MedChemComm最新文献

Alzheimer's disease (AD) and cancer are among the most devastating diseases of the 21st century. Although the clinical manifestations are different and the cellular mechanisms underlying the pathologies are opposite, there are different classes of molecules that are effective in both diseases, such as quinone-based compounds and histone deacetylase inhibitors (HDACIs). Herein, we investigate the biological effects of a series of compounds built to exploit the beneficial effects of quinones and histone deacetylase inhibition (compounds 1–8). Among the different compounds, compound 6 turned out to be a potent cytotoxic agent in SH-SY5Y cancer cell line, with a half maximal inhibitory concentration (IC₅₀) value lower than vorinostat and a pro-apoptotic activity. On the other hand, compound 8 was nontoxic up to the concentration of 100 μM and was highly effective in stimulating the proliferation of neural precursor cells (NPCs), as well as inducing differentiation into neurons, at low micromolar concentrations. In particular, it was able to induce NPC differentiation solely towards a neuronal-specific phenotype, without affecting glial cells commitment.

Hyperuricemia is characterized by higher-than-normal levels of uric acid in the bloodstream. This condition can increase the likelihood of developing gout, a form of arthritis triggered by the deposition of urate crystals in the joints, leading to inflammation and pain. An essential part of purine metabolism is played by the enzyme xanthine oxidase (XO), which transforms xanthine and hypoxanthine into uric acid. Despite its vital role, diseases such as gout have been associated with elevated uric acid levels, which are linked to increased XO activity. To manage hyperuricemia, this study focuses on potential nitrogen based heterocyclic compounds that may serve as XO inhibitors which may lower uric acid levels and prevent hyperuricemia. Xanthine oxidase inhibitors are a class of medications used to treat conditions like gout by reducing the production of uric acid. The present study demonstrates numerous compounds, particularly nitrogen containing heterocyclic compounds including their synthesis, structure–activity relationship, and molecular docking studies. This paper also contains drugs undergoing clinical studies and the xanthine oxidase inhibitors that have been approved by the FDA.

Antimicrobial peptides (AMPs) are naturally occurring or designed peptides up to a few tens of amino acids which may help address the antimicrobial resistance crisis. However, their clinical development is limited by toxicity to human cells, a parameter which is very difficult to control. Given the similarity between peptide sequences and words, large language models (LLMs) might be able to predict AMP activity and toxicity. To test this hypothesis, we fine-tuned LLMs using data from the Database of Antimicrobial Activity and Structure of Peptides (DBAASP). GPT-3 performed well but not reproducibly for activity prediction and hemolysis, taken as a proxy for toxicity. The later GPT-3.5 performed more poorly and was surpassed by recurrent neural networks (RNN) trained on sequence-activity data or support vector machines (SVM) trained on MAP4C molecular fingerprint-activity data. These simpler models are therefore recommended, although the rapid evolution of LLMs warrants future re-evaluation of their prediction abilities.

Inflammation is the body's response to defence against infection or injury, and is associated with the progression of many diseases, such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). LCA, a dibenzylbutane lignan extracted from the roots of traditional medicinal plant Litsea cubeba (Lour.) Pers., has demonstrated promising anti-inflammatory activity. In this study, a series of novel LCA derivatives were designed, synthesized, and evaluated for anti-inflammatory activity. Lipopolysaccharide (LPS)-induced RAW 264.7 cell model experiments showed that compound 10h (at 20 μM of concentration) had the strongest inhibitory effect on NO release, and inhibited the secretion and gene expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in vitro. In addition, western blot, immunofluorescence, and molecular docking showed that the anti-inflammatory mechanism of compound 10h may be related to the nuclear factor (NF)-κB signalling pathway. In vivo studies based on a carrageenan-induced mouse paw edema model have shown significant anti-inflammatory activity of compound 10h at 20 mg kg⁻¹. Preliminary in vitro and in vivo studies indicate that compound 10h has the potential to be developed as a novel anti-inflammatory agent.

In a recent paper in this journal (RSC Med. Chem., 2023, 14, 2429), we described an unusually strong impact of regiospecific exchange of phenylalanines by tyrosines in 10 gallium-68-labeled trimers of certain cyclic RGD peptides, c[XRGDLAXp(NMe)K] (X = F or Y), on non-specific organ uptakes. We found that there was, in part, no correlation of liver uptake with established polarity proxies, such as the octanol–water distribution coefficient (log D). Since this observation could not be explained straightforwardly, we suggested that the symmetry of the compounds had resulted in a synergistic interaction of certain components of the macromolecules. In the present work, we investigated whether a comparable effect also occurred for a series of 5 tetramers labeled with lutetium-177. We found that in contrast to the trimers, liver uptake of the tetramers was well correlated to their polarity, indicating that the unusual observations along the trimer series indeed was a unique feature, probably related to their particular symmetry. Since the Lu-177 labeled tetramers are also potential agents for treatment of a variety of αvβ6-integrin expressing cancers, these were evaluated in mice bearing human lung adenocarcinoma xenografts. Due to their tumor-specific uptake and retention in biodistribution and SPECT imaging experiments, these compounds are considered a step forward on the way to αvβ6-integrin-targeted anticancer agents. Furthermore, we noticed that the presence of tyrosines in general had a positive impact on the in vivo performance of our peptide multimers. In view of the fact that a corresponding rule was already proposed in the context of protein engineering, we argue in favor of considering peptide multimers as a special class of small or medium-sized proteins. In summary, we contend that the performance of peptide multimers is less determined by the in vitro characteristics (particularly, affinity and selectivity) of monomers, but rather by the peptides' suitability for the overall macromolecular design concept, and peptides containing tyrosines are preferred.

