ChemMedChem最新文献

Impaired endoplasmic reticulum (ER) Ca²⁺ homeostasis contributes to β-cell dysfunction under diabetic stressors such as methylglyoxal (MGX), a reactive byproduct that induces oxidative protein modifications and advanced glycation end-products. The calcium pump sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), essential for ER Ca²⁺ regulation, is inhibited by MGX-mediated carbonylation and thiol oxidation. Pharmacological SERCA activation has emerged as a promising strategy to restore ER Ca²⁺ balance, but whether protection results from direct allosteric modulation, indirect antioxidant effects, or both has remained unclear. Herein, it is shown that novel, potent synthetic activators directly stimulate SERCA and restore its activity following MGX-induced inhibition. While some compounds display antioxidant activity, recovery of SERCA function correlated with activation potency rather than radical scavenging or lipid peroxidation inhibition. It is demonstrated for the first time that direct SERCA activation alone is sufficient to significantly reverse oxidative damage, revealing a mechanistically distinct therapeutic approach to preserve ER Ca²⁺ homeostasis in diabetes.

Lung cancer remains a leading cause of cancer-related mortality worldwide, underscoring the need for novel therapeutic strategies. In this study, three hydroxamic acids derived from L–cysteine are synthesized to explore their biological dual effect as Glyoxalase 1 (Glo-1) inhibitors and ferroptosis inducers. Among the synthesized derivates, compound 2 exhibited the highest inhibitory potency against Glo-1 and is the most potent compound against nonsmall cell lung cancer cell lines. For this compound, an increase in intracellular reactive oxygen species (ROS), depletion of intracellular reduced glutathione (GSH) levels, and induced morphological changes is observed that correspond to ferroptosis. Furthermore, these effects are reversed by Liproxstatin-1, a potent and selective ferroptosis inhibitor. Acute and subacute toxicological assays in mice showed mild toxicity (LD₅₀ > 2000 mg kg⁻¹) and moderate organ damage. These in vitro and in vivo findings suggest that ferroptosis induction may serve as a side effect of Glo-1 inhibition, making compound 2 a promising lead for further development and optimization.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key drug target for the treatment of different hypercholesterolemia-related diseases. A new class of small-molecule inhibitors of PCSK9 transcription, characterized by a 4-amino-2-pyridone scaffold, has been recently identified by our research group. Among them, the early lead compound 5c shows high in vitro potency and favorable in vivo tolerability. However, given the suboptimal in vitro metabolic stability of 5c, its optimization is reported herein by modification of the predicted metabolic soft spots through chemistry-driven late-stage functionalization (LSF) strategies. Microsomal stability on the newly synthesized derivatives allows drawing structure–metabolism relationships (SMRs) that, coupled with a thorough pharmacological investigation on HepG2 cells, leads to the identification of novel C3- and dual C3/NHC4-functionalized pyridones with improved stability and superior pharmacological profiles. Notably, compounds 6b, 7, and 18a emerge as the best candidates, demonstrating markedly improved metabolic stability/PCSK9 IC₅₀ ratio and comparable or lower cytotoxicity with respect to the parent compound 5c. These findings underscore the value of LSF strategies in generating optimized analogs of 5c with strong potential for further preclinical development.

Structure–activity relationships (SARs) are a cornerstone of drug discovery, aiming to elucidate the connection between chemical structures and their biological properties. While widely applied in medicinal chemistry and computer-aided molecular design, SAR traditionally assumes a direct connection (i.e., relations) between chemical structures and their activity. However, given the complexity of biological responses, these connections are often better described as associations rather than strict relationships. Beyond semantics, relations usually imply a deterministic or functional mapping, whereas, associations are treated with statistical tools that capture probabilistic patterns without assuming causality. Adopting an association-based perspective helps to avoid overstated claims and manage uncertainty more realistically. In this article, structure–property associations (SPAs) are proposed as a more accurate framework to capture the connection between chemical structures and their properties in the context of drug discovery. SPA is particularly emphasized in describing the associations between chemical structures and biological activity across different experimental levels, including both in vitro and in vivo assays.

Rare-earth (RE) salicylate phenanthroline complexes [RE(sal)₃(phen)] (RE = Y, Eu, Dy, Yb; sal = salicylate; Phen = 1,10-phenanthroline) are conveniently prepared starting from RE homoleptic carbamate precursors and salicylic aldehyde in the presence of phenanthroline. The yttrium derivative is structurally characterized by single-crystal X-ray diffraction, IR, and NMR spectroscopy, showing the mononuclear nature of the complex, while the structure of the other paramagnetic complexes are assigned on comparative IR spectra bases and elemental analyses. The antiproliferative effect of the complexes are studied in vitro on a panel of human tumor cell lines (A2780, ovarian carcinoma sensitive to cisplatin; A2780cis, ovarian carcinoma resistant to cisplatin and LN229, glioblastoma), and on nontumorigenic mesothelial cells (MeT-5A). The reactive oxygen species production is determined to investigate the intracellular mechanism of action. For the most interesting complex [Dy(sal)₃(phen)] (3), the effects on mitochondrial transmembrane potential and on cell cycle are also analyzed. Finally, epifluorescence images allow to demonstrate the uptake of the complex and to observe relevant morphological changes in cells, suggesting the occurrence of mitotic catastrophe.

