Abstract Isochromans and aryl-C-glycosides are important structural motifs in many natural products and drug candidates with diverse therapeutic potentials. Here we present the first application of pyranosyl aldehydes in the oxa-Pictet–Spengler cyclization to conjugate the two pharmacophore motifs. Enantiomeric pairs of aryl-2-propanols were reacted with pyranosyl dialdoses and 1-formyl sugars in a BF3·Et2O-mediated oxa-Pictet–Spengler reaction. The effects of the substitution pattern, configuration, and protecting groups of the reactants on the efficiency and stereochemical outcome of the reactions were studied, and the reaction conditions were optimized. A series of 1,3-cis-substituted 1-(C-glycosyl)isochromans was prepared in high yields with good to complete stereoselectivity from glucosyldialdoses and 1-formyl glucopyranosides. The reaction efficiency dropped significantly with galacto-dialdose derivatives due to steric hindrance, leading to lower yields and anomerization, which slightly limits the universality of the method. ROESY-NMR, X-ray diffraction, and VCD methods were used to determine the structure and the absolute configuration of the compounds. The method developed represents a straightforward and stereocontrolled route to a new chemotype of isochroman C-glycosides.

The photoinitiated thiol-ene reaction is a metal-free click chemistry method for the synthesis of thioglycosides and sulfur-linked glycomimetics. Here we present a comparative study on the thiol-ene reactions of C2-substituted and unsubstituted glycals with some selected thiols, such as thioacetic acid, tert-butyl mercaptan, and per-O-acetylated 1-thio-β-d-galactose and 1-thio-β-d-lactose derivatives at -80 °C in the presence of 2,2-dimethoxy-2-phenylacetophenone photoinitiator. 2-Acetoxyglycals gave the 1,2-cis-α-thioglycosides with complete regio- and stereoselectivity, in high yields with all thiols tested, except for tert-butyl mercaptan. Unsubstituted glucal and galactal gave the 1-deoxy-2-thiolated products regioselectively, and in most cases as a mixture of C2 epimers. Hydrothiolation of galactal always yielded the galacto-isomer in greater proportion than the talo-isomer. In hydrothiolation of glucal, either manno- or gluco-selectivity prevailed, depending on the thiol size and reaction temperature. Remarkably, unsubstituted glycals showed higher reactivity towards thiols than C2-substituted glycals.

Despite the serious progress in the antitumor therapy, cancer did not cease to be one of the leading causes of death in the developed world. Hence still there is high interest for new anticancer agents. In 2025, the EMA approved 104 new medicines, 37 of them containing new active substances. 18 new anticancer medicines were approved (14 new active substances). In this review, we aim to shortly summarize the mechanism of action and use of the new drugs approved by the EMA in the year 2025.

Breast cancer (BC) is a major global public health problem. Classical therapies have limited success on the treatment of BC; therefore, new therapeutic options are needed. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that represent a revolutionary class of new drug candidates because they induce the degradation of harmful, undruggable proteins by activating the ubiquitination machinery of cells. Their unique mechanism of action offers several advantages over conventional drugs, but also disadvantages, as most of them are large molecules with unfavorable pharmacokinetic properties, which limits their bioavailability. Vepdegestrant (VeppanuTM) is an orally administered, estrogen receptor (ER) targeting chimera that was approved by the FDA on 1 May 2026, for the treatment of adults with ESR1-mutated advanced or metastatic breast cancer. Thus, vepdegestrant became the first-ever approved PROTAC drug. In this article, we briefly summarize the structure, mechanism of action, and key available pharmacokinetic and pharmacological data of vepdegestrant.

Background/Objectives: The lack of effective antiviral therapies for many viral infections highlights the need for the development of new antiviral agents. The broad antiviral effects of glycopeptide antibiotics (GPAs) and their derivatives have been previously described. In our studies, we investigated the in vitro viral inhibitory activity of newly synthesized GPA derivatives against Zika virus (ZIKV), chikungunya virus (CHIKV), o'nyong-nyong virus (ONNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: Antiviral activity (EC50) and cytotoxicity (CC50) of the active compounds were determined using cell-based assays. The mechanism of action of the lead compound was investigated using binding and entry assays, cell-free virion pre-incubation, a virion destabilization assay, a liposome-based capsid protection assay, and molecular docking analysis. Results: Seven of the compounds were able to inhibit ZIKV and two compounds inhibited all four tested viruses. Among them, a teicoplanin pseudoaglycone derivative, compound 7, showed the strongest antiviral activity, inhibiting all four viruses at low micromolar concentrations. Mechanistic studies demonstrated that compound 7 acts during an early stage of ZIKV infection and inhibits low-pH-triggered virus-liposome fusion. Molecular docking analysis suggested potential interactions between compound 7 and the viral envelope protein that could interfere with the conformational rearrangements required for membrane fusion. Conclusions: The present findings demonstrate that hydrophobic GPA derivatives, particularly compound 7, exhibit promising broad-spectrum antiviral activity in vitro. Whether similar mechanisms contribute to the antiviral activity against other viruses remains unknown. The studied GPA derivatives are promising candidates for further pre-clinical and clinical development as broad-spectrum antivirals.

Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic phytocannabinoids that have significant, broad-spectrum therapeutic potential in a variety of pharmacological areas, but their unfavorable pharmacokinetics, such as extensive first-pass metabolism and low bioavailability, hinder their effective medical applications. Therefore, there is a great need for appropriate chemical modifications to improve their physicochemical properties. Incorporation of fluorine atom(s) at appropriate positions often improves the metabolic stability of the parent compound, increasing its bioavailability, and enhances its binding affinity to therapeutic targets, making fluorine a highly valuable element in modern drug development. Furthermore, amino functional groups may improve the water solubility and bioavailability of the compounds. Building on these principles, our strategy focused on introducing groups containing mono-, di-, and trifluoroethylamine or fluorinated aniline moieties into cannabinoids to improve their pharmacokinetic and pharmacological profiles. Mannich-type reaction was applied, using commercially available 2-fluoroethylamine, 2,2-difluoroethylamine, 2,2,2-trifluoroethylamine, 3-fluoroaniline and 4-fluoroaniline as reagents. One or two oxazine rings with fluorine-containing side chains were condensed to the aromatic core of the cannabinoids, and the formation of mono- or disubstituted derivatives was controlled by the appropriate choice of reaction conditions. The biological activity of the derivatives was investigated in various relevant fields. Our findings indicate that aliphatic modifications positively influence pharmacokinetic parameters, including absorption, in contrast to aromatic groups, which increase lipophilicity and lead to decreased bioavailability. Among the modifications, the monosubstituted derivatives containing a single oxazine ring with an aliphatic fluorine-containing side chain, especially the mono- and trifluoroethyl moieties, proved to be the most promising. These modifications appeared particularly advantageous in the CBG series compared to the properties of the CBG parent compound. This may suggest that the presence of a phenolic OH group is beneficial for biological activity. Some of the derivatives showed anticancer potential against various tumor cell lines, while others modulated sebaceous lipogenesis, and certain compounds exhibited a notable antimalarial effect.

Hydrogen sulfide (H2S) is an endogenous gasotransmitter with cardioprotective and antiviral effects. In this work, new cysteine-selective nucleoside-H2S-donor hybrid molecules were prepared by conjugating nucleoside biomolecules with a thiol-activatable dithioacetyl group. 5'-Dithioacetate derivatives were synthesized from the canonical nucleosides (uridine, adenosine, cytidine, guanosine and thymidine), and the putative 5'-thio metabolites were also produced from uridine and adenosine. According to our measurements made with an H2S-specific sensor, nucleoside dithioacetates are moderately fast H2S donors, the guanosine derivative showed the fastest kinetics and the adenosine derivative the slowest. The antioxidant activity of 5'-thionucleosides is significantly higher than that of trolox, but lower than that of ascorbic acid, while intact dithioacetates have no remarkable antioxidant effect. In human Calu cells, the guanosine derivative showed a moderate anti-SARS-CoV-2 effect which was also confirmed by virus yield reduction assay. Dithioacetyl-adenosine and its metabolite showed similar acute cardiac effects as adenosine, however, it is noteworthy that both 5'-thio modified adenosines increased left ventricular ejection fraction or stroke volume, which was not observed with native adenosine.

