RSC medicinal chemistry最新文献

The Wnt/β-catenin signaling pathway plays a critical role in various biological processes, including cell proliferation, differentiation, and tissue homeostasis. Aberrant activation of this pathway is strongly associated with the development of various cancers, including colorectal, pancreatic, and gastric cancers, making it a promising therapeutic target. In recent years, inhibitors targeting different components of the Wnt/β-catenin pathway, including small molecules, peptides, and nucleic acid-based therapies, have been developed to suppress cancer cell growth. These inhibitors work by disrupting key interactions within the pathway, thereby preventing tumor progression. Antibody-based therapies have also emerged as potential strategies to block ligand-receptor interactions within this pathway. Despite these advancements, challenges such as the complexity of the pathway and toxicity concerns remain. Innovative approaches, including allosteric inhibitors, proteolysis-targeting chimeras (PROTACs), and peptide-based inhibitors, offer new opportunities to address these challenges. This review provides an overview of the latest progress in the development of Wnt/β-catenin pathway inhibitors and explores future directions in cancer therapy.

Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public–private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents. The substantial outputs of this programme include a chemogenomic compound library covering one third of the druggable proteome, as well as 100 chemical probes, both profiled in patient derived assays, as well as hundreds of data sets deposited in existing public data repositories and a project-specific data resource for exploring EUbOPEN outputs.

Inflammatory pain represents one of the unmet clinical needs for patients, as conventional therapies cause several side effects. Recently, new targets involved in inflammatory pain modulation have been identified, including the sigma-1 receptor (σ1R). Selective σ1R antagonists have demonstrated analgesic efficacy in acute and chronic inflammatory pain models. Considering these findings, a series of novel N-normetazocine derivatives has been designed and synthesized to investigate the pivotal role of N-normetazocine stereochemistry in their pharmacological fingerprint. The affinity profile of new ligands versus sigma receptors and opioid receptors was evaluated in vitro, and compound 7 showed a relevant σ1R affinity, with K _iσ1 = 27.5 ± 8.1 nM, and selectivity over sigma-2 receptor (σ2R) and opioid receptors. Furthermore, in vivo, compound 7 significantly reduced inflammatory pain in the second phase of the formalin test. Molecular modeling studies were also performed to analyze the binding mode and the key interactions between the new ligands and σ1R.

Radionuclide theranostics - a fast-growing emerging field in radiopharmaceutical sciences and nuclear medicine - offers a personalised and precised treatment approach by combining diagnosis with specific and selective targeted endoradiotherapy. This concept is based on the application of the same molecule, labelled with radionuclides possessing complementary imaging and therapeutic properties, respectively. In radionuclide theranostics, radionuclide pairs consisting of the same element, such as ^61/64Cu/⁶⁷Cu, ²⁰³Pb/²¹²Pb or ^123/124I/¹³¹I are of significant interest due to their identical chemical and pharmacological characteristics. However, such "true matched pairs" are seldom, necessitating the use of complementary radionuclides from different elements for diagnostics and endoradiotherapy with similar chemical characteristics, such as ^99mTc/^186/188Re, ⁶⁸Ga/¹⁷⁷Lu or ⁶⁸Ga/²²⁵Ac. Corresponding combinations of such two radionuclides in one and the same radioconjugate is referred to as a "matched pair". Notably, the pharmacological behavior remains consistent across both diagnostic and therapeutic applications with "true matched pairs", which may differ for "matched pairs". As "true matched pairs" of theranostic radioisotopes are rare and that some relevant radionuclides do not fit with the diagnostic or therapeutic counterpart, the radionuclide theranostic concept can be expanded and improved by the introduction of the radiohybrid approach. Radiohybrid (rh) ligands represent a new class of radiopharmaceutical bearing two different positions for the introduction of a (radio)metal and (radio)halogen in one molecule, which can be then used for both therapeutic and diagnostic purposes. The following review will give an insight into recent developments of this approach.

