RSC medicinal chemistry最新文献

The biological properties of peptides are determined by their amino acid sequences, but the diversity of naturally occurring amino acids is limited. Accordingly, this study aimed to investigate the impact of sulfonation modification on the functional characteristics of peptide LALFVPR (LR-7), such as water solubility, stability, and antioxidant, anti-inflammatory, and angiotensin-converting enzyme (ACE) inhibitory activity. The results showed that the sulfonated peptide LC(SO₃)LFVPR (LR-7S) exhibited significantly improved water solubility (a 46-fold increase) and greater stability in gastric fluid compared to LR-7. In HK-2 cells exposed to 5 μM angiotensin II (Ang II) for 24 h, treatment with 100 μM LR-7S more effectively mitigated cellular damage, as indicated by enhanced mitochondrial membrane potential and increased cell viability. Notably, LR-7S treatment resulted in lower reactive oxygen species (ROS) levels and higher activities of catalase (CAT) and superoxide dismutase (SOD) relative to LR-7. This antioxidant effect may be associated with the promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Both LR-7 and LR-7S significantly decreased the levels of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and nuclear factor kappa-B (NF-κB). Furthermore, LR-7S exhibited a lower binding energy (−6.16 kcal mol⁻¹) with ACE and its ACE inhibitory activity was 162% higher than that of LR-7 at a concentration of 25 μM. These findings highlight sulfonation as an effective strategy for modulating the peptide structure and enhancing bioactivity. Despite the challenges in clarifying the metabolic pathways in vivo, the sulfonated peptide holds great promise for the development of the management of hypertensive nephropathy.

The natural product-based hybrid strategy is a promising approach for innovative drug discovery. Leveraging the privileged architecture of sulforaphane—a prominent anticancer natural product—we engineered a novel library of magnolol–sulforaphane molecular hybrids for antitumor evaluation through a concise synthetic strategy for the pharmacophore of sulforaphane (SFN), culminating in the identification of CTNPC8 as a promising anticancer compound. Notably, CTNPC8 not only displays exceptional broad-spectrum anticancer activity with potency surpassing both parent compounds and cisplatin, but also exhibits potent in vitro efficacy against the challenging nasopharyngeal carcinoma (NPC) cell model. Mechanistic studies in nasopharyngeal carcinoma models reveal that CTNPC8 triggers mitochondrial-mediated apoptosis through regulating ROS generation and induces G₂/M phase arrest. Transcriptomic profiling coupled with validation experiments reveals that CTNPC8 exerts its anti-NPC activity primarily by modulating the Akt/mTOR pathway. The present study provided a valuable strategy for discovering new antitumor agents through hybrid molecular design, nominating CTNPC8 as a promising hit compound for anti-NPC research.

The field of computational medicinal chemistry has undergone significant advancements, transitioning from traditional methodologies to contemporary strategies powered by artificial intelligence, machine learning, and big data. Traditional approaches, such as molecular docking and QSAR modeling, have long been the foundation of drug discovery, offering reliable frameworks for target identification and lead optimization. However, contemporary methodologies, including AI-driven target identification, adaptive virtual screening, and generative models, are reshaping the landscape by increasing efficiency and expanding chemical space exploration. This article provides a comprehensive comparison between these two paradigms, highlighting their respective strengths, limitations, and the potential of their integration. By bridging traditional and contemporary approaches, researchers can establish innovative workflows to accelerate drug discovery, ultimately contributing to the development of safer and more effective therapeutics.

TMPRSS2 and HAT (or TMPRSS11D) are host serine proteases critically involved in the entry of several respiratory viruses, including SARS-CoV-2. To our knowledge, no dual inhibitors targeting both enzymes have been reported to date. Here, we describe a series of para-aminobenzylamine derivatives acting as potent dual TMPRSS2/HAT non-covalent inhibitors. In SARS-CoV-2 infection assays in lung epithelial cells, four compounds demonstrated significant antiviral activity without cytotoxicity at tested doses. Drug-likeness profiling confirmed compliance with Lipinski's and Veber's rules, as well as favourable solubility and microsomal stability. These findings highlight a novel chemical series with potential as broad-spectrum antivirals targeting host proteases.

Inhibition of the SARS-CoV-2 main protease (M^pro) by small-molecules is a validated strategy for COVID-19 treatment. There is a need for improved M^pro inhibitors, including because M^pro mutations can confer resistance to clinically used M^pro inhibitors. Previous work has revealed the potential of penicillin derivatives as covalently reacting M^pro inhibitors. Here we report studies on M^pro inhibition by C6-alkoxy substituted penicillin derivatives. The combined mass spectrometric and computational evidence imply most of the tested penicillin C6-alkoxy derivatives bind via non-covalent interactions at the M^pro active site, resulting in potent substrate-competitive inhibition. Some penicillin C6-alkoxy derivatives ((R)-, but not (S)-sulfoxides) manifest covalent reaction to different extents. Penicillins and related drugs are widely used antibiotics, acting via covalent reaction of their β-lactam with a nucleophilic serine in their transpeptidase targets to give an acyl–enzyme complex. The results imply penicillin derivatives can be developed to inhibit enzymes via mechanisms other than formation of stable acyl–enzyme complexes.

