scholarly journals Asymmetric catalytic synthesis of spirocyclobutyl oxindoles and beyond via [2+2] cycloaddition and sequential transformations

2021 ◽  
Author(s):  
Xia Zhong ◽  
Jiuqi Tan ◽  
Jianglin Qiao ◽  
Yuqiao Zhou ◽  
Cidan Lv ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Structural Diversity ◽  
Catalytic Synthesis ◽  
Efficient Synthesis ◽  
Asymmetric Catalytic ◽  
Cyclic Compounds

Asymmetric efficient synthesis of a collection of small molecules with structural diversity is highly important to drug discovery. Herein, three distinct types of chiral cyclic compounds were accessible by enantioselective...

scholarly journals Multiplexed screening of thousands of natural products for protein-ligand binding in native mass spectrometry

2021 ◽  
Author(s):  
Giang Nguyen ◽  
Jack Bennett ◽  
Sherrie Liu ◽  
Sarah Hancock ◽  
Daniel Winter ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Drug Discovery ◽  
Small Molecules ◽  
Natural Product ◽  
Drug Targets ◽  
Structural Diversity ◽  
Native Mass Spectrometry ◽  
Protein Targets ◽  
Rapid Measurement

The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, novel natural product ligands of human drug targets could be identified without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.

Multiplexed screening of thousands of natural products for protein-ligand binding in native mass spectrometry

2021 ◽  
Author(s):  
Giang Nguyen ◽  
Jack Bennett ◽  
Sherrie Liu ◽  
Sarah Hancock ◽  
Daniel Winter ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Natural Products ◽  
Drug Discovery ◽  
Small Molecules ◽  
Natural Product ◽  
Drug Targets ◽  
Structural Diversity ◽  
Native Mass Spectrometry ◽  
Protein Targets ◽  
Rapid Measurement

The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, novel natural product ligands of human drug targets could be identified without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.

Chemical genetics approach to drug discovery by diversity-oriented synthesis (DOS) of peptidomimetics

2011 ◽  
Vol 83 (3) ◽  
pp. 687-698 ◽  
Author(s):  
Andrea Trabocchi ◽  
Duccio Cavalieri ◽  
Antonio Guarna
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Anticancer Agents ◽  
Structural Diversity ◽  
Chemical Genetics ◽  
Biological Evaluation ◽  
Phenotypic Screening ◽  
Diversity Oriented Synthesis ◽  
Biological Phenotype ◽  
Lead Generation

Chemical genetics, which relies on selecting small molecules for their ability to induce a biological phenotype or to interact with a particular gene product, is a new powerful tool for lead generation in drug discovery. Accordingly, diversity-oriented synthesis (DOS) of small-molecule peptidomimetics gives access to collections of new chemotypes bearing high structural diversity. Biological evaluation using cell growth as a phenotypic screening on Saccharomyces cerevisiae deletant strains is a powerful tool to identify new chemotypes as hit compounds in the discovery of new antifungal and anticancer agents, and also in the dissection of their mode of action. Our contribution in this field focused on the screening of morpholine-based peptidomimetic collections toward yeast deletant strains, which provided the identification of new chemotypes involved in mitochondria metabolism and respiration.

Aim for the Readers! Bromodomains As New Targets Against Chagas’ Disease

2019 ◽  
Vol 26 (36) ◽  
pp. 6544-6563
Author(s):  
Victoria Lucia Alonso ◽  
Luis Emilio Tavernelli ◽  
Alejandro Pezza ◽  
Pamela Cribb ◽  
Carla Ritagliati ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Chagas Disease ◽  
Causative Agent ◽  
Current Knowledge ◽  
Sequence Similarity ◽  
Lysine Acetylation ◽  
Specific Manner ◽  
Lysine Residues ◽  
Antiparasitic Drugs

Bromodomains recognize and bind acetyl-lysine residues present in histone and non-histone proteins in a specific manner. In the last decade they have raised as attractive targets for drug discovery because the miss-regulation of human bromodomains was discovered to be involved in the development of a large spectrum of diseases. However, targeting eukaryotic pathogens bromodomains continues to be almost unexplored. We and others have reported the essentiality of diverse bromodomain- containing proteins in protozoa, offering a new opportunity for the development of antiparasitic drugs, especially for Trypansoma cruzi, the causative agent of Chagas’ disease. Mammalian bromodomains were classified in eight groups based on sequence similarity but parasitic bromodomains are very divergent proteins and are hard to assign them to any of these groups, suggesting that selective inhibitors can be obtained. In this review, we describe the importance of lysine acetylation and bromodomains in T. cruzi as well as the current knowledge on mammalian bromodomains. Also, we summarize the myriad of small-molecules under study to treat different pathologies and which of them have been tested in trypanosomatids and other protozoa. All the information available led us to propose that T. cruzi bromodomains should be considered as important potential targets and the search for smallmolecules to inhibit them should be empowered.

