Design, synthesis and biological evaluation of truncated 1'-homologated 4'-selenonucleosides as PPARγ/δ dual modulators.

This study explores the synthesis and evaluation of truncated 1'-homologated 4'-selenonucleosides as dual modulators of PPARγ and PPARδ. Starting with d-lyxose, a 4'-selenosugar was synthesized and condensed with a nucleobase via an S2 reaction, followed by modifications at the C2- and N-positions, yielding compounds 3a-l. Structure-activity trend analysis identified compound 3h, featuring 2-chloro and N-3-iodobenzylamine substituents, as a potent PPARγ partial agonist and PPARδ antagonist (PPARγ K = 2.

Synthesis and biological evaluation of sugar-modified truncated carbanucleosides as A and A adenosine receptor ligands to explore conformational effect to the receptors.

This study investigated the impact of conformation on the binding affinity of carbanucleosides to A and A adenosine receptors (ARs). A series of nucleosides, including saturated, unsaturated, North (N)-methano, and South (S)-methanocarbanucleosides was prepared, and their binding affinities to AAR and AAR were assessed. Biological evaluations revealed that all synthesized (S)-methanocarbanucleosides had negligible binding to both receptors, and most (N)-methanocarbanucleosides exhibited high binding affinities.

Exploring C2 and N Substituent Effects on Truncated 4'-Thioadenosine Derivatives as Dual A and A Adenosine Receptor Ligands.

Based on high binding affinity of truncated 2-hexynyl-4'-thioadenosine (3 a) at both A adenosine receptor (AR) and A AR, we explored structure-activity relationship (SAR) of the C2-substitution by altering chain length of the 2-hexynyl moiety, thereby evaluating the hydrophobic pocket size. A series of truncated N-substituted 4'-thioadenosine derivatives with C2-alkynyl substitution were successfully synthesized from D-mannose, using a palladium-catalyzed Sonogashira coupling reaction as the key step, whose structures were confirmed by the X-ray crystal structure of 4 h. As the size of the alkynyl group at the C2-position increased, the binding affinity improved; however, when the substituted group was larger than hexynyl, the binding affinity decreased.

Stereochemical influence of 4'-methyl substitutions on truncated 4'-thioadenosine derivatives: Impact on A adenosine receptor binding and antagonism.

Herein, we investigated the stereochemical effects of 4'-methyl substitution on A adenosine receptor (AAR) ligands by synthesizing and evaluating a series of truncated 4'-thioadenosine derivatives featuring 4'-α-methyl, 4'-β-methyl, and 4',4'-dimethyl substitutions. We successfully synthesized these derivatives, using the stereoselective addition of an organometallic reagent, KSAc-mediated sulfur cyclization, and Vorbrüggen condensation. Binding assays demonstrated that the 4'-β-methyl substitution conferred the highest affinity for AAR, with compound 1 h exhibiting a K = 3.

Structure-Activity Relationship of Truncated 4'-Selenonucleosides: A Adenosine Receptor Activity and Binding Selectivity.

This study explored the impact of structural modifications on truncated 4'-selenonucleosides as ligands for the A adenosine receptor (AR). We synthesized and evaluated a series of these compounds for their binding affinities, functional activities, and structural interactions by using computational modeling. The SAR study revealed that all compounds exhibited selective and notable hAAR binding, among which ( = 5.

Antitumor activity and transcriptome sequencing (RNA-seq) analyses of hepatocellular carcinoma cells in response to exposure triterpene-nucleoside conjugates.

Fifteen betulonic/betulinic acid conjugated with nucleoside derivatives were synthesized to enhance antitumor potency and water solubility. Among these, the methylated betulonic acid-azidothymidine compound (8c) exhibited a broad-spectrum of antitumor activity against three tested tumor cell lines, including SMMC-7721 (IC = 5.02 μM), KYSE-150 (IC = 5.

Structural Modification and Biological Evaluation of 2,8-Disubstituted Adenine and Its Nucleosides as A Adenosine Receptor Antagonists: Exploring the Roles of Ribose at Adenosine Receptors.