In addition to classic small-molecule drugs and modern protein-based biologics, an intriguing class of medicines is the therapeutic oligonucleotides. Most approved drugs in this category are antisense oligomers or those acting via RNA interference, both of which use base hybridization. Aptamers, also known as chemical antibodies form a smaller, yet equally interesting group of oligonucleotides that can recognize a wide range of molecular targets. Despite their high potential, only two aptamers have been approved to date, pegaptanib (MacugenTM) and avacincaptad pegol (IzervayTM), both for the treatment of age-related macular degeneration (AMD). Targeting vascular endothelial growth factor (VEGF), which plays an important role in the pathogenesis of many eye diseases, pegaptanib emerged as the first anti-VEGF agent and was used in various indications, further inspiring the development of other anti-VEGF therapies. In this review, we summarize the history of the first approved aptamer medicine, pegaptanib. We describe its chemistry and track its development from the earliest stages to the preclinical phase, clinical trials, and eventual regulatory approval. Additionally, we evaluate its position among other therapeutic agents and provide a comprehensive overview of pegaptanib’s efficacy, safety, and cost-effectiveness, comparing these aspects with those of monoclonal antibodies with similar indications, bevacizumab and ranibizumab.

D-xylofuranosyl nucleoside analogues bearing alkylthio and glucosylthio substituents at the C3'-position were prepared by photoinitiated radical-mediated hydrothiolation reactions from the corresponding 2',5'-di-O-silyl-3'-exomethylene uridine. Sequential desilylation and 5'-O-butyrylation of the 3'-thiosubstituted molecules produced a 24-membered nucleoside series with diverse substitution patterns, and the compounds were evaluated for their in vitro antiviral activity against three dangerous human RNA viruses, SARS-CoV-2, SINV and CHIKV. Eight compounds exhibited SARS-CoV-2 activity with low micromolar EC50 values in Vero E6 cells, and two of them also inhibited virus growth in human Calu cells. The best anti-SARS-CoV-2 activity was exhibited by 2',5'-di-O-silylated 3'-C-alkylthio nucleosides. Twelve compounds showed in vitro antiviral activity against CHIKV and fourteen against SINV with low micromolar EC50 values, with the 5'-butyryl-2'-silyl-3'-alkylthio substitution pattern being the most favorable against both viruses. In the case of the tested nucleosides, removal of the 2'-O-silyl group completely abolished the antiviral activity of the compounds against all three viruses. Overall, the most potent antiviral agent was the disilylated 3'-glucosylthio xylonucleoside, which showed excellent and specific antiviral activity against SINV with an EC50 value of 3 μM and no toxic effect at the highest tested concentration of 120 μM.

Tumorous diseases are among the leading causes of death in the developed world, therefore there is a constant need for new antineoplastic medicines. In 2024, the EMA approved 28 anticancer drugs, of which 13 contains new active substances. In this review, we briefly summarize the mechanism of action and use of the new drugs approved by the EMA.

Cardiac hypertrophy is a compensatory response often associated with cardiovascular diseases. While myocardial hypertrophy provides some advantages at the initial stages of these conditions, sustained hypertrophy can damage the heart, leading to arrhythmia and heart failure. An increasing number of H2S donors, with diverse chemical and pharmacological properties, have been identified as potential therapeutic agents against oxidative stress and myocardial hypertrophy, with the possibility of regulating autophagy. The aim of this project was to investigate the effect of H2S on isoproterenol (ISO)-induced cardiac hypertrophy and oxidative stress, as well as its impact on mitochondrial function and autophagy. As exogenous H2S sources, we employed a newly synthesized fast H2S-releasing aspirin derivative (BM-112) and GYY4137 a known slow releasing donor. Our results confirmed that H2S was successfully released from BM-112 in a cell culture medium, and each compound enhanced significantly the intracellular level of H2S, as measured using the HSip-1 DA probe. Biocompatibility of BM-112 was assessed using MTT assay, which showed no cytotoxic effect on H9c2 at concentrations below 50 µM. Both H2S releasing molecules, BM-112 and GYY4137, significantly inhibited ISO-induced hypertrophy in cardiomyocytes, as evidenced by decreased cell size. GYY4137 effectively inhibited ISO-induced oxidative stress (DCF-DA) and mitigated mitochondrial dysfunction (MitoSOX Red and JC-1), whereas BM-112 failed to alleviate these effects. Changes in autophagic protein expressions were analyzed by Western blot, and LC3B/p62 colocalization was visualized with Lysotracker Red. We identified impaired autophagic flux in the presence of ISO and BM-112. However, GYY4137 treatment promoted autophagy beyond basal levels.Taken together, GYY4137, but not BM-112, successfully prevented adrenergic overstimulation-induced hypertrophy by reducing oxidative stress, mitigating mitochondrial dysfunction, and enhancing autophagic flux.

