Current medicinal chemistry最新文献

{"title":"Paneth Cells: Recent Updates on Elucidating Therapeutic Implications in Gastroenterological Disease Management.","authors":"Maria V Sankova, Vladimir N Nikolenko, Anastasia A Bolotskaia, Marine V Oganesyan, Negoriya A Rizaeva, Aleksey V Sankov, Tatyana S Zharikova, André Pontes-Silva, Narasimha Murthy Beeraka, Hemanth Vikram P R, Padmanabha Reddy Y, Dilip Kumar Reddy Kandula, B M Gurupadayya, Yury O Zharikov","doi":"10.2174/0109298673357073250526104619","DOIUrl":"10.2174/0109298673357073250526104619","url":null,"abstract":"<p><strong>Background: </strong>The human intestine is continuously exposed to a variety of aggressive agents, including food antigens, xenobiotics, numerous pathogenic microorganisms, metabolic products, and toxins. Consequently, it has developed a specialized system for protection against these adverse factors.</p><p><strong>Objective: </strong>This study aims to investigate the biochemical compounds synthesized by Paneth cells and their mechanisms of action to develop new therapeutic approaches for gastroenterological diseases.</p><p><strong>Methods: </strong>We conducted a systematic review, excluding a comprehensive meta-analysis, of the current scientific literature sourced from electronic libraries (CyberLeninka, e-Library.ru, and Cochrane Library), search engines (Google Scholar, Embase, and Global Health), and scientific databases (Elsevier, Medline, PubMed-NCBI, and Scopus). Following PRISMA guidelines, a total of 104 articles were initially selected based on defined inclusion and exclusion criteria. After careful evaluation, 63 articles were included in this study.</p><p><strong>Results: </strong>Our findings indicate that Paneth cells play a crucial role in regulating small intestine homeostasis by secreting numerous biologically active molecules. A key feature of these cells is their ability to recognize soluble microbial products via pattern recognition receptors and respond by releasing a variety of antimicrobial peptides and enzymes. These secretions contribute to the formation of a biochemical barrier that prevents pathogen adhesion and translocation. Paneth cells are integral to immunological protection, maintaining protective inflammatory responses under both normal and pathological conditions. Additionally, they regulate the division, growth, and differentiation of intestinal stem cells, ensuring proper enterocyte localization. Paneth cells also aid digestive processes through enzyme secretion and are the only epithelial cells capable of eliminating activated autoreactive lymphocytes and abnormal enterocytes.</p><p><strong>Conclusion: </strong>Paneth cells are unique epithelial cells that, through the synthesis of numerous biologically active molecules, control the timely regeneration of the intestinal epithelium, maintain a healthy microbiota, and prevent infectious, autoimmune, and cancerous diseases. Understanding their role in these processes is crucial for developing new therapies for gastroenterological diseases.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of TRIM65 Inhibits Neoangiogenesis in Proliferative Diabetic Retinopathy by Regulating miR29a-3p.","authors":"Xinxin Chen, Xiaolong Chen, Shuai Huang, Yang Xian, Ruining Han","doi":"10.2174/0109298673325802240813103408","DOIUrl":"10.2174/0109298673325802240813103408","url":null,"abstract":"<p><strong>Introduction: </strong>High glucose-induced angiogenesis is the main component in Proliferative Diabetic Retinopathy (PDR) development. In PDR, ischemia and hypoxia have been identified as key stimuli that promote pathological neoangiogenesis by increasing Vascular Endothelial Growth Factor A (VEGFA). Furthermore, it has been demonstrated that TRIM65 knockdown in tumor cells reduces VEGFA expression. Building on these findings, the present study aimed to study the role of TRIM protein members in proliferative diabetic retinopathy.</p><p><strong>Method: </strong>In comparison to the control group, TRIM65 expression was significantly increased in human retinal endothelial cells (HREC) after high glucose treatment. Moreover, FITC/PI staining, cell wound scratch assay, transwell assay, tube formation assay, and immunofluorescence staining of VEGFA and HIF-3α were carried out, which indicated that TRIM65 knockdown inhibited high glucose-induced HREC cell apoptosis and angiogenesis and decreased the expression of VEGFA and HIF-3α, both of which are potential targets of miR-29a-3p. MIR-29a-3p inhibitor significantly reduced the effects of TRIM65 knockdown on VEGFA and HIF-3α expression levels in cells. TRIM65 induced ubiquitination and degradation of TNRC6A, resulting in suppressed miR-29a-3p expression.