Acinetobacter baumannii is one of the deadliest Gram-negative bacteria (GNB), responsible for 2–10% of hospital-acquired infections. Several antibiotics are used to control the growth of A. baumannii. However, in recent decades, the abuse and misuse of antibiotics to treat non-microbial diseases have led to the emergence of multidrug-resistant A. baumannii strains. A. baumannii possesses a complex cell wall structure. Cell wall-targeting agents remain the center of antibiotic drug discovery. Notably, the antibacterial drug discovery intends to target the membrane of the bacteria, offering several advantages over antibiotics targeting intracellular systems, as membrane-targeting agents do not have to travel through the plasma membrane to reach the cytoplasmic targets. Microorganisms, insects, and mammals produce antimicrobial peptides as their first line of defense to protect themselves from pathogens and predators. Importantly, antimicrobial peptides are considered potential alternatives to antibiotics. This communication summarises the recently identified peptides of natural origin and their synthetic congeners acting against the A. baumannii membrane by cell wall disruption.

In this paper, the isopropyl ester derivatives L^OiPr and L^2OiPr of bis(pyrazol-1-yl)acetic acid and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid were used as chelators for the preparation of new Cu(I) phosphane complexes 1–4. They were synthesized by the reaction of [Cu(CH₃CN)₄]PF₆ and triphenylphosphine or 1,3,5-triaza-7-phosphaadamantane with L^OiPr and L^2OiPr ligands, in acetonitrile or acetonitrile/methanol solution. The authenticity of the compounds was confirmed by CHN analysis, ¹H-, ¹³C- and ³¹P-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). Furthermore, the electronic and molecular structures of the selected Cu(I) coordination compound 3 were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), and the local structure around the copper ion site was studied combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modelling. Triphenylphosphine as a coligand confers to [Cu(L^OiPr)(PPh₃)]PF₆ (1) and [Cu(L^2OiPr)(PPh₃)]PF₆ (3) a significant antitumor activity in 3D spheroidal models of human colon cancer cells. Investigations focused on the mechanism of action evidenced protein disulfide-isomerase (PDI) as an innovative molecular target for this class of phosphane copper(I) complexes. By hampering PDI activity, copper(I) complexes were able to cause an imbalance in cancer cell redox homeostasis thus leading to cancer cell death – a non-apoptotic programmed cell death.

In the current study, we have designed and prepared a series of quinoxaline-based compounds, which were derived from o-phenylenediamine. Among them, compounds 5m–5p displayed good to moderate antibacterial activity with MICs of 4–16 μg mL⁻¹ against S. aureus, 8–32 μg mL⁻¹ against B. subtilis, 8–32 μg mL⁻¹ against MRSA and 4–32 μg mL⁻¹ against E. coli, respectively. Compound 5p, identified as a potent broad-spectrum antibacterial agent, demonstrated the strongest inhibitory effects against a range of bacterial strains and low cytotoxicity, thereby warranting further investigation. Compound 5p not only demonstrated the ability to disperse established bacterial biofilms but also induced a slower development of bacterial resistance compared to norfloxacin. Moreover, bactericidal time-kill kinetic studies revealed that at a high concentration of 3MIC, compound 5p was capable of directly killing MRSA cells. The subsequent postcontact effect (PCE) results showed that the growth rate of viable bacteria (MRSA) was greatly impacted and did not recover in less than 24 hours, even after antibacterial agent 5p was removed. The drug-like properties and ADME prediction exhibited that 5m–5p obeyed Lipinski's rule of five and therefore presumably maintained moderate to good bioavailability and human intestinal absorption rate when administered orally. Mechanistic investigations have elucidated that compound 5p exerted its antibacterial effect by compromising the structural integrity of bacterial cell membranes, resulting in the leakage of intracellular constituents and ultimately causing bacterial demise. Further studies in vivo have demonstrated that 5p exhibited potent antibacterial efficacy against MRSA in murine corneal infection models, particularly at elevated concentrations. The current dataset has also been meticulously analyzed to delineate the structure–activity relationships (SARs) of the synthesized compounds.

