Chemical biology & drug design最新文献

Atherosclerosis (AS) is a chronic inflammatory condition with complex molecular underpinnings, where mitophagy-selective mitochondrial autophagy-plays a critical yet poorly defined role. By integrating bulk and single-cell RNA sequencing data from human atherosclerotic plaques, we analyzed 20 mitophagy-related genes and identified 15 that were dysregulated in AS. Machine learning approaches (Random Forest and SVM-RFE) pinpointed four hub genes-PINK1, TOMM40, TOMM7, and VDAC1-which formed the basis of a diagnostic model with solid predictive performance. Single-cell analysis of over 106,000 cells revealed endothelial cells as mitophagy-active and dominant in AS lesions. Trajectory analysis distinguished disease-associated endothelial subtypes, while CellChat uncovered intensified MIF signaling via CD74-CD44 and CD74-CXCR4 axes in mitophagy-high endothelial cells. SCENIC analysis further identified CEBPD, FOS, and JUN family transcription factors as key regulators. Experimental validation using ox-LDL-treated RAW264.7 macrophages confirmed differential expression of all four hub genes. Collectively, our findings highlight endothelial mitophagy dysregulation and immune crosstalk as central to AS pathogenesis and offer promising diagnostic markers and therapeutic targets.

Since cisplatin was discovered and used as an anti-cancer agent in clinical settings, research into cancer treatments has revealed a number of possible drugs based on metal-containing scaffolds. This has produced a large number of metallodrugs suitable for use in medicine. The roles and mechanisms of action of these metallodrugs are more diverse than those of pure organic compounds. Since they demonstrated efficacy against numerous cancer cell lines, metallodrugs based on osmium are among the most researched and produced substitutes for platinum-based anti-cancer drugs. The metal-based drugs are a new, well-developed type of drug in anticancer therapy with specific mechanisms of action that are much different from the organic chemical drugs used in chemotherapy. They have the potential to disrupt cellular processes necessary for the survival and growth of cancer cells since they are able to interact with a variety of biological targets such as DNA, proteins, and enzymes. This review article focuses on the role of Os-complexes in cancer treatment, their mechanism of action, challenges, and future perspectives of Os-complexes in cancer therapy.

Neutral sphingomyelinase 2 (nSMase2) plays a pivotal role in exosome biogenesis and the progression of several neurodegenerative disorders and cancers. In this study, a series of hexahydropyrimidine and tetrahydropyrimidine derivatives were synthesized to explore their potential as nSMase2 inhibitors. The compounds were evaluated for Bacillus cereus SMase inhibition, which shares a highly conserved substrate-binding site with human nSMase2. The hexahydropyrimidine derivatives exhibited superior activity, with 4-(4-fluorophenyl)-6-oxo-2-thioxohexahydropyrimidine-5-carbonitrile (compound 1j, IC₅₀ = 1.88 μM) emerging as the most potent inhibitor fourfold more active than the reference compound Cambinol (IC₅₀ = 7.49 μM). Compound 1j also demonstrated metal-chelating ability with Fe³⁺ and Cu²⁺ ions, which are implicated in the pathology of these diseases. Molecular docking studies revealed favorable interactions with the B. cereus SMase structure, and in silico ADME profiling suggested drug-like properties. These findings highlight novel hexahydropyrimidine derivatives as promising nSMase2 inhibitors for further investigation.

In a world where cancer continues to be a major health problem, the urgency continues to find new effective treatments. This work involved the synthesis of more than 10 anticancer fluoroquinolones (FQs) and pyridoquinoxaline (PQ) derivatives originating from FQs and studied their cytotoxicity, anti-adhesion, anti-invasion, and pro-apoptotic properties. Synthesis of the new compounds of the PQ series was carried out by reacting 1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid with L-proline, 3 and 4-hydroxy proline derivatives (compounds 2a-2f), followed by reductive cyclization to yield compounds 3a-3f. Compounds 2a and 3a gave favorable activities on MCF-7 with respective IC₅₀ values of 5.9 and 0.9 μM, respectively, while the hydroxy derivatives almost lost activity on all tested cells. Due to the fact that the activity of PQs and precursor FQs was correlated to increased lipophilicity, the lipophilic FQs series 10a, 10b, 11a, and 11b were prepared by direct reaction of 1-cyclohexyl-6-fluoro-8-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylate with chloro or fluoro aniline, followed by ester hydrolysis 10a and 10b and reduction to yield the amine compounds 11a and 11b. All FQs 10a, 10b, 11a, and 11b showed very excellent cytotoxicity against all tested cell lines (mammary MCF-7, MDA-MB-231, and invasive prostate DU-145) with IC₅₀ values below 20 μM with impressively favorable lack of any cytotoxicity in normal ligament PDL fibroblasts (in 3.125-200 μM). Only FQs exerted comparable or superior anti-adhesion and anti-invasion activity versus the antineoplastic reference quercetin. Significant incremental increases in the pro-apoptogenesis Bax/anti-apoptosis Bcl ratio revealed a physiologically regulated cytotoxicity via DNA fragmentation harvested in cytolysates. The structure activity relationship (SAR) and quantitative structure activity relationship (QSAR) reveal that planarity due to a fused polycyclic system and lipophilicity were essential requirements for anticancer PQs, whereas a high number of hydrogen bonds (HBs) and increased number of chelators, in addition to lipophilic balance, are the major requirements for anticancer FQs. In vitro cell viability assays revealed pronounced affinity for reductions in cell viabilities for the targeted PQ-bearing AuNPs versus PQsalone (induced) incubations and basal (non-induced) controls after 48 h incubation with HT29 cells. These results are very promising upon optimization of the system.

