar antiviral effect against tick-borne encephalitis virus (TBEV), Zika virus, and West Nile (WNV) virus (EC50 values from 1.1 ± 0.1 μM to 4.7 ± 1.5 μM), which was manifested in host cell lines of neural and extraneural origin. The compound did not display any measurable cytotoxicity up to concentrations of 25 μM but had an observable cytostatic effect, resulting in suppression of cell proliferation at concentrations of >12.5 μM. Novel approaches based on quantitative phase imaging using holographic microscopy were developed for advanced characterization of antiviral and cytotoxic profiles of 3′-deoxy-3′-fluoroadenosine in vitro. In addition to its antiviral activity in cell cultures, 3′-deoxy-3′-fluoroadenosine was active in vivo in mouse models of TBEV and WNV infection. Our results demonstrate that fluoro-modified nucleosides represent a group of bioactive molecules with excellent potential to serve as prospective broad-spectrum antivirals in antiviral research and drug development.

scholarly journals Elucidating the druggable interface of protein−protein interactions using fragment docking and coevolutionary analysis

2016 ◽  
Vol 113 (50) ◽  
pp. E8051-E8058 ◽  
Author(s):  
Fang Bai ◽  
Faruck Morcos ◽  
Ryan R. Cheng ◽  
Hualiang Jiang ◽  
José N. Onuchic
Keyword(s):  
Drug Design ◽  
Protein Interactions ◽  
Binding Sites ◽  
Hot Spots ◽  
Therapeutic Agents ◽  
Molecular Probes ◽  
Therapeutic Drug ◽  
Protein Protein Interactions ◽  
Protein Surface ◽  
Fragment Docking

Protein−protein interactions play a central role in cellular function. Improving the understanding of complex formation has many practical applications, including the rational design of new therapeutic agents and the mechanisms governing signal transduction networks. The generally large, flat, and relatively featureless binding sites of protein complexes pose many challenges for drug design. Fragment docking and direct coupling analysis are used in an integrated computational method to estimate druggable protein−protein interfaces. (i) This method explores the binding of fragment-sized molecular probes on the protein surface using a molecular docking-based screen. (ii) The energetically favorable binding sites of the probes, called hot spots, are spatially clustered to map out candidate binding sites on the protein surface. (iii) A coevolution-based interface interaction score is used to discriminate between different candidate binding sites, yielding potential interfacial targets for therapeutic drug design. This approach is validated for important, well-studied disease-related proteins with known pharmaceutical targets, and also identifies targets that have yet to be studied. Moreover, therapeutic agents are proposed by chemically connecting the fragments that are strongly bound to the hot spots.

Gastric Adenocarcinoma: An Update on Genomics, Immune System Modulations, and Targeted Therapy

2016 ◽  
pp. 104-111 ◽  
Author(s):  
Jeeyun Lee ◽  
Adam J. Bass ◽  
Jaffer A. Ajani
Keyword(s):  
Immune System ◽  
Gastric Adenocarcinoma ◽  
Median Overall Survival ◽  
Therapeutic Agents ◽  
The Novel ◽  
The Third ◽  
Genomic Knowledge ◽  
Genomic Analyses ◽  
Novel Targets ◽  
Related Mortality

Gastric adenocarcinoma (GAC) is a global health burden on all societies, and it was the third-leading cause of cancer-related mortality in 2012, causing 723,000 deaths worldwide. The prognosis of patients with metastatic GAC remains poor, with a median overall survival of less than 1 year in patients treated with currently available therapies. A limited number of therapeutic agents is currently available. Recent additions to the armamentarium include trastuzumab and ramucirumab, which have shown some survival advantage when added to cytotoxic(s). Genomic analyses have defined various genotypes of GACs. The novel genomic knowledge can lead to discovery of novel targets and novel therapeutic agents. In this update, we focus on the current genomic data, targeted therapies including immune system modulators, and expand on HER2/neu testing and the use of agents against this target. Several other facets of GAC and its therapy are not to be included in this review but have been discussed elsewhere.

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