</p><p><strong>Result: </strong>Furthermore, in vivo studies revealed that intravitreal injection of miR-29a-3p inhibited neoangiogenesis in mice with Oxygen-Induced Retinopathy (OIR). The retinal tissues of OIR mice showed higher TRIM65 mRNA expression and lower miR-29a-3p expression than those of control mice. Furthermore, the analysis showed a negative correlation between the expression of miR-29a-3p and TRIM65 in the retinal tissues of OIR mice.</p><p><strong>Conclusion: </strong>In conclusion, this study demonstrated that the knockdown of TRIM65 inhibits neoangiogenesis in proliferative diabetic retinopathy by regulating miR-29a-3p.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Prognostic Lysine Crotonylation Signature Shapes the Immune Microenvironment in Hepatocellular Carcinoma.","authors":"Weiping Su, Kuo Kang, Xuanxuan Li, Heyuan Huang","doi":"10.2174/0109298673381518250529110617","DOIUrl":"https://doi.org/10.2174/0109298673381518250529110617","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Hepatocellular carcinoma (HCC) has a poor prognosis due to late diagnosis and rapid progression, highlighting the need for a deeper understanding of its pathogenesis. Lysine crotonylation (Kcr), a unique post-translational modification, plays a crucial role in epigenetic regulation. However, the role of crotonylation-related genes (CRGs) in HCC remains poorly understood, necessitating an investigation of their prognostic and therapeutic relevance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Transcriptomic and clinical data were obtained from TCGA and GEO databases. A CRG-based risk score was developed using Cox and LASSO regression analyses. To enhance survival prediction, a nomogram incorporating the risk score was constructed. Immune cell infiltration and drug sensitivity were assessed using CIBERSORT and 'OncoPredict.' Single-cell sequencing was employed to examine CRG expression within the HCC tumor microenvironment.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;An 8-gene risk score model (HDAC2, ACADS, HDAC1, ENO1, PPARG, ACADL, ACSL6, and AGPAT5) was established, effectively stratifying patients into high- and low-risk groups in the training set. Cox regression and Kaplan-Meier analyses validated its prognostic value in the test set. The nomogram demonstrated enhanced prognostic accuracy for survival prediction. Differences in immune cell infiltration and immune checkpoint expression between risk groups highlighted the association between CRGs and the tumor immune microenvironment. Single-cell sequencing revealed that CRGs were highly expressed in key immune cells within the HCC microenvironment. Additionally, drug sensitivity analysis suggested that specific targeted therapies may be more effective in HCC patients.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;Crotonylation-related gene signature demonstrates strong prognostic value in hepatocellular carcinoma (HCC), effectively stratifying patients into high- and low-risk groups and recapitulating known oncogenic roles of HDAC1/2, ENO1, PPARG, AGPAT5 and the protective functions of ACADS, ACADL, and ACSL6. It was found that crotonylation not only influences tumor cell metabolism and epigenetic regulation but also shapes the immune microenvironment, highlighted by distinct checkpoint expression, differential immune cell infiltration, and drug sensitivity profiles, which positions our model as a promising tool for personalized therapeutic decision-making. However, clinical translation will require standardized, reproducible assays for crotonylation measurement and rigorous validation across diverse HCC etiologies (e.g., viral vs. non-viral), along with mechanistic and longitudinal studies to dissect causality versus correlation, assess off-- target effects of crotonylation modulators, and confirm functional impacts on immune modulation before routine diagnostic or therapeutic use.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This study identifies a prognostic CRG signature for HCC and provides novel ins","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis of Pan-Specific Inhibitors of Oncogenic Mutant Forms of KRAS GTPase.","authors":"Ilya A Eliseev, Dmitrii O Shkil, Valentina S Shumakova, Vladimir V Chernyshov, Konstantin V Balakin, Roman A Ivanov","doi":"10.2174/0109298673372217250515031136","DOIUrl":"https://doi.org/10.2174/0109298673372217250515031136","url":null,"abstract":"<p><p>The KRAS protein is one of the key targets in cancer therapy. The clinical application of covalent KRAS inhibitors (sotorasib, adagrasib) is limited to the treatment of only certain KRASG12C-mediated types of cancer. In addition, using covalent inhibitors has several drawbacks, the main ones being limited to specific mutations (e.g., G12C) and the potential development of mutagenic resistance in tumors. Recently, the first representatives of a new class of allosteric inhibitors, termed