Chemical Biology & Drug Design最新文献

{"title":"The Role of the Sirt1/Foxo3a Pathway in Mitigating Myocardial Ischemia–Reperfusion Injury by Dexmedetomidine","authors":"Hanlin Ding,&nbsp;Danyong Liu,&nbsp;Jianfeng He,&nbsp;Dongcheng Zhou,&nbsp;Chan Wang,&nbsp;Changming Yang,&nbsp;Zhongyuan Xia","doi":"10.1111/cbdd.70100","DOIUrl":"https://doi.org/10.1111/cbdd.70100","url":null,"abstract":"<p>Myocardial ischemia–reperfusion injury (MIRI) significantly affects the prognosis of cardiac surgery patients. The anesthetic dexmedetomidine (Dex) has shown protective effects against ischemia–reperfusion injury in cardiomyocytes; however, its exact mechanism remains unclear. In this study, hypoxia/reoxygenation (H/R) and ischemia/reperfusion (I/R) models were used to investigate the effects of Dex on H9c2 cells and MIRI in mice. The roles of the Sirtuin 1/Forkhead box O3a (Sirt1/FoxO3a) pathway in the protective effects of Dex were explored using the Sirt1 inhibitor EX527 and FoxO3a gene silencing. Results showed that H/R significantly reduced H9c2 cell viability, increased Lactate Dehydrogenase (LDH) leakage, and elevated reactive oxygen species (ROS) production. Dex pretreatment reversed these effects. Additionally, Dex significantly reduced the expression of Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2), cleaved caspase-3, Beclin-1, and microtubule-associated protein 1A/1B-light chain 3B (LC3B), inhibiting apoptosis and autophagy while increasing the expression of p62, Sirt1, and FoxO3a. The protective effects of Dex against H/R injury were abolished by EX527 or FoxO3a silencing. In the mouse MIRI model, Dex pretreatment decreased serum LDH and Creatine Kinase-MB (CK-MB) levels, reduced myocardial infarct size and cardiac injury, and significantly improved left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). These protective effects were markedly reversed by EX527. These findings indicate that Dex alleviates MIRI by restoring Sirt1 expression and activating FoxO3a.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Journey Around Boronic Acids: Sulfonyl Hydrazone-Containing Derivatives as Carbonic Anhydrase Inhibitors","authors":"Deniz A. Anakök,&nbsp;Andrea Angeli,&nbsp;Ilaria D'Agostino,&nbsp;Gioele Renzi,&nbsp;Maria Luisa Massardi,&nbsp;Camilla Tavani,&nbsp;Servet Çete,&nbsp;Simone Carradori,&nbsp;Roberto Ronca,&nbsp;Clemente Capasso,&nbsp;Fabrizio Carta,&nbsp;Claudiu T. Supuran","doi":"10.1111/cbdd.70108","DOIUrl":"https://doi.org/10.1111/cbdd.70108","url":null,"abstract":"<div>\u0000 \u0000 <p>Recently, a rising interest in boronic acids and their derivatives was recorded in the Medicinal Chemistry field due to their high versatility and broad applicability as bioactive compounds in several diseases, including cancer and microbial infections. The ability of boronic acid moieties to bind zinc ions was first hypothesized by the inhibitory activity of bortezomib, a boron-containing protease inhibitor, on different isoforms of the Carbonic Anhydrase (CA, EC: 4.2.1.1) enzyme family and then assessed through X-ray crystallographic studies on benzoxaboroles in complex with hCA II. These findings, along with the overexpression of isoforms IX and XII in hypoxic cancer and, in particular, breast cancer, drove us to explore the chemical space around the phenylboronic acids by generating a focused library of 16 derivatives (1–4a–d) decorated with alkyl sulfonyl hydrazones. The compounds were then subjected to stopped flow-based inhibition assays on a panel of hCAs, including the tumor-associated isoforms, revealing low micromolar inhibition constants (<i>K</i>_Is) in some cases. However, antiproliferative assays conducted on a human triple-negative breast cancer cell line showed a lack of activity at the tested concentrations.