ChemMedChem最新文献

Quaternary ammonium compounds (QACs) have been essential for protecting human health for almost a century, functioning as surface disinfectants and sanitizers. With bacterial resistance increasing against commercially available QACs, the development of novel antimicrobials with divergent architectures is essential for effective infection prevention and control. Toward this end, our group has expanded beyond traditional ammonium scaffolds and explored the development of quaternary phosphonium compounds (QPCs). Herein, we report the synthesis and biological investigation of a series of 20 novel multicationic QPCs, bearing multiple short alkyl or aryl chains, also referred to as "bushy-tailed" multiQPCs; these structures were hypothesized to have strong bioactivity while displaying low mammalian toxicity. Select bushy-tailed QPC derivatives with trishexylphosphonium groups displayed single-digit or sub-micromolar activity against all seven bacteria tested, and MIC values of 2- to 8-fold better than their bushy-tailed QAC counterparts. Importantly, therapeutic indices of these bushy-tailed QPCs were favorable in many cases, and were ≥4 against the entire bacterial panel for pX-P6*,P6* and 1,8-P6*,P6*, superior to more traditional architectures. This work highlights the promise of a novel set of multicationic phosphonium compounds as novel disinfectants with potent bioactivities and low toxicity.

The advancement of tissue engineering (TE) is driven by the development of scaffolds that mimic the mechanical, spatial, and biological environment of the extracellular matrix (ECM), crucial for regulating cell behavior and tissue repair. Hydrogels, 3D networks of polymer chains, are particularly suited for TE due to their high biocompatibility, ability to mimic tissue water content, facilitate cell migration, sustain growth factor release, and offer controllable physical properties. However, hydrogels mimicking the ECM often face challenges related to cell adhesion due to the absence of specific receptors. This issue can be addressed by incorporating ECM components into the polymer matrix, such as the peptide sequence arginine-glycine-aspartic acid (RGD), known for its role in cell adhesion. Additionally, carbon nanomaterials (CNMs) offer unique physicochemical properties that can improve scaffold-cell interactions. Despite the potential benefits, there are limited reports on their combination. RGD-CNM hydrogels enable a more accurate emulation of the natural cellular environment, enhancing tissue engineering applications. This hybrid approach may promote robust cell adhesion along with exceptional mechanical and electrical properties. This review outlines the potential benefits of these hybrid scaffolds and their synergistic potential, aiming to inspire new research directions in this innovative field.

In this concept, we present a comprehensive study on the development and application of COX-2-specific fluorescent probes for cancer imaging and diagnosis. To target cancer cells and measuring cancer-related activities in specific organelles quickly and accurately are crucial factors for early diagnosis and research on cancer pathology and treatment. This concept explores a variety of probes based on indomethacin (IMC), celecoxib, rofecoxib as well as CoxFluor and each one demonstrates unique mechanisms and high selectivity towards COX-2 enzymes. These probes were designed to enhance fluorescence upon binding to COX-2 which enable precise visualization of tumor and inflamed tissues. The research emphasizes the importance of COX-2 as a biomarker in cancer diagnostics, particularly in identifying cancer stem cells and inflamed tissues. This concept highlights the potentiality of these probes in non-invasive imaging techniques which offering significant advancements in cancer diagnosis and monitoring. The in vivo and in vitro experiments, including applications in mouse models and human tissue samples, confirm the efficacy of these probes in providing detailed imaging for clinical and research applications.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDL-R) degradation. We previously identified and optimized 13-mer cyclic peptides that bind to a novel, induced-fit pocket adjacent to the binding interface of PCSK9 and LDL-R and effectively disrupted the PCSK9/LDL-R protein-protein interaction (PPI) both in vitro and in vivo. However this series of large cyclic peptides required charged groups for function and lacked oral bioavailability in rodents. We describe herein multiple structure-based modifications to these original peptides to yield truncated, neutral molecules with full PPI function in both biochemical and cellular assays. In parallel, new mRNA-peptide display screens identified non-functional 8- and 9-mer compounds which ligand the induced-fit pocket in a distinct manner. Taken together, these studies indicate multiple directions to reduce the size and complexity of this peptide class toward a true small molecule oral agent.

A series of xylose-based ligands was obtained using a convenient approach, in a few steps from D-xylose. The complexation properties of these ligands towards Au3+ cations have been studied through different methods (multinuclear NMR, mass spectrometry, elemental analysis). The biological properties (antibacterial and anti-tumoral) of all the isolated xyloside Au(III) complexes were investigated in vitro. The xyloside Au(III) complexes gave the highest activities against E. coli(vs P. aeruginosa, S. aureus and S. epidermidis). The study also revealed that the nature of the sugar may play an important role in determining the selectivity of the antibacterial effect. Preliminary anti-tumoral evaluations showed that one complex containing a polyamine chain, exhibited interesting anti-proliferative activities on breast tumor cell lines MDA-MB-231 and BT-20. The anti-migratory effect of this complex also showed an average 35% reduction in cell migration on the same two cancer cell lines.