One of the biggest obstacles to treating breast cancer effectively is chemotherapy resistance, which emphasizes the need for innovative therapeutic approaches. An important factor in tumor progression is the mitochondrial enzyme monoamine oxidase-A (MAO-A). In the development of anticancer drugs, isatin (1H-indole-2,3-dione), a MAO inhibitor obtained from Isatis microcarpa, has shown great promise. This study assessed isatin's ability to fight resistance in tamoxifen-resistant LCC2 breast cancer cells, both by itself and in combination with tamoxifen. Chromatographic techniques were used to extract and purify isatin, which was subsequently examined for cytotoxicity, cell cycle arrest, colony formation, and migratory inhibition. Isatin and tamoxifen together dramatically decreased cell viability, prevented migration, stopped the advancement of the cell cycle, and repressed proliferation. Using qRT-PCR, gene expression analysis showed that important indicators for treatment resistance and metastasis, including MAO-A, HIF-1α, TWIST, MMP2, MMP9, and ABCB1, were downregulated. ELISA-based protein expression analyses further validated the modification of proteins linked to migration and apoptosis, including BAX, BCL2, and caspases 3, 8, and 9. The ATP-binding cassette transporter ABCB1, which is intimately linked to multidrug resistance, was similarly impacted by the isatin–tamoxifen combination. In conclusion, our findings demonstrate that isatin, alone or in combination with tamoxifen, exerts significant anticancer effects in tamoxifen-resistant breast cancer cells by promoting apoptosis, cell cycle arrest, and suppression of resistance-associated pathways. These effects may involve modulation of MAO-A and HIF-1α signaling, highlighting MAO-A as a lesser-studied but promising target in breast cancer.

Glioblastoma multiforme (GBM) is an aggressive and treatment-resistant brain tumor. The expansion of a phenolic Mannich base library via the Petasis reaction unexpectedly led to the unsymmetrical tetrahydroquinoline-derived triarylmethanes, confirmed by single-crystal X-ray diffraction. Optimization of reaction conditions revealed the influence of solvent, temperature, and substituent patterns on product yield and regioselectivity. Several of the newly synthesized triarylmethanes demonstrated potent cytotoxicity against human GBM cell lines LN229 and SNB19, with compound 8a′ exhibiting IC₅₀ values (35.3 μM and 23.5 μM, respectively) significantly lower than those of the standard chemotherapeutic agent temozolomide (309.7 μM and 344.4 μM, respectively). In addition to inhibiting cell proliferation, 8a′ disrupted GBM cell migration in scratch assays, suggesting a strong link between cytotoxicity and impaired motility. The SiRNA experiment confirmed that the specific interaction of 8a′ with EGFR modulates intracellular calcium levels in GBM. These findings highlight the therapeutic potential of triarylmethane scaffolds in GBM treatment via EGFR interaction and underscore the importance of fine-tuning multicomponent reactions to discover biologically active chemotypes.

Pyridine carbothioamides (PCAs) are recognized for their gastric mucosal protective effects and low in vivo toxicity, making them attractive scaffolds for anticancer drug development. In this study, a series of N-phenyl 4-substituted and 2,4-disubstituted PCAs (1–8) incorporating a sulfonamide pharmacophore were synthesized, fully characterized, and evaluated as tubulin polymerization inhibitors. The compounds were tested against four cancer cell lines (A549, MCF-7, PC-3, HepG2) with colchicine and doxorubicin as reference drugs. Among them, compounds 3 and 5 exhibited potent cytotoxicity, being 2–6-fold more active than colchicine and up to 2.5-fold stronger than doxorubicin in PC-3 cells. Importantly, both showed ∼4-fold lower toxicity toward normal HLMEC cells and displayed higher selectivity towards tested cancer cells than doxorubicin. Tubulin polymerization assays confirmed their activity, with IC₅₀ values of 1.1 μM (3) and 1.4 μM (5), outperforming colchicine (10.6 μM) and CA-4 (2.96 μM). Molecular docking revealed strong binding at the colchicine site, supported by favorable inhibition constants and free binding energies. In silico ADME predictions indicated that the most lipophilic compounds 3 and 5 demonstrated favorable drug-likeness, as expected from computational studies, along with excellent gastrointestinal absorption, favorable bioavailability, and low hemolytic activity. Collectively, these findings highlight compounds 3 and 5 as promising lead candidates for the development of orally active anticancer and antimitotic agents.

Disruption of protein homeostasis (proteostasis), whether by acute proteotoxic stress or chronic expression of mutant proteins, can lead to the accumulation of toxic protein aggregates. Such aggregation is a hallmark of numerous diseases and is often associated with impaired protein clearance mechanisms. The transcription factor nuclear factor erythroid 2-related factor 1 (encoded by NFE2L1, also known as Nrf1) plays a central role in restoring proteostasis by increasing proteasome synthesis. Therefore, pharmacological activation of NFE2L1 under non-stress conditions represents a promising therapeutic strategy for neurodegenerative and other proteostasis-related diseases. In our previous study, we identified bis(phenylmethylene)cycloalkanone derivatives as NFE2L1 activators capable of inducing proteasome subunit expression, increasing heat shock protein levels, and stimulating autophagy. Building upon these findings, we have now developed a new library of structurally related compounds to identify novel more potent NFE2L1 activators. By systematically examining how specific chemical substitutions affect NFE2L1 activation, this work advances our understanding of the structure–activity relationships within this pathway.

Quite frequently, it is the progression of initial crystallographic fragment screening hits into more potent binders to their target, which constitutes the major bottleneck in many academic compound or drug development projects. While high quality starting points are critical to the success of a drug development project, it is equally important to have accessible pathways for further compound development. Here, we present two crystallographic fragment screening campaigns using a 96 fragment sub-selection of the European Fragment Screening Library (EFSL) provided by EU-OPENSCREEN. The two campaigns against the targets endothiapepsin and the NS2B–NS3 Zika protease, yielded hit rates of 31% and 18%, respectively. Further, we present how within the framework of the EU-OPENSCREEN European Research Infrastructure Consortium (ERIC) fast identification of follow-up compounds can be realized. With just one round of testing related compounds from the European Chemical Biology Library, two follow-up binders for each of the two targets could be identified proving the feasibility of this approach.