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809510","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":"Echinacoside Alleviates Non-Alcoholic Fatty Liver Disease in Rats: Potential Involvement of AMPK Pathway and Autophagy","authors":"Wei-fang Song,&nbsp;Sheng-nan Li,&nbsp;Rui-xin Yao,&nbsp;Qiu-yan Jiang,&nbsp;Ting Shi,&nbsp;Dan-dan Fan,&nbsp;Hai-juan Zhang,&nbsp;Wen-hui Zhang,&nbsp;Rui-jun Wang","doi":"10.1111/cbdd.70097","DOIUrl":"https://doi.org/10.1111/cbdd.70097","url":null,"abstract":"<div>\u0000 \u0000 <p>The primary objective aims to evaluate the therapeutic efficacy of echinacoside in ameliorating hepatic steatosis and exploring its role in modulating autophagic flux through AMP-activated protein kinase (AMPK) signaling, positioning it as a potential treatment for non-alcoholic fatty liver disease (NAFLD). A well-established NAFLD rat model was employed, administering varying concentrations of echinacoside. Biochemical parameters, including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alongside liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), were measured to assess liver function. To elucidate the molecular mechanisms, western blot analyses were performed to assess the expressions of p-AMPK, total AMPK, and key autophagy markers LC-3 I/II and Beclin-1. Echinacoside significantly improved the lipid profile by lowering plasma TG, TC, and LDL-C levels while increasing HDL-C. It also reduced serum ALT, AST, and ALP activities, demonstrating hepatoprotective effects. Notably, echinacoside reversed the p-AMPK levels in NAFLD rats in a dose-dependent manner, with the highest dosage showing the strongest effect. This was accompanied by increased expression of LC-3 I/II and Beclin-1. Echinacoside is expected to be a therapeutic drug for NAFLD by activating AMPK activity and enhancing autophagy to improve liver function. These findings suggest its clinical potential, with autophagy modulation via the AMPK pathway as a possible therapeutic mechanism for NAFLD treatment.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809514","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":"Isoxazole and Pyrazole Derivatives of 28-Oxo-Allobetulone Target Viral Membrane Glycoprotein Hemagglutinin","authors":"Irina E. Smirnova,&nbsp;Alexandrina S. Volobueva,&nbsp;Iana L. Esaulkova,&nbsp;Sergei B. Fedij,&nbsp;Vladimir V. Zarubaev,&nbsp;Oxana B. Kazakova","doi":"10.1111/cbdd.70099","DOIUrl":"https://doi.org/10.1111/cbdd.70099","url":null,"abstract":"<div>\u0000 \u0000 <p>A series of [2,3]-isoxazoles and pyrazole annulated with the A-ring of lupane, oleanane, and ursane type triterpenoids was synthesized and screened for antiviral activity. It was found that 28-oxo-allobetulone isoxazole <b>4</b> with IC₅₀ 7.3 μM (SI 86) and pyrazole <b>5</b> with IC₅₀ 62.1 μM (SI 10) demonstrated a high inhibitory activity against Flu A/Puerto Rico/8/34 (H1N1) strain virus. The compounds <b>4</b> and <b>5</b> appeared to be the most active at the earlier stages of the viral cycle (0–2 h post infecting). No inhibiting effect of compounds <b>4</b> and <b>5</b> on the fusogenic activity of hemagglutinin HA has been detected, but the compounds prevented the binding of virions with the cell receptor. According to the results of molecular docking, compounds <b>4</b> and <b>5</b> preferentially bound to the interface between HA1 and HA2 subunits of hemagglutinin, near the heptad repeat domain.