Accurate predictions of compound properties are crucial for enhancing drug discovery by expediting processes and increasing success rates. This study focuses on predicting key pharmacokinetic endpoints related to Absorption, Distribution, Metabolism, and Excretion (ADME), leveraging extensive internal and newly available public hiqh-quality ADME data. Data-integration strategies are assessed for ADME prediction across six endpoints using single-source (internal or public), pooled single-task, and multitask learning models. Models trained on combined data—especially multitask models—generally outperform single-source baselines, with consistent gains on public tests and frequent gains on internal tests when public data complement and are proportionally balanced with in-house data size. Applicability domain analyses show that multitask learning reduces error for compounds with higher similarity to the training space, indicating better generalization across combined spaces. Analysis of prediction uncertainties mirrors these observations. Our study underscores that curated integration of high-quality public datasets with proprietary data can deliver more accurate and better-calibrated in silico ADME models to support computational compound design in drug discovery.

Colorectal cancer (CRC) is a major global health burden, driven by complex genetic and epigenetic alterations and an immunosuppressive tumor microenvironment (TME). The PD-1/PD-L1 immune checkpoint plays a central role in CRC immune evasion, making it a critical therapeutic target. Immune checkpoint inhibitors (ICIs) have achieved notable efficacy in microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) CRC, attributed to their high neoantigen burden. However, most CRC cases are microsatellite stable (MSS) and exhibit limited responsiveness to PD-1/PD-L1 blockade due to immune escape mechanisms, including β2-microglobulin and JAK/STAT mutations, HLA loss, and infiltration of regulatory T cells and myeloid-derived suppressor cells. Small-molecule inhibitors targeting PD-1/PD-L1 are emerging as promising alternatives to monoclonal antibodies, offering advantages such as oral administration, improved tissue penetration, and modulation of upstream and downstream signaling pathways. Compounds such as MPT0G612, Panaxadiol, Butyrate, Licochalcone A, and Demethylzeylasteral exhibit antitumor effects by suppressing PD-L1 expression, promoting its degradation, or enhancing T cell infiltration in the TME. Early clinical trials of CA-170, INCB086550, and ASC61 indicate encouraging activity in solid tumors, including CRC. This review summarizes the role of the PD-1/PD-L1 axis in CRC and discusses the therapeutic potential and future prospects of small-molecule inhibitors as next-generation immunotherapies for CRC.

The COVID-19 pandemic, caused by the highly transmissible SARS-CoV-2 virus, has highlighted the urgent need for effective small-molecule antivirals. To date, only a few such agents, including molnupiravir and remdesivir, have been approved by the FDA. In our previous study, a novel class of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors based on an N,N′-diphenylurea scaffold was identified; however, these compounds exhibited poor aqueous solubility and significant cytotoxicity. Herein, the design, synthesis, and evaluation of twenty-seven new derivatives aimed at improving solubility and reducing cytotoxicity through targeted scaffold modifications are reported. Seven analogs display enhanced aqueous solubility (kinetic solubility > 10 µM), and nine compounds show residual RdRp activity (RA—determined at 10 μM concentration of screened compounds) below 50%, with the most potent analog achieving an RA value of 34%. Despite these improvements, cytotoxicity remains a limitation across the series. These findings provide valuable structure–activity relationship insights and direct ongoing optimization efforts toward developing less toxic, soluble RdRp inhibitors with improved antiviral profiles.

Heparan sulfate (HS) is a ubiquitously expressed glycosaminoglycan (GAG) found on most mammalian cells. Its heterogeneous structure and dense negative charge allow HS to interact with a wide range of proteins, regulating their stability, localization, and engagement with cell-surface receptors. Given the role of disrupted HS-protein interactions in numerous diseases, HS mimetics represent a promising avenue for therapeutic intervention. These mimetics are designed to reproduce the functional properties of native HS while offering improved stability, scalability, and selectivity. Whereas most HS mimetics exploit naturally occurring sulfate groups to provide anionic character, this study explores phosphates as a sulfate bioisostere. Using a dendrimer-based scaffold, a focused library of phosphorylated maltose constructs was synthesized, comprising four (dimer), six (trimer), or eight (tetramer) units, with lipid-modified variants prepared for the dimer and trimer series. In vitro screening against four clinically relevant DNA viruses reveal that these phosphorylated HS mimetics display antiviral activity, albeit with reduced potency relative to their sulfated analogs.

Targeting oxidative phosphorylation (OXPHOS) in cancer metabolism offers a promising alternative to glycolytic inhibition. Herein, the synthesis and in vitro biological evaluation of 30 6-indolyl ester derivatives as potential OXPHOS inhibitors are reported. Screening against a panel of 5 mammalian cancerous cell lines and 1 noncancerous cell line using galactose- and glucose-containing media identified 11 hits with strong activity under OXPHOS-dependent conditions. Selectivity index (SI) and OXPHOS inhibition index (OI) analyses using IC₅₀ values obtained across a panel of 8 cancerous and noncancerous cell lines confirm compound 28 as a standout inhibitor, with an OI value of  >91 and a SI value of 9.88 against pancreatic cancer cell line MiaPaCa-2. Additional hits (e.g., compounds 13, 20, 37) also demonstrate strong OXPHOS-specific activity and moderate to good selectivity with breast cancer and pancreatic cancer cell lines. In silico assessment using OSIRIS and SwissADME tools validate their physicochemical properties and drug-likeness. These findings support further investigation of 6-indolyl esters, specifically compound 28, as a structurally simple and synthetically accessible scaffold for the development of novel OXPHOS-targeting anticancer agents.