Building on the preceding structural analysis and a structure-activity relationship (SAR) of 8-aryl-2-hexynyl nucleoside hAAR antagonist , we strategically inverted C2/C8 substituents and eliminated the ribose moiety. These modifications aimed to mitigate potential steric interactions between ribose and adenosine receptors. The SAR findings indicated that such inversions significantly modulated hAAR binding affinities depending on the type of ribose, whereas removal of ribose altered the functional efficacy via hAAR.

Stereoselective Approach for the Synthesis of Diverse 1'-Modified Carbanucleosides.

We describe an efficient and stereoselective synthesis of 1'-substituted-β-carbocylic nucleosides via -dichlorooxirane intermediate , which directly condensed with weak nucleophiles such as pyrimidines or purines. The formation of -dichlorooxirane and direct nucleobase condensation exclusively proceeded in protic polar solvents like MeOH. This method provides a general and modular route for the late-stage diversification of 1'-modified nucleosides.

In Silico Discovery of 5'-Modified 7-Deoxy-7-ethynyl-4'-thioadenosine as a HASPIN Inhibitor and Its Synergistic Anticancer Effect with the PLK1 Inhibitor.

Despite genetic perturbations resulting in embryo lethality for most mitotic kinases, loss of the histone H3 mitotic kinase HASPIN reveals no adverse effect in mice models, establishing HASPIN as a promising target for anticancer therapy. However, developing a HASPIN inhibitor from conventional pharmacophores poses a technical challenge as this atypical kinase shares slight similarities with eukaryotic protein kinases. Chemically modifying a cytotoxic 4'-thioadenosine analogue through high genotoxicity yielded several novel nongenotoxic kinase inhibitors.

Structure-Activity Relationships of Truncated 1'-Homologated Carbaadenosine Derivatives as New PPARγ/δ Ligands: A Study on Sugar Puckering Affecting Binding to PPARs.

Peroxisome proliferator-activated receptors (PPARs) are associated with the regulation of metabolic homeostasis. Based on a previous report that 1'-homologated 4'-thionucleoside acts as a dual PPARγ/δ modulator, carbocyclic nucleosides - with various sugar conformations were synthesized to determine whether sugar puckering affects binding to PPARs. ()-conformer was synthesized using Charette asymmetric cyclopropanation, whereas ()-conformer was synthesized using stereoselective Simmons-Smith cyclopropanation.

Discovery of 2-aminoquinolone acid derivatives as potent inhibitors of SARS-CoV-2.

The COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to threaten human health and create socioeconomic problems worldwide. A library of 200,000 small molecules from the Korea Chemical Bank (KCB) were evaluated for their inhibitory activities against SARS-CoV-2 in a phenotypic-based screening assay to discover new therapeutics to combat COVID-19. A primary hit of this screen was the quinolone structure-containing compound 1.

Synthesis of oligonucleotides containing 5'-homo-4'-selenouridine derivative and its increased resistance against nuclease.

As technologies using RNA or DNA have been developed, various chemical modifications of nucleosides have been attempted to increase the stability of oligonucleotides. Since it is known that 2'-OMe-modification greatly contributes to increasing the stability of oligonucleotides, we added 2'-OMe to our previously developed 4'-selenonucleoside and 5'-homo-4'-selenonucleoside as the modified monomers for oligonucleotide: 2'-methoxy-4'-selenouridine (2'-OMe-4'-Se-U) and 5'-homo-2'-methoxy-4'-selenouridine (5'-homo-2'-OMe-4'-Se-U). We synthesized oligonucleotides containing the chemically modified 4'-selenouridine and evaluated their thermal stability and nuclease resistance.

Synthesis of Enantiomerically Pure Pyrimidine Ribonucleosides Locked in the South Conformation.

The conformation of the central five-membered ring of a nucleoside plays an important role in enzyme recognition. Bicyclo[3.1.

Anti-obesity effects of the dual-active adenosine A/A receptor-ligand LJ-4378.