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143793591","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":"NAD_MCNN: Combining Protein Language Models and Multiwindow Convolutional Neural Networks for Deacetylase NAD+ Binding Site Prediction","authors":"Van-The Le,&nbsp;Yu-Chen Liu,&nbsp;Yan-Yun Chang,&nbsp;Yu-Cheng Lee,&nbsp;Yi-Jing Lin,&nbsp;Muhammad-Shahid Malik,&nbsp;Yu-Yen Ou","doi":"10.1111/cbdd.70085","DOIUrl":"https://doi.org/10.1111/cbdd.70085","url":null,"abstract":"<div>\u0000 \u0000 <p>Sirtuins, a class of NAD+ -dependent deacetylases, play a key role in aging, metabolism, and longevity. Their interaction with NAD+ at the catalytic site is crucial for function, but experimental methods to map NAD+ binding sites are time consuming. To address this, we developed a computational method integrating pretrained protein language models with multiwindow convolutional neural networks (CNNs). This method captures sequence information and diverse local patterns, achieving state-of-the-art performance, with AUC of 0.9733 for human sirtuin proteins and 0.9701 for other NAD-dependent deacylation enzymes. These findings offer insights into the role of sirtuins in aging and their broader biological functions while providing a new path for identifying therapeutic targets in aging-related diseases.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770339","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":"Reviewing the IDH1 Mutation-Mediated Mechanism of Drug Resistance and Revisiting Its Overcoming Strategies","authors":"Yifan Wang,&nbsp;Hailong Bai,&nbsp;Aixin Wang,&nbsp;Jun Zhao,&nbsp;Hui Guo,&nbsp;Yuping Tang,&nbsp;Yuwei Wang,&nbsp;Qinjian Xie","doi":"10.1111/cbdd.70102","DOIUrl":"https://doi.org/10.1111/cbdd.70102","url":null,"abstract":"<div>\u0000 \u0000 <p>Isocitrate dehydrogenase 1 (IDH1) is a pivotal enzyme in cellular energy metabolism, playing a crucial role in the conversion of isocitrate into α-ketoglutarate (α-KG). When IDH1 undergoes mutation, it catalyzes the conversion of α-KG into the oncogenic metabolite 2-hydroxyglutarate (2-HG). Subsequently, 2-HG competitively suppresses a range of α-KG-dependent dioxygenase activities, ultimately leading to hypermethylation of DNA or histones, which in turn causes the occurrence of various malignant tumors, including acute myeloid leukemia (AML), glioma, and chondrosarcoma. Currently, the FDA has granted approval for the use of the small molecule inhibitor Ivosidenib (AG-120) in the treatment of IDH1-mutated AML and cholangiocarcinoma. Although AG-120 has benefited patients clinically, drug resistance has gradually emerged and has become a major problem in the treatment of mutant IDH1 (mIDH1) diseases. In this review, we highlighted the function of IDH1 mutations in cancer treatment and described detailed resistance mechanisms in terms of IDH1-specific mutation sites. Representative mIDH1 inhibitors and their binding modes were also discussed. In particular, we summarized seven strategies to overcome drug resistance, which provide a basis for understanding the mechanism of drug resistance for IDH1 mutations and exploring guidance to overcome drug resistance.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143770430","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 Development of Selective Chemical Probes for Serine Arginine Protein Kinase 3","authors":"Danielle Hanke,&nbsp;Conall McCutcheon,&nbsp;Brent D. G. Page","doi":"10.1111/cbdd.70101","DOIUrl":"https://doi.org/10.1111/cbdd.70101","url":null,"abstract":"<p>The serine arginine protein kinases (SRPKs) are a family of kinases whose irregular function is implicated in cancer and viral infections. While the roles of SRPK1 and SRPK2 in disease are well established, much less is known about SRPK3. There are several studies implicating SRPK3 in breast cancer, but the mechanism is still unknown. This work describes the first-reported SRPK3 chemical probes that show excellent selectivity over the other SRPKs. 