Baicalein, one of the active ingredients of banxia xiexin decoction, has good therapeutic efficacy in treating diarrhea and improving gastrointestinal dysfunction. The role and mechanism of Baicalein on irinotecan (CPT-11)-induced gastrointestinal dysfunction are the focus of this study. Concretely, CPT-11 induced delayed diarrhea rat model and intestinal epithelial cell (IEC)-6 cell injury model with Baicalein treatment as needed. Colonic pathological changes were analyzed by hematoxylin-eosin staining, and inflammatory factor expressions in serum were determined by enzyme-linked immunosorbent assay. Immunohistochemistry and western blot were performed to quantify ferroptosis-related protein expressions. Thiobarbituric acid reactive substances (TBARS) kits and colorimetric assay kit were applied to detect lipid peroxidation levels and Fe²⁺ content, respectively. In vitro experiments also included quantitative real-time polymerase chain reaction, cell counting kit-8, and C11 BODIPY staining. CPT-11 induced aggravation of intestinal tissue damage, inflammatory factor release, Fe²⁺ accumulation, upregulation of lipid peroxidation and 15-Lipoxygenase (ALOX15) expression, and downregulation of glutathione peroxidase 4 (Gpx4) and SLC7A11 in vivo in rats; however, Baicalein dose-dependently reversed the effects of CPT-11. Baicalein elevated cell viability, reduced lipid peroxidation and Fe²⁺ accumulation, and elevated Gpx4 and SLC7A11 levels, whereas ALOX15 overexpression reversed the effects of Baicalein on a CPT-11-induced IEC-6 cell injury model. In conclusion, Baicalein plays a mitigating role in CPT-11-induced delayed diarrhea via ALOX15-mediated ferroptosis.

Pouzolzia zeylanica (L.) Benn. is a Chinese herbal medicine widely used for its anti-inflammatory and pus-removal properties. To explore its potential anti-inflammatory mechanism, quercetin 3,7-dirhamnoside (QDR), the main flavonoid component of P. zeylanica (L.) Benn., was extracted and purified. The potential anti-inflammatory targets of QDR were predicted using network analysis. These potential targets were verified using molecular docking, molecular dynamics simulations, and in vitro experiments. Consequently, 342 potential anti-inflammatory QDR targets were identified. By analyzing the intersection between the protein-protein interaction and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we identified several potential protein targets of QDR, including RAC-alpha serine/threonine-protein kinase (AKT1), Ras-related C3 botulinum toxin substrate 1 (RAC1), nitric oxide synthase 3 (NOS3), serine/threonine-protein kinase mTOR (mTOR), epidermal growth factor receptor (EGFR), growth factor receptor-bound protein 2 (GRB2), and endothelin-1 receptor (EDNRA). QDR has anti-inflammatory activity and regulates immune responses and apoptosis through chemokines, Phosphatidylinositol 3-kinase 3(PI3K)/AKT, cAMP, T-cell receptor, and Ras signaling pathways. Molecular docking analysis showed that QDR has good binding abilities with AKT1, mTOR, and NOS3. In addition, molecular dynamics simulations demonstrated that the protein-ligand complex systems formed between QDR and AKT1, mTOR, and NOS3 have high dynamic stability, and their protein-ligand complex systems possess strong binding ability. In RAW264.7 macrophages, QDR significantly inhibited lipopolysaccharides (LPS)-induced inducible nitric oxide synthase expression, nitric oxide (NO) release and the generation of proinflammatory cytokines IL-6, IL-1β, and TNF-α. QDR downregulated the expression of p-AKT1(Ser473)/AKT1 and p-mTOR (Ser2448)/mTOR, and upregulated the expression of NOS3, Rictor, and Raptor. This indicates that the anti-inflammatory mechanisms of QDR involve regulation of AKT1 and mTOR to prevent apoptosis and of NOS3 which leads to the release of endothelial NO. Thus, our study elucidated the potential anti-inflammatory mechanism of QDR, the main flavonoid found in P. zeylanica (L.) Benn.