α‐Glycosyl thiols are key building blocks for the formation of stable thioglycoside mimetics of widespread and biologically relevant α‐ O ‐glycosides, which urges their efficient synthesis. Here, we demonstrate that the photoinitiated radical‐mediated addition of thioacetic acid to 2‐substituted glycals followed by selective S ‐deacetylation is a generally applicable and fully stereoselective method for the synthesis of 1,2‐ cis ‐α‐glycosyl thiols. The low reactivity of thioacetic acid in the radical reaction was overcome by carrying out the reaction in AcOH at −80 °C, in frozen state, with UVA irradiation, achieving high yields irrespective of the sugar configurations. For effective irradiation and simultaneous effective cooling, a self‐made spiral vessel reactor was used, which also enables large‐scale synthesis. By subjecting 1,2‐ cis ‐α‐1‐thiosugars to a second thiol‐ene coupling reaction with 2‐substituted glycals, 34 trehalose‐type symmetrical and unsymmetrical α,α’‐thiodi‐ and oligosaccharides were obtained with full stereoselectivity. Moreover, the oxidation of α‐1‐thiosugars provided an easy access to α,α’‐diglycosyl disulfides.

Hydrogen sulfide (H2S), a gasotransmitter, plays a crucial role in vasorelaxation, anti-inflammatory processes and mitigating myocardial ischemia/reperfusion-induced injury by regulating various signaling processes. We designed a water soluble H2S-releasing ascorbic acid derivative, BM-164, to combine the beneficial cardiovascular and anti-inflammatory effects of H2S with the excellent water solubility and antioxidant properties of ascorbic acid. DPPH antioxidant assay revealed that the antioxidant activity of BM-164 in the presence of a myocardial tissue homogenate (extract) increased continuously over the 120 min test interval due to the continuous release of H2S from BM-164. The cytotoxicity of BM-164 was tested by MTT assay on H9c2 cells, which resulted in no cytotoxic effect at concentrations of 10 to 30 μM. The possible beneficial effects of BM-164 (30 µM) was examined in isolated 'Langendorff' rat hearts. The incidence of ventricular fibrillation (VF) was significantly reduced from its control value of 79 % to 31 % in the BM-164 treated group, and the infarct size was also diminished from the control value of 28 % to 14 % in the BM-164 treated group. However, coronary flow (CF) and heart rate (HR) values in the BM-164 treated group did not show significantly different levels in comparison with the drug-free control, although a non-significant recovery in both CF and HR was observed at each time point. We attempted to reveal the mechanism of action of BM-164, focusing on the processes of autophagy and apoptosis. The expression of key autophagic and apoptotic markers in isolated rat hearts were detected by Western blot analysis. All the examined autophagy-related proteins showed increased expression levels in the BM-164 treated group in comparison to the drug-free control and/or ascorbic acid treated groups, while the changes in the expression of apoptotic markers were not obvious. In conclusion, the designed water soluble H2S releasing ascorbic acid derivative, BM-164, showed better cardiac protection against ischemia/reperfusion-induced injury compared to the untreated and ascorbic acid treated hearts, respectively.

Epigenetic therapy is a relatively novel, but undoubtedly a promising area of pharmacology. Most epigenetic drugs act by affecting enzymes and play a role in post-translational modifications of histones. The molecular targets of these medicines include histone methyltransferases, histone demethylases, isocitrate dehydrogenases, histone acetyltransferases and histone deacetylases. Since histone modifications are important regulatory signals, abnormalities in this process often lead to tumorigenesis, therefore these medicines constitute an important class of antitumor therapy. In this tutorial review, we would like to briefly overview the medicines that affect histone modifications, focusing on the currently approved ones, and briefly mention other interesting examples.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms of action and some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. The most effective small-molecule drug approved to date for the treatment of COVID-19 is PaxlovidTM, which is a combination of two protease inhibitors, nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (Mpro) of SARS-CoV-2, which enzyme plays a crucial role in viral reproduction. In this combination, ritonavir serves as a pharmacokinetic enhancer, it irreversibly inhibits the cytochrome CYP3A4 enzyme responsible for the rapid metabolism of nirmatrelvir, thereby increasing the half-life and bioavailability of nirmatrelvir. In this tutorial review, we summarize the development and pharmaceutical chemistry aspects of Paxlovid, covering the evolution of protease inhibitors, the warhead design, synthesis and the mechanism of action of nirmatrelvir, as well as the synthesis of ritonavir and its CYP3A4 inhibition mechanism. The efficacy of Paxlovid to novel virus mutants is also overviewed.

