ChemMedChem最新文献

The interaction of G-quadruplex (non-canonical DNA) with suitable compounds for their stabilization at the promoter region of oncogenes has become a potential anticancer approach. We have studied the interaction of phenanthroimidazoisoindol-acrylates derivatives with c-MYC G-quadruplex. A series of 20 compounds were evaluated for their anticancer activity against human cancer cell lines, where compounds 3 fa, 3 ha, and 3 ae have shown the broad-spectrum anticancer activities against most of the cancer cell lines and inactive towards normal cell lines. Various spectroscopic techniques have been used to study the interaction of these compounds. The studies reveal the strong binding of all three compounds with c-MYC G-quadruplex with significant selectivity over dsDNA, with binding constant of the order of 10⁶ M^-1. All three compounds bind effectively with HSA, which is a carrier protein, with binding constant of the order of 10⁵ M^-1. These results show that phenanthroimidazoisoindol-acrylate derivatives exhibit specificity towards G4 DNA, highlighting their potential as effective anticancer agents targeting the c-MYC G-quadruplex.

Phosphate-containing Glycolipids are structures that are not as widely understood as glycolipids. They are divided into two classes: phosphoglycolipids and glycophospholipids – depending on the position of the phosphate. They are inspired by natural sources of various origins. Because of their lipidic portion they are often associated with biological membranes. Their bioactivities concern mainly anti-metastasis, platelet aggregation, inflammatory, antifungal, antibiotic and neurogenic activities. More details can be found in article 10.1002/cmdc.202400315 by Luís Pinheiro and co-workers.

This illustration depicts the molecular interactions of isocryptolepine-triazole hybrids with Acetylcholinesterase (AChE) in the brain related to Alzheimer′s disease. Central to the image is AChE, an enzyme involved in neurotransmitter regulation. Surrounding AChE are potential new compounds designed to inhibit its activity, thereby enhancing cholinergic signaling and potentially alleviating symptoms of Alzheimer′s. The visual emphasizes the innovative research aimed at developing effective therapeutics for this progressive neurodegenerative disorder. More details can be found in article 10.1002/cmdc.202400447 by Jumreang Tummatorn, Nutchapong Suwanwong, and co-workers.

Galectins are a family of galactoside-binding proteins involved in various pathophysiological processes, which makes them attractive targets for drug discovery. The derivatization of d-galactose at C3 and C1 positions has been shown to increase the affinity of synthetic galectin antagonists. In this study, two small libraries of d-galactose derivatives have been designed and synthesized. The first series involved the development of novel aromatic 3-azolyl-3-deoxy-d-galactopyranoses. The second series consisted of epimeric analogs of glyceryl β-S-d-galactopyranosides, which were also derivatized. Binding-affinity evaluations for galectin-1 and galectin-3 have revealed that galactose analogs from both series have potential for further optimization. Notably, a combination of modifications at the C3 position of the galactose ring and on the aglycone has led to the identification of promising galectin inhibitors, specifically the compounds 29R and 32S.

Inhibitors of ʟ-lactate transport are in development as a novel mode of action in antitumor therapy and malaria. Previously, we used radiolabeled ʟ-lactate to assay transport via the human monocarboxylate transporter 1, MCT1, and the structurally unrelated malaria parasite's transporter, PfFNT. We encountered a sensitivity limit at IC₅₀ around 100 nM possibly resulting from the required high cell number per sample. Here, we describe a sensitive background-free high-throughput assay in yeast based on fluorescent iLACCO biosensors. We used iLACCO for co-expression and fusions with the transporter protein. Uptake of ʟ-lactate produced strong intensiometric fluorescent responses that could be monitored in cell suspensions using a fluorometer and in individual cells by fluorescence microscopy. The signal decreased dose-dependently in the presence of specific MCT1 and PfFNT inhibitors. Re-evaluation of 36 PfFNT inhibitors yielded IC₅₀ values below 100 nM now matching previous data on K_i compound affinity to isolated transporter protein.