pan-KRAS, have been discovered and studied due to their activity against multiple mutant forms of the KRAS protein. The development of pan-KRAS inhibitors represents a promising new direction in the therapeutic approach to treating KRAS-mediated cancers. The possibility to target multiple mutant forms of KRAS will significantly enlarge the number of patients that benefit from the therapy and reduce the likelihood of mutagenic resistance in tumors. This study reviews patents published between 2022 and 2024 that present new pan-specific KRAS inhibitors. The consideration of 28 patents included descriptions of the structures of the presented molecules, identification of the most active and selective examples of compounds, as well as results from structure-activity relationship (SAR) analyses for each sample. As a result of this work, some structural features of the most active examples of pan-KRAS inhibitors were identified.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between Maternal Hypertension and Cleft Lip and Palate: A Mendelian Randomization Study.","authors":"Wenkang Luan, Shujun Fan, Haojun Liang, Dongwen Jiang, Leren He","doi":"10.2174/0109298673364806250523062350","DOIUrl":"https://doi.org/10.2174/0109298673364806250523062350","url":null,"abstract":"<p><strong>Background: </strong>There is still no consensus on the etiology and risk factors of cleft lip and palate, and the causal relationship between maternal hypertension and cleft lip and palate remains uncertain.</p><p><strong>Objective: </strong>We used two-sample Mendelian Randomization (MR) to investigate the causal effect of maternal hypertension on cleft lip and palate.</p><p><strong>Methods: </strong>The MR study was performed using the statistics from the Genome-Wide Association Studies (GWAS) of maternal hypertension and cleft lip and palate. Using 25 Single-Nucleotide Polymorphisms (SNPs) robustly associated with maternal hypertension as instrumental variables, we employed several MR approaches, including Inverse Variance Weighted (IVW), weighted median, simple mode, MR-Egger, and weighted mode. Heterogeneity and pleiotropy tests were also conducted.</p><p><strong>Results: </strong>The causal relationship between maternal hypertension and cleft lip and palate (CL/P) was identified using IVW (OR = 3.603, 95% CI = 1.184-10.964, p = 0.024). Additionally, a causal effect of maternal hypertension on cleft lip (CL) risk was identified using IVW (OR = 5.968, 95% CI = 1.023-34.819, p = 0.047). However, no significant association between maternal hypertension and Cleft Palate Only (CPO) was observed across all MR methods.</p><p><strong>Conclusion: </strong>The MR analysis indicated that maternal hypertension is causally associated with the risk of CL/P and CL.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of Circadian Rhythm-related Genes for Prognosis Modeling and Immune Characterization in Thyroid Cancer.","authors":"Xiuping Qiu, Gang Chen, Mei Tu","doi":"10.2174/0109298673374398250523073407","DOIUrl":"https://doi.org/10.2174/0109298673374398250523073407","url":null,"abstract":"<p><strong>Background: </strong>Circadian rhythm-related genes (CRRGs) play a crucial role in regulating cellular processes, including survival, invasion, proliferation, and metastasis across various tumors. However, their specific function in thyroid cancer (THCA) remains uncertain. This study explores the prognostic significance of CRRGs in THCA and evaluates their potential as therapeutic targets.</p><p><strong>Methods: </strong>Clinical and gene expression data from the Cancer Genome Atlas (TCGA) were analyzed to assess the relevance of CRRGs in THCA. Somatic mutation analysis, risk model development, and comparisons between high- and low-risk patient groups were carried out using Gene Set Variation Analysis (GSVA). Tumor immune microenvironment characteristics were evaluated, and data from Kaplan-Meier (K-M) survival analysis was used to examine prognostic outcomes. Functional validation of nine CRRGs, namely CHEK1, GHR, ID3, IDI1, MAGEL2, NLGN1, PPARGC1A, TBL1X, and TF, was conducted through in vitro experiments.</p><p><strong>Results: </strong>The CRRG-based risk model stratified patients into high- and low-risk groups, with K-M analysis revealing that patients in the low-risk group had significantly poorer outcomes. Functional analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), identified pathways associated with THCA in both groups. Using single-sample GSEA (ssGSEA), patients were further categorized by circadian rhythm scores (CRscores), highlighting distinct immune profiles between the two groups. A clinical Cox model was developed, and differential gene expression was validated through in vitro experiments.