A series of novel 1,2,3,4-tetrazines were designed and synthesized. ¹H-NMR spectroscopy, ¹³C NMR spectroscopy, and HRMS were used to determine the structures of this novel compounds. Computational approaches suggested that DHFR is a putative target for the newly synthesized 11 compounds. Extensive molecular dynamics simulations followed by molecular docking simulations were employed to evaluate DHFR as a potential target protein. The anticancer activities of the compounds were evaluated against five different types of leukemia cell lines (Jurkat, Nalm-6, Reh, K562, and Molt-4) and one non-leukemic cell line (Hek293T) by MTT test in vitro and imatinib was used as a control drug. Among these compounds, 3a exhibited the best activity against all the leukemic cell lines, except Reh cell line. For Nalm-6, K562, Jurkat, and Molt-4 cell lines, IC₅₀ values were found to be 15.98, 19.12, 23.15, and 25.80 μM, respectively. Our work focuses on the synthesis of original and novel 1,2,3,4-tetrazine derivatives while contributing to the ongoing effort to discover more potent new antileukemia agents.

In nuclear medicine, cancers that cannot be cured or can only be treated partially by traditional techniques like surgery or chemotherapy are killed by ionizing radiation as a form of therapeutic treatment. Actinium-225 is an alpha-emitting radionuclide that is highly encouraging as a therapeutic approach and more promising for targeted alpha therapy (TAT). Actinium-225 is the best candidate for tumor cells treatment and has physical characteristics such as high (LET) linear energy transfer (150 keV per μm), half-life (t_1/2 = 9.92d), and short ranges (400–100 μm) which prevent the damage of normal healthy tissues. The introduction of various new radiopharmaceuticals and radioisotopes has significantly assisted the advancement of nuclear medicine. Ac-225 radiopharmaceuticals continuously demonstrate their potential as targeted alpha therapeutics. ²²⁵Ac-labeled radiopharmaceuticals have confirmed their importance in medical and clinical areas by introducing [²²⁵Ac]Ac-PSMA-617, [²²⁵Ac]Ac-DOTATOC, [²²⁵Ac]Ac-DOTA-substance-P, reported significantly improved response in patients with prostate cancer, neuroendocrine, and glioma, respectively. The development of these radiopharmaceuticals required a suitable buffer, incubation time, optimal pH, and reaction temperature. There is a growing need to standardize quality control (QC) testing techniques such as radiochemical purity (RCP). This review aims to summarize the development of the Ac-225 labeled compounds and biomolecules. The current state of their reported resulting clinical applications is also summarized as well.

Resveratrol (Res) has been identified to reduce neurodegeneration. Circular RNAs (circRNAs) are stable noncoding RNAs that are considered to be ideal biomarkers for molecular targeting treatment. Here, this study focused on investigating the function and relationship of circ_0050263 and Res in Alzheimer's Disease (AD). Human neuroblastoma cell line SK-N-SH was exposed to amyloid-β (Aβ) to induce AD cell model in vitro. Cell viability, apoptosis, and inflammatory reaction were evaluated by CCK-8 assay, flow cytometery, and ELISA analysis. The oxidative stress and endoplasmic reticulum stress (ERS) were determined by detecting related markers. Levels of genes and proteins were detected by qRT-PCR and Western blot. Dual-luciferase reporter assay was adopted to verify the binding between miR-361-3p and circ_0050263 or PDE4A (Phosphodiesterase 4A). Subsequently, we found that Res treatment alleviated Aβ-induced apoptosis, inflammatory response, oxidative stress, and ERS in SK-N-SH cells. Circ_0050263 is a stable circRNA, which was increased by Aβ, but decreased by Res in SK-N-SH cells. Circ_0050263 overexpression reversed Res-induced neuroprotective effects. Mechanistically, circ_0050263 acted as a sponge for miR-361-3p, which targeted PDE4A. Circ_0050263 silencing abated Aβ-induced neuronal injury, which were counteracted by following PDE4A overexpression. Moreover, PDE4A upregulation could attenuate Res-mediated neuroprotective effects. In all, Res alleviated Aβ-induced neuronal apoptosis, inflammation, oxidative stress, and ERS via circ_0050263/miR-361-3p/PDE4A axis, providing new insights for AD therapy.

The series of N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives as potential polyfuctional agents against Alzheimer's disease that have been designed, synthesized and then evaluated biologically using in vitro assays for the inhibition of acetylcholinesterase (AChE) activity, AGEs, and free radical formation. The majority of synthesized compounds inhibited AChE & AGEs with additional free radical scavenging activities at nanomolar concentrations. Among these, compound 5k was found to have potent AChE inhibitory activity (IC₅₀ = 11.6 nM), superior than the reference compound donepezil (15.68 nM) along with the good anti-AGEs and free radical formation effect. Its potency was justified by docking studies that revealed its dual binding characteristic with both catalytic active site and peripheral anionic site of AChE, simultaneously. Furthermore, the in vivo evaluation of 5k against streptozotocin (STZ)-induced dementia in rats also showed improvement of memory functions (Morris water maze test) in animals. Also, 5k inhibited STZ-inudced brain AChE activity and oxidative stress which further strengthen the observed in vitro effects. The stability of the ligand-protein complex was then analyzed using a simulation-based interaction protocol. The results revealed that these N-methylpiperazinyl and piperdinylalkyl-O-chalcone derivatives could be considered for potential polyfunctional anti-Alzheimer's molecules.