Herein, we report the design, synthesis, and characterisation of a new library of enantiopure aminoalcohol fluorenes, as well as their in vitro evaluation for biological properties, including activity against two strains of P. falciparum (3D7 and W2) and cytotoxicity on the HepG2 cell line. All tested compounds exhibited good to excellent antimalarial potency with IC₅₀ values ranging from 0.7 to 70.2 nM whatever the strain. Interestingly, most compounds showed equal or better antimalarial activity compared to the reference drugs lumefantrine, mefloquine and chloroquine. Despite moderate cytotoxicity in the micromolar range, all aminoalcohol fluorenes displayed an excellent selectivity index higher than 100 due to strong antimalarial activity. Furthermore, we report in silico analyses of physicochemical and pharmacokinetic properties for all compounds, highlighting the drug-likeness of compound 10 and its promising potential for further studies.

Various series of 4,6-disubstituted-2-thiopyridine derivatives were synthesized and evaluated as potential ecto-5'-nucleotidase (CD73) inhibitors. Altogether, about ninety compounds were prepared using a general synthetic pathway involving one or two steps (eventually one-pot) procedures. Variation of the nature of the substituents in positions 4 and 6 (methyl, trifluoromethyl or phenyl) of the thiopurine ring, as well as on the thiol function, was examined and led to marked differences both in term of reactivity and ability to interfere with the putative target protein. Using a functional assay on immune cells, few compounds belonging to series 4 were shown to be able to antagonize the inhibition of the T-cell proliferation at both 100 μM and 10 μM (completely for 4 ab and partially for 4 ai), that is as potent as AOPCP which entirely reversed the inhibitory impact of exogenous ATP on T cell proliferation until 62.5 μM. In addition, we have shown that both compounds (4 ab and 4 ai) were also capable of moderately inhibiting the hA_2A receptor with Ki in the μmolar range in HEK-293 cells. Thus, with the aim to reduce the molecular size and the lipophilicity of our initial scaffold, we finally observed by serendipity a modification of the potential target of our compounds.

Autophagy is an evolutionarily conserved turnover process in eukaryotes, mediating the delivery of various cellular components to lysosomes for degradation and facilitating the recycling of the breakdown products to maintain homeostasis. By harnessing this powerful autophagy-lysosomal degradation system, strategies for targeted protein degradation (TPD) have been emerging to remove specific disease-related proteins (both intracellular and cell-surface proteins) for complete elimination of their functions, bringing new insights to drug discovery. Herein, we give a brief introduction on how autophagy works followed by a focus on available small-molecule and macromolecule-based strategies for TPD mediated by autophagy.

The development of non-nucleoside inhibitors targeting human cytomegalovirus (HCMV) polymerase presents a promising approach for enhancing therapeutic treatment for patients with sustained HCMV viremia. A series of non-nucleoside HCMV DNA polymerase inhibitors with various substitution groups at 2-postition of the novel pyrido[2,3-b]pyrazine core was synthesized and investigated. The study focused on optimizing HCMV polymerase inhibition while minimizing off-target inhibition of human ether-à-go-go (hERG) ion channel. Several compounds exhibited strong antiviral activity against HCMV (typical EC₅₀<1 μM), with favorable cytotoxicity profiles. A potent lead compound, 27, with an EC₅₀ of 0.33 μM and improved aqueous solubility was identified. Further antiviral assessments revealed the potential of select compounds to target a broad spectrum of herpesviruses, including herpes simplex virus (HSV-1, HSV-2) and Epstein-Barr virus (EBV).

[⁸⁹Zr]Zr⁴⁺ is a radionuclide of increasing clinical relevance for PET (positron emission tomography). However, an ideal chelator for stable Zr-chelation remains to be discovered. This study describes the solid-phase synthesis of octadentate Zr-chelators based on an isopeptidic (ip) scaffold derived from the natural siderophore desferrioxamine (DFOB). Several analogues with different spacers separating the chelating hydroxamates have been prepared and converted to [⁸⁹Zr]Zr-complexes. The stability of these complexes was evaluated in human serum and in competition to excess of competing chelators. The assays revealed a beneficial effect of long hydroxamate spacing (9 atoms). Shorter spacing led to a decrease in complex stability. The most stable [⁸⁹Zr]Zr-ipDFO complex had a high stability in challenging competition experiments with a large excess of EDTA for 72 h as determined by radio TLC and LC/MS. The straightforward synthesis, high complex stability and a modular character make ipDFO derivatives promising chelators for applications in targeted PET.