Background And Objectives: A adenosine receptor (AAR)-mediated signaling in adipose tissues has been investigated as a potential target for obesity-related metabolic diseases. LJ-4378 has been developed as a dual-acting ligand with AAR agonist and A adenosine receptor (AAR) antagonist activity. The current study aimed to investigate the anti-obesity effects of LJ-4378 and its underlying molecular mechanisms.

GPCR Agonist-to-Antagonist Conversion: Enabling the Design of Nucleoside Functional Switches for the A Adenosine Receptor.

Modulators of the G protein-coupled A adenosine receptor (AAR) have been considered promising agents to treat Parkinson's disease, inflammation, cancer, and central nervous system disorders. Herein, we demonstrate that a thiophene modification at the C8 position in the common adenine scaffold converted an AAR agonist into an antagonist. We synthesized and characterized a novel AAR antagonist, (LJ-4517), with = 18.

Molecular basis of specific viral RNA recognition and 5'-end capping by the Chikungunya virus nsP1.

Many viruses encode RNA-modifying enzymes to edit the 5' end of viral RNA to mimic the cellular mRNA for effective protein translation, genome replication, and evasion of the host defense mechanisms. Alphavirus nsP1 synthesizes the 5' end Cap-0 structure of viral RNAs. However, the molecular basis of the capping process remains unclear.

Optimization of 2-Aminoquinazolin-4-(3)-one Derivatives as Potent Inhibitors of SARS-CoV-2: Improved Synthesis and Pharmacokinetic Properties.

We previously reported the potent antiviral effect of the 2-aminoquinazolin-4-(3)-one , which shows significant activity (IC = 0.23 μM) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with no cytotoxicity. However, it is necessary to improve the in vivo pharmacokinetics of compound because its area under the curve (AUC) and maximum plasma concentration are low.

Design, Synthesis, and Biological Activity of l-1'-Homologated Adenosine Derivatives.

On the basis of the previously reported polypharmacological profile of truncated d-1'-homologated adenosine derivatives [J. Med. Chem.

Discovery of a Novel Template, 7-Substituted 7-Deaza-4'-Thioadenosine Derivatives as Multi-Kinase Inhibitors.

The development of anticancer drugs remains challenging owing to the potential for drug resistance. The simultaneous inhibition of multiple targets involved in cancer could overcome resistance, and these agents would exhibit higher potency than single-target inhibitors. Protein kinases represent a promising target for the development of anticancer agents.

Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary.

Distinguishing compounds' agonistic or antagonistic behavior would be of great utility for the rational discovery of selective modulators. We synthesized truncated nucleoside derivatives and discovered ( = 2.40 nM) as a potent human A adenosine receptor (hAAR) agonist, and subtle chemical modification induced a shift from antagonist to agonist.

Stereoselective Synthesis of ()- and ()-Cyclopropyl-Fused Carbocyclic Nucleosides Using Stereoselective Cyclopropanation.

To determine which sugar conformation is favorable in binding to peroxisome proliferator-activated receptors, the conformationally locked south () and north () analogues were asymmetrically synthesized using a bicyclo[3.1.0]hexane template.

Dual Actions of A and A Adenosine Receptor Ligand Prevents Obstruction-Induced Kidney Fibrosis in Mice.

Kidney fibrosis is the final outcome of chronic kidney disease (CKD). Adenosine plays a significant role in protection against cellular damage by activating four subtypes of adenosine receptors (ARs), AAR, AAR, AAR, and AAR. AAR agonists protect against inflammation, and AAR antagonists effectively inhibit the formation of fibrosis.

Design and Synthesis of 2,6-Disubstituted-4'-Selenoadenosine-5'-,-Dimethyluronamide Derivatives as Human A Adenosine Receptor Antagonists.

A new series of 4'-selenoadenosine-5'--dimethyluronamide derivatives as highly potent and selective human A adenosine receptor (hAAR) antagonists, is described. The highly selective AAR agonists, 4'-selenoadenosine-5'--methyluronamides were successfully converted into selective antagonists by adding a second -methyl group to the 5'-uronamide position. All the synthesized compounds showed medium to high binding affinity at the hAAR.