1-(4-cyanophenyl)-3-phenylurea was identified as an initial hit for SRPK3 through a kinase screen. Subsequent rounds of in silico docking, medicinal chemistry optimization, and biochemical assays were performed to increase its potency and selectivity for SRPK3. Six top compounds were identified that displayed single digit micromolar IC₅₀ values in SRPK3 activity assays and negligible inhibition of SRPK1 or SRPK2. These six compounds demonstrated impairment of breast cancer cell viability that correlated with their biochemical IC₅₀ values, suggesting that they can be used as tools to study the biological functions of SRPK3 in breast cancer. With an enhanced understanding of SRPK3's biological function, it may emerge as a meaningful drug target, wherein our top inhibitors could be further optimized to produce novel cancer therapeutics.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tanshinone IIA Ameliorates Myocardial Ischemia–Reperfusion Injury via Activating HDAC1-Repressed Nrf2-xCT/Gpx4/HO-1 Axis","authors":"Ke Yan,&nbsp;Shenghui Yu,&nbsp;Xiang Gao,&nbsp;Lei Li,&nbsp;Li Ding","doi":"10.1111/cbdd.70095","DOIUrl":"https://doi.org/10.1111/cbdd.70095","url":null,"abstract":"<div>\u0000 \u0000 <p>Myocardial ischemia/reperfusion injury (MIRI) brings secondary injury to heart tissues and involves complicated pathophysiological activities, such as cell death, oxidative stress, and inflammation. HDAC1 (Histone Deacetylase 1) has been documented to strengthen MIRI; our study intended to investigate the concrete regulatory mechanisms and functions of tanshinone IIA on HDAC1 in MIRI, which might provide experimental proofs for the adjuvant application of tanshinone IIA in the treatment of MIRI. Genecards and SwissTargetPrediction websites were utilized to download the myocardial infarction-related and tanshinone IIA-targeted genes respectively, and then the String website was applied to display protein–protein interaction (PPI) network. The Cytoscape software was subsequently used to select and display the PPI network of hub genes. AutoDockTools and PyMOL software were utilized to operate molecular docking and visualize the docking results between tanshinone IIA and HDAC1, and Oxygen–glucose deprivation/reoxygenation (OGD/R)-treated myocardiocytes were used as the cell model of MIRI. The protein levels of HDAC1 and nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated pathway were examined by western blot, and cell viability and apoptosis were evaluated by CCK8, Tunnel, and flow cytometry assays. The levels of lactate dehydrogenase, creatine kinase-MB, malondialdehyde, reduced glutathione, and Fe²⁺ were assessed by corresponding kit, and MIRI rat models were constructed to verify the therapeutic effects of tanshinone IIA in vivo. Finally, hematoxylin and eosin staining and immunohistochemistry were used to display the pathological changes of MIRI heart tissues and the levels of 4-hydroxynonenal respectively. HDAC1 was the possible target of tanshinone IIA and was involved in the myocardial infarction process. Tanshinone IIA could bind to amino acid residues of HDAC1 with high affinity. Besides, HDAC1 was elevated in OGD/R-treated myocardiocytes, and tanshinone IIA pretreatment ameliorated myocardiocyte apoptosis, the release of inflammatory mediators, and ferroptosis under the following OGD/R treatment, which were abolished by HDAC1 upregulation. Besides, tanshinone IIA pretreatment suppressed HDAC1 expression and further activated the Nrf2-xCT/Gpx4/HO-1 axis in myocardiocytes with OGD/R operation. Functionally, tanshinone IIA pre-injection ameliorated myocardial infarcted areas via activating the HDAC1-suppressed Nrf2-xCT/Gpx4/HO-1 pathway in vivo. Tanshinone IIA could attenuate myocardial apoptosis, inflammatory response, and ferroptosis via activating the HDAC1-repressed Nrf2-xCT/Gpx4/HO-1 axis, which promoted myocardial salvage in the MIRI process.