Phosphonate and phosphate prodrugs are integral to enhancing drug permeability, but the potential toxicity of their metabolites requires careful consideration. This study evaluates the impact of widely used phosphoramidate, bis-amidate, and cycloSal phosph(on)ate prodrug metabolites on BxPC3 pancreatic cancer cells, GL261-Luc glioblastoma cells, and primary cultured mouse astrocytes. 1-Naphthol and 2-naphthol demonstrated the greatest toxicity. Notably, 2-naphthol exhibited an ED₅₀ of 21 μM on BxPC3 cells, surpassing 1-naphthol with an ED₅₀ of 82 μM. Real-time xCELLigence experiments revealed notable activity for both metabolites at a low concentration of 16 μM. On primary cultured mouse astrocyte cells, all prodrugs exhibited reduced viability at 128 to 256 μM after only 4 hours of exposure. A cell-type-dependent sensitivity to phosph(on)ate prodrug metabolites was evident, with normal cells showing greater susceptibility than corresponding tumour cells. The results suggest it is essential to consider the potential cytotoxicity of phosph(on)ate prodrugs in the drug design and evaluation process.

Decades ago, the application of cyclic sulfonamide (sultam) and its derivatives primarily focused on their antibacterial properties. However, recent years have seen a shift in research attention towards exploring their potential as anticancer, anti-inflammatory, antidiabetic, and antiviral agents. Despite this broadening scope, only a few sultam drugs have made it to the commercial market, as much of the research on sultams remains in the discovery phase. This class of compounds holds significant promise and remains pertinent in pharmaceutical research. Due to sultam's relevance and growing importance in drug discovery, this review paper aims to consolidate and examine the biological activities of sultam derivatives ranging from 4 to 8-membered ring structures.

MANIO is an efficient p53-activating anticancer agent with remarkable selectivity to the p53 pathway and promising antitumor activity against colorectal cancer (CRC). Herein, a library of novel MANIO derivatives, including hydroxymethyl- and bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles, was synthesized by rational structural modulation. The antiproliferative activity of twenty derivatives was evaluated in a panel of human CRC cells with different p53 status. From this library, five compounds with R- and S-configuration and with aromatic or heteroaromatic groups at position 3, including the enantiomer of MANIO, were identified as selective towards p53-expressing cancer cells. On the other hand, two compounds with S-configuration, 6-hydroxymethyl- and 7-hydroxymethyl-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazoles, showed high cytotoxicity against WTp53-expressing HCT116 colon cells but, unlike MANIO, exhibited p53-independent inhibitory activity in CRC. The results described provide relevant structural and pharmacophoric data for the design of new p53-activating agents for precision therapy of CRC or other p53-related cancers harboring both wild-type or mutated p53 forms.

Endometrial cancer (EC) is a common malignancy among women worldwide, and its recurrence makes it a common cause of cancer-related death. Surgery and external radiation, chemotherapy, or a combination of strategies are the cornerstone of therapy for EC patients. However, adjuvant treatment strategies face certain drawbacks, such as resistance to chemotherapeutic drugs; therefore, it is imperative to explore innovative therapeutic strategies to improve the prognosis of EC. With the development of pathology and pathophysiology, several biological targets associated with EC have been identified, including PI3K/Akt/mTOR, PARP, GSK-3β, STAT-3, and VEGF. In this review, we summarize the progress of small molecule targeted therapies in terms of both basic research and clinical trials and provide cases of small molecules combined with fluorescence properties in the clinical applications of integrated diagnosis and treatment. We hope that this review will facilitate the further understanding of the regulatory mechanism governing the dysregulation of oncogenic signaling in EC and provide insights into the possible future directions of targeted therapeutic regimens for EC treatment by developing new agents with fluorescence properties for the clinical applications of integrated diagnosis and treatment.

Synthetic cannabinoid receptor agonists (SCRAs) comprise the second largest class of new psychoactive substances (NPS), and typically α-amino acid moieties are incorporated as part of their design. Limited investigation has been performed into elucidating structure–activity relationships around commonly used α-amino acid-derived head groups, mainly with valine and tert-leucine-derived compounds previously described. As such, proactive synthesis, characterisation and pharmacological evaluation were performed to explore structure–activity relationships of 15 α-amino acid derivatives, with both the natural isomers and their enantiomers at CB₁ and CB₂ investigated using a fluorescence-based membrane potential assay. This library was based around the detected SCRAs MPP-5F-PICA, MMB-5F-PICA, and MDMB-5F-PICA, with the latter showing significant receptor activation at CB₁ (pEC₅₀ = 8.34 ± 0.05 M; E_max = 108 ± 3%) and CB₂ (pEC₅₀ = 8.13 ± 0.07 M; E_max = 99 ± 2%). Most valine and leucine derivatives were potent and efficacious SCRAs, while smaller derivatives generally showed reduced activity at CB₁ and CB₂, and larger derivatives also showed reduced activity. SAR trends observed were rationalised via in silico induced fit docking. Overall, while natural enantiomers showed equipotent or greater activity than the unnatural isomers in most cases, this was not universal. As such, a number of these compounds should be monitored as emerging NPS, and various substituents described herein.