Natural Sesquiterpene Lactones in the Prevention and Treatment of Inflammatory Disorders and cancer: A Systematic Study of this Emerging Therapeutic Approach based on Chemical and Pharmacological Aspect

2020 ◽  
Vol 17 (9) ◽  
pp. 1102-1116
Author(s):  
Sudip Kumar Mandal ◽  
Utsab Debnath ◽  
Amresh Kumar ◽  
Sabu Thomas ◽  
Subhash Chandra Mandal ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Biological Activities ◽  
Sesquiterpene Lactones ◽  
Structural Diversity ◽  
Cancer Drug ◽  
Cancer Drug Discovery ◽  
Anti Cancer ◽  
Drug Discovery Program ◽  
Anti Inflammatory ◽  
Family Based

Background and Introduction: Sesquiterpene lactones are a class of secondary metabolite that contains sesquiterpenoids and lactone ring as pharmacophore moiety. A large group of bioactive secondary metabolites such as phytopharmaceuticals belong to this category. From the Asteraceae family-based medicinal plants, more than 5,000 sesquiterpene lactones have been reported so far. Sesquiterpene lactone-based pharmacophore moieties hold promise for broad-spectrum biological activities against cancer, inflammation, parasitic, bacterial, fungal, viral infection and other functional disorders. Moreover, these moiety based phytocompounds have been highlighted with a new dimension in the natural drug discovery program worldwide after the 2015 Medicine Nobel Prize achieved by the Artemisinin researchers. Objective: These bitter substances often contain an α, β-unsaturated-γ-lactone as a major structural backbone, which in recent studies has been explored to be associated with anti-tumor, cytotoxic, and anti-inflammatory action. Recently, the use of sesquiterpene lactones as phytomedicine has been increased. This study will review the prospect of sesquiterpene lactones against inflammation and cancer. Methods: Hence, we emphasized on the different features of this moiety by incorporating its structural diversity on biological activities to explore structure-activity relationships (SAR) against inflammation and cancer. Results: How the dual mode of action such as anti-inflammatory and anti-cancer has been exhibitedby these phytopharmaceuticals will be forecasted in this study. Furthermore, the correlation of anti-inflammatory and anti-cancer activity executed by the sesquiterpene lactones for fruitful phytotherapy will also be revealed in the present review in the milieu of pharmacophore activity relation and pharmacodynamics study as well. Conclusion: So, these metabolites are paramount in phytopharmacological aspects. The present discussion on the future prospect of this moiety based on the reported literature could be a guide for anti-inflammatory and anti-cancer drug discovery programs for the upcoming researchers.

scholarly journals Druggable Transient Pockets in Protein Kinases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 651
Author(s):  
Koji Umezawa ◽  
Isao Kii
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Screening Methods ◽  
Research Attention ◽  
Folding Process ◽  
Chemical Screening ◽  
Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

Synthesis of sp3-Enriched β-Fluoro Sulfonyl Chlorides

Synthesis ◽  
2020 ◽  
Author(s):  
Oleksandr O. Grygorenko ◽  
Rustam Gurbanov ◽  
Andriy Sokolov ◽  
Sergey Golovach ◽  
Kostiantyn Melnykov ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Double Bond ◽  
Building Blocks ◽  
Protecting Groups ◽  
Sulfonyl Chlorides ◽  
Wide Range ◽  
Cyclic Compounds

AbstractA three-step approach to the synthesis of sp3-enriched β-fluoro sulfonyl chlorides starting from alkenes is reported. The method was successfully applied to a wide range of acyclic and cyclic substrates, bearing either an exocyclic or an endocyclic double bond. The procedure worked with a wide range of substrates and tolerated a number of functional and protecting groups. Moreover, the target cyclic compounds were obtained as single cis diastereomers on a multigram scale. The title compounds are promising building blocks for drug discovery that can be used to obtain sp3-enriched β-fluoro and α,β-unsaturated sulfonamides.

Asymmetric catalytic synthesis of lysine by hydrogenation of α-nitrocaprolactam

1987 ◽  
Vol 36 (7) ◽  
pp. 1475-1478 ◽  
Author(s):  
E. I. Klabunovskii ◽  
D. D. Gogoladze ◽  
E. S. Levitina ◽  
E. I. Karpeiskaya ◽  
L. F. Godunova ◽  
...  
Keyword(s):  
Catalytic Synthesis ◽  
Asymmetric Catalytic

scholarly journals SAR by kinetics for drug discovery in protein misfolding diseases

2018 ◽  
Vol 115 (41) ◽  
pp. 10245-10250 ◽  
Author(s):  
Sean Chia ◽  
Johnny Habchi ◽  
Thomas C. T. Michaels ◽  
Samuel I. A. Cohen ◽  
Sara Linse ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Misfolding ◽  
Amyloid Beta Peptide ◽  
Oligomer Formation ◽  
Chemical Derivatives ◽  
Structure Activity ◽  
Beta Peptide ◽  
Misfolding Diseases ◽  
Aβ Oligomer

To develop effective therapeutic strategies for protein misfolding diseases, a promising route is to identify compounds that inhibit the formation of protein oligomers. To achieve this goal, we report a structure−activity relationship (SAR) approach based on chemical kinetics to estimate quantitatively how small molecules modify the reactive flux toward oligomers. We use this estimate to derive chemical rules in the case of the amyloid beta peptide (Aβ), which we then exploit to optimize starting compounds to curtail Aβ oligomer formation. We demonstrate this approach by converting an inactive rhodanine compound into an effective inhibitor of Aβ oligomer formation by generating chemical derivatives in a systematic manner. These results provide an initial demonstration of the potential of drug discovery strategies based on targeting directly the production of protein oligomers.

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