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762161","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":"SAIAME: Semi-Parameter Adaptation Information-Assisted Multi-Objective Evolutionary for Protein-Ligand Docking","authors":"Wei Xiao,&nbsp;Haichuan Shu,&nbsp;Chen Xu,&nbsp;Wangyan Li,&nbsp;Juhui Ren","doi":"10.1111/cbdd.70094","DOIUrl":"https://doi.org/10.1111/cbdd.70094","url":null,"abstract":"<div>\u0000 \u0000 <p>Molecular docking, which simulates the binding pose of a drug molecule to target proteins and predicts the binding affinity, is an important computational tool in structure-based drug discovery. However, the difficulties of high ligand connectivity and dimensionality reduce the search ability of the conformational sampling. To this end, a semi-parameter adaptation information-assisted multi-objective evolution method named SAIAME is proposed for protein-ligand docking optimization. SAIAME employs a staged and dynamic semi-parameter adaptive updating strategy, in which the crossover rate is updated by a weighted arithmetic average algorithm in the exploration phase, as well as the scaling factor is updated by the Lehmer mean in the exploitation phase. It integrates a gradient enhancement based on infinity norms to smooth the decay of the weights of the learning rate during gradient descent to enhance the handling of outliers. It introduces a population size reduction strategy that combines linear and bilateral symmetric sawtooth functions to enhance its execution efficiency. The experimental results demonstrate that SAIAME not only achieves the accuracies of 87.02% for the best poses and 72.98% for the top-score poses within an RMSD of 2 Å, but also has certain advantages in execution efficiency.</p>\u0000 </div>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762001","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":"Selective Antiproliferative and Apoptotic Effects of 2,6-Diketopiperazines on MDA-MB-231 Triple-Negative Breast Cancer","authors":"Flor Paulina Garrido González,&nbsp;Martha Edith Macías Pérez,&nbsp;Octavio Rodríguez Cortés,&nbsp;Elvia Mera Jiménez,&nbsp;Teresa Mancilla Percino","doi":"10.1111/cbdd.70098","DOIUrl":"https://doi.org/10.1111/cbdd.70098","url":null,"abstract":"<p>Diketopiperazines (DKPs) have emerged as promising candidates for treating diverse diseases, particularly cancer. In this context, 2,5-diketopiperazines have been extensively investigated in comparison with 2,6-diketopiperazines. This work explores the selectivity and impact of 2,6-diketopiperazine enantiomers derived from α-amino acids on MDA-MB-231 triple-negative breast cancer cells (TNBC). This subtype of cancer is recognized for its aggressiveness and the lack of effective therapeutic options. The evaluation utilized MTT and flow cytometry assays to examine the impact of 2,6-DPKs on the MDA-MB-231 breast cancer cell line. The obtained IC₅₀ values for compounds <b>1</b> and (<i>S</i>)-enantiomers ranged from 4.6 μM to 4.944 mM, where <b>1</b> and (<i>S</i>)-<b>2a</b> exhibited the lowest values. The IC₅₀ values for (<i>R</i>) enantiomers ranged from 0.021 to 3.639 mM, whereas (<i>R</i>)-<b>2b</b> was the lowest. Flow cytometry results revealed that compounds increase in apoptosis at 48 h compared to 24 h, ranging from 54.1% to 76.2%; however, (<i>S</i>)-<b>12a</b> exhibited a 3% decrease in apoptotic induction at 48 h. All investigated 2,6-diketopiperazines derived from α-amino acids showed potential as anticancer agents against MDA-MB-231 cancer cells. In particular, compounds <b>1</b>, (<i>S</i>)-<b>2a</b>, -4a, and -<b>5a</b> showed remarkable inhibitory effects on proliferation, viability, and apoptosis. The MTT results in the culture of healthy cells of the kidney line Vero did not display cytotoxicity at the tested concentrations up to 12.0 mM. Hence, these 2,6-DPKs are suitable for in vivo testing shortly.</p>","PeriodicalId":143,"journal":{"name":"Chemical Biology & Drug Design","volume":"105 4","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cbdd.70098","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}