</p><p><strong>Conclusion: </strong>This study presents a novel CRRG-based prognostic model for THCA, providing a valuable tool for patient stratification and providing insights for optimizing immunotherapy strategies.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic Pan-Cancer Analysis of the Oncogenic and Immunological Function of Stanniocalcin-1 (STC1).","authors":"Long Zhao, Changjiang Yang, Zhidong Gao, Yingjiang Ye, Lin Gan","doi":"10.2174/0109298673358794250531003706","DOIUrl":"https://doi.org/10.2174/0109298673358794250531003706","url":null,"abstract":"<p><strong>Background: </strong>Stanniocalcin 1 (STC1) has been implicated in cancer pathogenesis, yet its pan-cancer implications and mechanistic roles in tumor progression and immune modulation remain incompletely characterized. The clinical relevance of STC1 in predicting prognosis and its interaction with tumor immune microenvironment components require systematic investigation.</p><p><strong>Objective: </strong>This study aims to establish the pan-cancer prognostic significance of STC1 and elucidate its associations with immunological characteristics, including immune checkpoint proteins, tumor mutational burden (TMB), microsatellite instability (MSI), and immune cell infiltration. We specifically focus on validating its role in gastric adenocarcinoma (STAD) pathogenesis.</p><p><strong>Methods: </strong>Multi-omics analysis was performed using TCGA pan-cancer datasets and bioinformatics tools (UALCAN, cBioPortal, HPA, GTA). Experimental validation included multiplex fluorescence staining of STAD tissue microarrays (n=30) and Western blot analysis of STAD cell lines. Key parameters analyzed encompassed clinical outcomes, cancer stemness indices, neoantigen load, and epithelial-mesenchymal transition (EMT) signatures.</p><p><strong>Results: </strong>Pan-cancer analysis revealed significant STC1 overexpression in 18/33 cancer types (54.5%), particularly in prostate adenocarcinoma (94% deep deletions). STC1 expression correlated with poor prognosis (HR=1.32, p<0.01), elevated TMB (r=0.43), and MSI (r=0.38) across multiple malignancies. Single-cell RNA sequencing demonstrated strong EMT association (NES=2.18, FDR<0.001). In STAD, we confirmed 3.7-fold protein overexpression (p=0.008) and identified positive correlations with CD8+ T cell (r=0.62, p=0.002) and CD4+ T cell infiltration (r=0.58, p=0.004).</p><p><strong>Conclusion: </strong>This multi-modal study establishes STC1 as a novel pan-oncogenic factor with dual roles in tumor progression (via EMT and stemness regulation) and immune microenvironment remodeling. The strong association with immune checkpoints (PD-L1, CTLA4) and T cell infiltration patterns positions STC1 as a promising immunotherapeutic target, particularly in STAD and MSI-high cancers. Our findings provide mechanistic insights for developing STC1-directed therapeutic strategies.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144316129","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Markers Auxiliary in Distinguishing Between Nodal Nevi and Melanoma Metastases.","authors":"Łukasz Kuźbicki","doi":"10.2174/0109298673358592250408170859","DOIUrl":"https://doi.org/10.2174/0109298673358592250408170859","url":null,"abstract":"<p><p>Nodal nevus (NN) and melanoma metastasis (MM) have distinct biological and prognostic significance. They are characterized by different cytomorphological features and varying intranodal localization. However, in some cases, distinguishing them in standard hematoxylin and eosin-stained specimens can be challenging. The aim of this review is to evaluate the usefulness of markers in the diagnosis of NN and MM. The expression of selected markers in NN and MM was examined immunohistochemically in 27 studies. The frequency of HMB-45 and PRAME staining was significantly higher, while p16 was lower in MM than in NN. A slight increase of Ki-67 and decrease of 5- hmC expression in MM compared to NN were also observed. Meanwhile, staining of Melan-A/Mart-1, S-100, and SOX-10 was similar in NN and MM. However, none of the markers applied was completely specific for melanocytes. Although PRAME proved to have the strongest diagnostic potential, it was also detectable in other cell types, especially in lymphocytes and some breast cancers. Immunohistochemical staining of PRAME, HMB-45, and p16 may aid the diagnosis of NN and MM. Ki-67 and 5-hmC may also be of promising significance, whereas the expression of Melan-A/Mart-1, S-100, and SOX-10 does not allow distinguishing NN from MM.