The mitotic kinase Aurora A, a pivotal regulator of the cell cycle, is overexpressed in various cancers and has emerged as one of the most promising targets for anticancer drug discovery. However, the lack of specificity and potential toxicity have impeded clinical trials involving orthosteric inhibitors. In this study, allosteric sites of Aurora A were predicted using the AlloReverse web server. Based on the non-ATP competitive inhibitor Tripolin A and molecular docking information targeting the desired allosteric site 3 of Aurora A, a series of (E)-3-benzylideneindolin-2-one derivatives were designed and synthesized. Compared to Tripolin A, our compounds AK09, AK34 and AK35 have stronger inhibitory effects and can be further investigated as potential allosteric inhibitors. Moreover, the compound AK34 with the strongest inhibitory activity (IC₅₀ = 1.68 μM) has a high affinity for Aurora A (K_D = 216 nM). According to the analysis of the structure–activity relationship of the compounds and the results of their molecular docking models, these compounds tend to act on the allosteric site 3 of Aurora A.

Invasive fungal infections caused by C. albicans are becoming increasingly serious and there is an urgent need for exploring new antifungal drugs. In the present work, a series of new azole derivatives containing a 1,2,3-triazole moiety have been prepared, and in vitro antifungal activity have been evaluated. The results revealed that most compounds showed excellent antifungal activity against C. albicans SC5314 and drug-resistant SC5314-FR. In particular, compounds 4h, 4j, 4l, 4s and 4w exhibited better antifungal activity than FLC. The preliminary mechanism study indicated that 4s could damage the integrity of the cell structure, increase the permeability of the cell membrane, and cause the leakage of cell contents of C. albicans. The molecular docking study indicated that 4s showed an obvious binding site with the target CYP51 (PDB ID: 5TL8). Therefore, 4s could be considered as a new antifungal agent targeting CYP51 for further study.

A series of amides of selected plant triterpenoids, moronic acid and morolic acid, with the tripeptides MAG and GAM, was designed and synthesized. Two required tripeptides 5 and 10 were synthesized by a step-wise chain elongation of the ethyl esters of either glycine or L-methionine at their N-terminus using Boc-protected amino acids in each step. The tripeptides 5 and 10 were used for the synthesis of 13–23, the derivatives of moronic acid (11) and morolic acid (12), to get a series of amide derivatives of the less frequently studied triterpenoids 11 and 12. The target compounds, and their intermediates, were subjected to an investigation of their antimicrobial, antiviral and cytotoxic activity. Selectivity of the pharmacological effects was found. Generally, the target compounds inhibited only the G⁺ microorganisms. Compound 16 inhibited Staphylococcus aureus (I = 99.6%; c = 62.5 μM) and Enterococcus faecalis (I = 85%; c = 250 μM). Several compounds showed moderate antiviral effects, both anti-HIV-1, 19 (EC₅₀ = 57.0 ± 4.1 μM, CC₅₀ > 100 μM), 20 (EC₅₀ = 17.8 ± 2.1 μM, CC₅₀ = 41.0 ± 5.2 μM) and 23 (EC₅₀ = 12.6 ± 0.82 μM, CC₅₀ = 38.0 ± 4.2 μM), and anti-HSV-1, 22 (EC₅₀ = 27.7 ± 3.5 μM, CC₅₀ > 100 μM) and 23 (EC₅₀ = 30.9 ± 3.3 μM, CC₅₀ > 100 μM). The target compounds showed no cytotoxicity in cancer cells, however, several of their intermediates were cytotoxic. Compound 21 showed cytotoxicity in HeLa (IC₅₀ = 7.9 ± 2.1 μM), G-361 (IC₅₀ = 8.0 ± 0.6 μM) and MCF7 (IC₅₀ = 8.6 ± 0.2 μM) cancer cell lines, while being non-toxic in normal fibroblasts (BJ; IC₅₀ > 50 μM).