Human Galectin-3 (hGal-3) is a protein that selectively binds to β-galactosides and holds diverse roles in both normal and pathological circumstances. Therefore, targeting hGal-3 has become a vibrant area of research in the pharmaceutical chemistry. As a step towards the development of novel hGal-3 inhibitors, we synthesized and investigated derivatives of thiodigalactoside (TDG) modified with different aromatic substituents. Specifically, we describe a high-yielding synthetic route of thiodigalactoside (TDG); an optimized procedure for the synthesis of the novel 3,3′-di-O-(quinoline-2-yl)methyl)-TDG and three other known, symmetric 3,3′-di-O-TDG derivatives ((naphthalene-2yl)methyl, benzyl, (7-methoxy-2H-1-benzopyran-2-on-4-yl)methyl). In the present study, using competition Saturation Transfer Difference (STD) NMR spectroscopy, we determined the dissociation constant (Kd) of the former three TDG derivatives produced to characterize the strength of the interaction with the target protein (hGal-3). Based on the Kd values determined, the (naphthalen-2-yl)methyl, the (quinolin-2-yl)methyl and the benzyl derivatives bind to hGal-3 94, 30 and 24 times more strongly than TDG. Then, we studied the binding modes of the derivatives in silico by molecular docking calculations. Docking poses similar to the canonical binding modes of well-known hGal-3 inhibitors have been found. However, additional binding forces, cation–π interactions between the arginine residues in the binding pocket of the protein and the aromatic groups of the ligands, have been established as significant features. Our results offer a molecular-level understanding of the varying affinities observed among the synthesized thiodigalactoside derivatives, which can be a key aspect in the future development of more effective ligands of hGal-3.

Hypoxanthine-tricyclano is a synthetic adenosine analogue, in which adenine and ribose have been replaced by hypoxanthine and a morpholino-derived tricyclic moiety, respectively. We investigated whether hypoxanthine-tricyclano could influence atrial inotropy and/or chronotropy, two important functions regulated by the A1 receptor, the main adenosine receptor type of the supraventricular myocardium. Paced left atria and spontaneously beating right atria, isolated from male, 30-35 weeks old, Wistar rats, were used. The ino- and chronotropic effects of adenosine and hypoxanthine-tricyclano (separately and together) were assessed in the absence and presence of 8-cyclopentyl-1,3-dipropylxanthine (CPX), a selective, orthosteric, reversible A1 adenosine receptor antagonist. We found that adenosine exerted a strong negative inotropic effect (similar in left and right atria). However, hypoxanthine-tricyclano elicited a moderate positive inotropic effect (also similar in all atria). In right atria, adenosine evoked a robust negative chronotropic effect, whereas hypoxanthine-tricyclano produced a slight positive chronotropy. CPX blunted the effects of both adenosine and hypoxanthine-tricyclano, although this antagonism was strong (and significant) for adenosine, while smaller (and non-significant) for hypoxanthine-tricyclano. Both effects of hypoxanthine-tricyclano were easily surmountable with adenosine. Thus, hypoxanthine-tricyclano may act as a week, orthosteric, reversible, inverse and low-affinity agonist of the A1 receptor, although alternative mechanisms of action cannot be excluded.

Pseudomonas aeruginosa is a prevalent opportunistic human pathogen, particularly associated with cystic fibrosis. Among its virulence factors are the LecA and LecB lectins. Both lectins play an important role in the adhesion to the host cells and display cytotoxic activity. In this study, we successfully synthesized hardly hydrolysable carbohydrate ligands targeting these pathogenic lectins, including two bispecific glycans. The interactions between LecA/LecB lectins and synthetic glycans were evaluated using hemagglutination (yeast agglutination) inhibition assays, comparing their efficacy with corresponding monosaccharides. Additionally, the binding affinities of bispecific glycans were assessed using isothermal titration calorimetry (ITC). Structural insight into the lectin-ligand interaction was obtained by determining the crystal structures of LecA/LecB lectins in complex with one of the bispecific ligands using X ray crystallography. This comprehensive investigation into the inhibitory potential of synthetic glycosides against P. aeruginosa lectins sheds light on their potential application in antimicrobial therapy.