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Antiproliferative Activity against Melanoma Cells of New Heterocyclic Hybrids Based on Pyridine and Pyrimidine Scaffolds.","authors":"Magdalena Perużyńska, Radosław Birger, Tomasz J Idzik, Zofia M Myk, Magdalena M Lubowicz, Łukasz Struk, Jacek G Sośnicki, Patrycja Kłos, Dariusz Chlubek, Marek Droździk","doi":"10.2174/0109298673370617250330151330","DOIUrl":"https://doi.org/10.2174/0109298673370617250330151330","url":null,"abstract":"<p><strong>Background: </strong>Over 85% of biologically active compounds are heterocycles or contain heterocyclic groups, underscoring their vital importance in contemporary drug development. Among them, nitrogen-containing derivatives, such as pyridines and pyrimidines, are considered privileged structures in approved drugs or are extensively studied due to their promising therapeutic effects.</p><p><strong>Objective: </strong>In the current work, we would like to verify the hypothesis that incorporating heterocyclic pharmacophores into derivatives of pyrimidine-2(1H)-thione (PMT), 2-pyridone (P), pyridine-2(1H)-thione (PT), dihydropyrimidine-2(1H)-thione (DHPMT), dihydropyridin- 2(1H)-one (DHP), and dihydropyridine-2(1H)-thione (DHPT) rings enhances antitumor activity.</p><p><strong>Methods: </strong>A range of novel pyridine- and pyrimidine-based compounds were synthesized and assessed for their anticancer properties against the melanoma A375 cell line. The two most potent compounds (16b and 29) were then chosen for further evaluation of their effects on non-cancerous human dermal fibroblasts, cancer cell apoptosis, cell cycle phase distribution, and tubulin polymerization. Furthermore, in silico analyses were performed to assess the pharmacokinetics, toxicity, drug-likeness, and molecular target of the selected compounds.</p><p><strong>Results: </strong>Among the 33 compounds tested, pyridine analogs 16b and 29 demonstrated the strongest antiproliferative activity (with IC50 values of 1.85 ± 0.44 μM and 4.85 ± 1.67 μM, respectively) and selectivity (SI=65.08 and SI> 100, respectively) against cancer cells. Additional studies revealed that compound 16b, which features a thiophene ring at the C-5 position and a 3,4,5-trimethoxyphenyl (TMP) group, showed the most promising cell cycle arrest and tubulin polymerization inhibition (IC50=37.26 ± 10.86 μM), resulting in cancer cell apoptosis. In silico ADMET analysis confirmed the drug-- likeness of the synthesized compounds.</p><p><strong>Conclusion: </strong>This research reinforced the significance of heterocyclic rings as valuable pharmacophores. Additionally, it highlighted the antiproliferative and antimitotic potential of modified pyridine derivatives.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel Small Molecule Inhibitors of Cyclin-dependent Kinases as Anticancer Agents.","authors":"Nitin Srivastava, Anil K Saxena","doi":"10.2174/0109298673331685241205180307","DOIUrl":"https://doi.org/10.2174/0109298673331685241205180307","url":null,"abstract":"<p><p>Cyclin and Cyclin-dependent kinases (CDKs) play a key role in the progression of the cell cycle including transcription, metabolism, apoptosis, etc. Different phases of the cell cycle like G1, S, G2, and M have specific cyclins and CDKs, each with specific functions as checkpoints to regulate the transfer of cells from one phase to another. The kinases ensure proper replication of DNA in the daughter cells while fault at any stage of the cell phase induces apoptosis of the faulty cell. Hence, CDKs are considered important targets for developing chemotherapeutics against cancers. To review the published work on small molecules belonging to diverse chemical classes with potential CDK inhibitory and anticancer activities reported in the last ten years and to give an overview of the chemical structures that may be employed in designing novel CDK inhibitors with improved cancer therapeutic. Literature search has been carried out using different search engines like Google, Elsevier, Science Direct, RSC, PubMed, etc. for the publications of small molecules as CDK inhibitors and anticancer agents. All the structures have been drawn using Chemdraw software. Several classes of molecules, including nitrogen heterocycles, macrocyclic, and natural products have been the most promising CDK inhibitors with anticancer activities. Though CDK 4/6 inhibition is most significant for anticancer activity and has been shown by most of the molecules but the inhibition to other CDKs including 1, 2, 7, 9 has also been observed. Further CDK4/6 inhibitors have been investigated for the treatment of breast cancer in combination with radiotherapy where no untoward toxicities were observed. Several molecules have shown promising CDKs inhibition with anticancer activities against different cancer cell lines. The most important class being of nitrogen heterocycles. Though some of these molecules are in different phases of clinical trials and there are many lead molecules for judicious structural modulation to develop more specific and selective CDKs inhibitors as anticancer agents.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}