RSC medicinal chemistry最新文献

Considering the multifactorial and complex nature of Alzheimer's disease and the requirement of an optimum multifunctional anti-Alzheimer's agent, a series of triazole tethered coumarin-eugenol hybrid molecules was designed as potential multifunctional anti-Alzheimer's agents using donepezil and a template. The designed hybrid molecules were synthesized via a click chemistry approach and preliminarily screened for cholinesterase and Aβ_1-42 aggregation inhibition. Among them, AS15 emerged as a selective inhibitor of AChE (IC₅₀ = 0.047 μM) over butyrylcholinesterase (BuChE: IC₅₀ ≥ 10 μM) with desired Aβ_1-42 aggregation inhibition (72.21% at 50 μM) properties. In addition, AS15 showed protective effects against DNA damage caused by hydroxyl radicals originating from H₂O₂. Molecular docking and simulation studies confirmed the favorable interactions of AChE and the Aβ_1-42 monomer desired for their inhibition. AS15 exhibited an LD₅₀ value of 300 mg kg^-1 and showed significant improvements in memory and learning behavior in scopolamine-induced cognition impairment mouse-based animal models (Y-maze test and Morris water maze test) for behavioral analysis. Overall outcomes suggest AS15 as a potential preclinical multifunctional candidate for the management of Alzheimer's disease, and it serves as a promising lead for further development of potent and safer multifunctional anti-Alzheimer's agents.

Estrogen receptor β (ERβ) is aberrantly expressed in castration-resistant prostate cancer (CRPC). Therefore, a diagnostic and therapeutic ERβ probe not only helps to reveal the complex role of ERβ in prostate cancer (PCa), but also promotes ERβ-targeted PCa therapy. Herein, we reported a novel ERβ-targeted near-infrared fluorescent probe D3 with both imaging and therapeutic functions, which had the advantages of high ERβ selectivity, good optical performance, and strong anti-interference ability. In addition, it displayed excellent antiproliferative activity in CRPC cells. Finally, D3 was also successfully applied to the in vivo imaging of ERβ in the prostate cancer mouse model. Thus, this ERβ-targeted near-infrared fluorescent probe can be used as a potential tool for the study of ERβ-targeted diagnostic and therapeutic PCa.

Some novel sulphonyl thiourea derivatives (7a-m) containing 4,6-diarylpyrimidine rings were designed and synthesized using a one-pot procedure. These compounds exhibited remarkable dual inhibitory activity against human carbonic anhydrase hCA I, hCA II, hCA IX, and XII isoenzymes and some cancer cell lines. Among them, some thioureas had significantly more potent inhibitory activities in the order of 7l > 7c > 7f (against the hCA I isoform), 7f > 7b > 7c (against the hCA II isoform), 7c > 7g > 7a > 7b (against the hCA IX isoform), and 7d > 7c > 7g > 7f (against the hCA XII isoform). The obtained inhibitory activity data against the hCA IX and XII isoforms showed that compound 7c was the most potent inhibitor in this sulphonyl thiourea series against enzyme hCA IX, with K _I = 125.1 ± 12.4 nM, while compound 7d was the most potent inhibitor against enzyme hCA XII, with K _I = 111.0 ± 12.3 nM. Compound 7c exhibited strong inhibitory activity among all four tested hCA enzymes, while thiourea 7f was a potent inhibitor for enzymes hCA I, II and XII. All these compounds demonstrated non-competitive inhibition of both enzymes. Some selected potential inhibitory compounds, including 7c, 7d, and 7g, exhibited remarkable cytotoxic activity against human cancer cell lines, including human breast adenocarcinoma (MCF-7), human liver adenocarcinoma (HepG2), human cervical epithelial carcinoma (HeLa), and human lung adenocarcinoma cells (A549). These compounds exhibited low cytotoxicity in the WI-38 cell line. The compounds 7c and 7d were the most potent inhibitors against tumour-associated hCA IX and hCA XII isoenzymes. Furthermore, these compounds exhibited remarkable inhibition against some cancer cell lines, such as MCF-7, HepG2, HeLa, and A549. They were subjected to in silico screening for molecular docking and molecular dynamics simulations. The results of in vitro and in silico studies revealed that compounds 7c and 7d were the most promising derivatives in this series owing to their significant effects on the studied hCA IX and hCA XII isoenzymes, respectively. The results showed that the sulphonyl thiourea moiety was deeply accommodated in the active site and interacted with zinc ions in the receptors.

The N/OFQ-NOP receptor is a fascinating peptidergic system with the potential to be exploited for the development of analgesic drugs devoid of side effects associated with classical opioid signalling modulation. To date, up to four X-ray and cryo-EM structures of the NOP receptor in complex with the endogenous peptide agonist N/OFQ and three small molecule antagonists have been solved and released. Despite the available structural information, the details of selective small molecule agonist binding to the NOP receptor in the active state remain elusive. In this study, by leveraging the available structural information and using N/OFQ(1-13)-NH₂ as a reference compound, we developed a computational protocol based on docking followed by short molecular dynamics (MD) simulations that can suggest small molecule agonist binding modes at the NOP receptor that are reproducible and stable over time in the solvated membrane-embedded receptor active state and in agreement with known structure-activity relationship (SAR) data.