Natural stilbenoids, polyphenolic compounds notably found in Scots pine and Norway spruce, have been shown to exhibit analgesic and anti-inflammatory effects through the TRPA1 channel, making them promising hits for the development of novel agents to treat inflammatory diseases and pain. In this study, we computationally investigated the putative binding sites of natural stilbenoids at the TRPA1 channel. Specifically, we employed molecular docking and MD simulation approaches to explore three known ligand binding sites at TRPA1. Furthermore, the biological effect of the studied compounds on TRPA1 was assessed in vitro using a fluorescent imaging plate reader (FLIPR™) calcium assay. Our modeling results suggest the stilbenoids exhibit higher affinity to the two agonist binding sites than the antagonistic site. Consistent with this, the in vitro results showed that the stilbenoids act as moderate TRPA1 channel agonists and likely inhibit the channel through a desensitization mechanism rather than act as pure TRPA1 antagonists. Additionally, our bias-force pulling simulations proposed an additional binding pocket for the natural stilbenoids that is distinct from the known ligand binding sites at TRPA1. The results of the study give useful insights into structure-based design and development of novel therapeutic TRPA1 modulators.

Benzofuropyridines (BFP) are polycyclic compounds with known applications in neuronal diseases. However, its derivatization patterns and anticancer potential remains unexplored. Leveraging the idea of diversity-oriented synthesis (DOS), we developed a highly efficient synthetic route for BFP, to increase the library of available analogs producing three compounds in one reaction set up, including the 2O-, 6O-, and the 1 N-substituted species, also synthesizing the unusual 2-pyridone derivatives. Key bromination reaction of the BFP moiety was successfully described which can widen the available variation in the compound's structure. The cytotoxic activity of the compounds was assessed against SH-SY5Y (neuroblastoma), HepG2 (hepatocellular carcinoma), Kb (human oral epidermoid), HeLa (cervical) and MCF-7 (breast) cancer cell lines. In the series, the m-bromobenzyl (5 b), methylcyano (5 g) and propargyl (5 h) 2O-derivatives demonstrated good selectivity against cancer cells with selectivity index (SI) of >71 for 5 g against HeLa over the normal cells, as compared to the standard drug, Doxorubicin (SI=6.7). The quantitative structure-activity relationship (QSAR) analysis revealed an impressive correlation of the defined descriptors with the bioactivity having an R² value of 0.971 and 0.893 for Kb and HeLa respectively. Altogether, our work highlighted new information on the synthesis of BFP derivatives with potent cytotoxic activity.

Therapeutic nucleic acids (TNAs) are a new class of drugs that exhibit different properties and mechanisms of action from those of small molecules or biological drugs. Over twenty oligonucleotide drugs and several COVID-19 vaccines have received regulatory approval for clinical use. A characteristic feature of these TNAs is that they are directed against one specific biological target and one specific RNA or DNA sequence. Consequently, TNAs currently used are administered as monotherapy. Due to the known advantages of multidrug therapy with low molecular weight drugs, it may be time to intensify work on such a treatment protocol, also in the case of TNAs.

Ruthenium complexes incorporating 2,2':6',2''-terpyridine ligands have emerged as promising candidates due to their versatile biological activities including DNA-binding, anti-inflammatory, antimicrobial, and anticancer properties. In this study, three novel 4'-functionalized bis(terpyridine) ruthenium (II) complexes were synthesized. These complexes feature one ligand as 4-(2,2':6',2''-terpyridine-4'-yl) benzoic acid and the second ligand as either 4'-(2-thienyl)-2,2':6',2''-terpyridine, 4'-(3,4-dimethoxyphenyl)-2,2':6',2''-terpyridine, or 4'-(4-dimethylaminophenyl)-2,2':6',2''-terpyridine. Besides the chemical characterization by 1H and 13C NMR, mass spectrometry, and absorption and emission spectroscopy, the complexes were tested for their biological activity as anti-inflammatory, anticancer, and antimicrobial agents. Moreover, the toxicity of the Ru(II) complexes was assessed and benchmarked against diclofenac potassium and ibuprofen using a haemolysis assay. Biological evaluations demonstrate that these ruthenium complexes exhibit promising therapeutic potential with reduced haemolytic activity compared to standard drugs. They demonstrate substantial anti-inflammatory effects through inhibition of albumin denaturation along with moderate cytotoxicity against cancer cell lines and broad-spectrum antimicrobial activity. These findings highlight the multifaceted biomedical applications of 4'-functionalized bis(terpyridine) ruthenium (II) complexes, suggesting their potential for further development as effective and safe therapeutic agents.

The cover represents an approach to creating a diverse chemical library with unique scaffolds. Combining the expertise of chemoinformaticians, organic synthetic chemists, and medicinal chemists, two libraries were developed. Starting with over 10000 in-stock compounds, the essential chemical library (eIMS) consists of 578 original and diverse compounds on plates, ready for high-throughput screening. Additionally, using chemoinformatics tools the virtual chemical library (vIMS) featuring 821070 unique, original, virtual compounds was created. This emphasized efficient hit-to-lead optimization, based on established synthetic pathways and medicinal chemistry guidelines. More details can be found in article 10.1002/cmdc.202400381 by Esther Kellenberger and co-workers. Cover design by Teodora Djikic-Stojsic.