Traditional small molecule drugs often target protein activity directly, but challenges arise when proteins lack suitable functional sites. An alternative approach is targeted protein degradation (TPD), which directs proteins to cellular machinery for proteolytic degradation. Recent studies have identified additional E3 ligases suitable for TPD, expanding the potential of this approach. Among these, DCAF16 has shown promise in facilitating protein degradation through both PROTAC and molecular glue mechanisms. In this study, we developed a homogeneous time resolved fluorescence (HTRF) assay to discover new DCAF16 binders. Using an in-house electrophile library, we identified two diastereomeric compounds, with one engaging DCAF16 at cysteines C177–179 and another reducing its expression. We demonstrated that the compound covalently engaging DCAF16 can be transformed into a PROTAC capable of degrading FKBP12.

Melanoma, the most fatal form of skin cancer, often becomes resistant to the current therapeutic approaches in most patients. To explore new treatment options, fused thiazole derivatives were synthesized, and several of these compounds demonstrated potent anti-melanoma activity both in vitro and in vivo. These compounds exhibited significant cytotoxicity against melanoma cell lines at low concentrations. The lead molecules induced apoptosis and caused G2/M phase cell cycle arrest to a lesser extent. These compounds also displayed remarkable antimetastatic activities in several cell-based and molecular assays, significantly inhibiting key processes of metastasis, such as cell migration and adhesion. mRNA sequencing revealed significant downregulation of β-actin (ACTB) and γ-actin (ACTG1) at the transcriptional level, and a similar effect was observed at the protein level by western immunoblotting and proteomics assays. Actin-rich membrane protrusions formation is crucial for facilitating metastasis by promoting cell migration. Fluorescence microscopy demonstrated that compounds E28 and E47 inhibited the formation of these membrane protrusions and impaired actin cytoskeleton dynamics. Docking studies suggested the lead compounds may suppress tumor proliferation and metastasis by targeting the mechanistic target of Rapamycin complex 2 (mTORC2). All these findings unanimously indicated the translational perspective of ethisterone and androstenone fused thiazole derivatives as potent antimetastatic and antimelanoma agents. In a preclinical mouse melanoma model, compounds E2 and E47 significantly reduced tumor growth and greatly improved overall mice survival, while showing a favorable safety profile based on a comprehensive blood plasma metabolite profile. These lead molecules also displayed promising physicochemical properties, making them strong candidates for further drug development studies.

Cathepsin C (Cat C) is a potential candidate for addressing inflammatory conditions associated with neutrophil serine proteases (NSPs). The high reactivity of electrophilic warheads and the metabolic instability of peptide structures are among the primary challenges in developing potent cathepsin C inhibitors. Compound 36, a lead compound derived from compound 1 through structure-based drug design and structure–activity relationship (SAR), exhibited strong Cat C inhibitory activity with an IC₅₀ value of 437 nM. It also showed a substantial enhancement in overall anti-inflammatory activity, achieving an inhibitory effect on NO release at 4.1 μM. Furthermore, molecular docking was conducted to analyze the mode of action with Cat C. And cell thermal shift analysis (CETSA) revealed that this compound increases the temperature tolerance of Cat C in a concentration-dependent manner, suggesting strong binding to the target Cat C. Prolonged pharmacological inhibition activity may result in the depletion of active NSPs.

Correction for ‘A comprehensive apoptotic assessment of niloticin in cervical cancer cells: a tirucallane-type triterpenoid from Aphanamixis polystachya (Wall.) Parker’ by Anuja Gracy Joseph et al., RSC Med. Chem., 2024, 15, 3444–3459, https://doi.org/10.1039/D4MD00318G.

This review highlights the potential of asialoglycoprotein receptor (ASGPR)-mediated targeting in advancing liver-specific treatments and underscores the ongoing progress in the field. First, we provide a comprehensive examination of the nature of ASGPR ligands, both natural and synthetic. Next, we explore various drug delivery strategies leveraging ASGPR, with a particular emphasis on the delivery of therapeutic nucleic acids such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). An in-depth analysis of the current status of RNA interference (RNAi) and ASO-based therapeutics is included, detailing approved therapies and those in various stages of clinical development (phases 1 to 3). Afterwards, we give an overview of other ASGPR-targeted conjugates, such as those with peptide nucleic acids or aptamers. Finally, targeted protein degradation of extracellular proteins through ASGPR is briefly discussed.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in babies across the world. Irrespective of progress in the development of RSV vaccines, effective small molecule drugs are still not available on the market. Based on our previous data we designed and synthesized triazole-linked coumarin-monoterpene hybrids and showed that they are indeed effective in inhibiting the RSV replication. The most effective compounds are active against both RSV serotypes, A and B, with IC₅₀ in the low micromolar or submicromolar range of concentrations. These are the most active coumarin derivatives found so far. Compound 45 combining 3,7-dimethyloctane and cyclopentane-annealed coumarin fragments has a selectivity index of 160 for serotype A and 1147 for serotype B. According to the results of the time-of-addition experiments, the conjugates are active at the early stages of the virus cycle. Based on biological evaluation and molecular modeling data, RSV F protein is a possible target.