Drug Development Research最新文献

{"title":"Exploring chromone-2-carboxamide derivatives for triple-negative breast cancer targeting EGFR, FGFR3, and VEGF pathways: Design, synthesis, and preclinical insights","authors":"Dalia S. El-Gamil,&nbsp;Mohamed Y. Zaky,&nbsp;Patrick M. Maximous,&nbsp;Marwa Sharaky,&nbsp;Ahmed M. El-Dessouki,&nbsp;Noura M. Riad,&nbsp;Saad Shaaban,&nbsp;Mohammad Abdel-Halim,&nbsp;Ahmed A. Al-Karmalawy","doi":"10.1002/ddr.22228","DOIUrl":"10.1002/ddr.22228","url":null,"abstract":"<p>Chromone-based compounds have established cytotoxic, antiproliferative, antimetastatic, and antiangiogenic effects on various cancer cell types via modulating different molecular targets. Herein, 17 novel chromone-2-carboxamide derivatives were synthesized and evaluated for their in vitro anticancer activity against 15 human cancer cell lines. Among the tested cell lines, MDA-MB-231, the triple-negative breast cancer cell line, was found to be the most sensitive, where the <i>N</i>-(2-furylmethylene) (<b>15</b>) and the α-methylated <i>N</i>-benzyl (<b>17</b>) derivatives demonstrated the highest growth inhibition with GI₅₀ values of 14.8 and 17.1 μM, respectively. <i>In vitro</i> mechanistic studies confirmed the significant roles of compounds <b>15</b> and <b>17</b> in the induction of apoptosis and suppression of EGFR, FGFR3, and VEGF protein levels in MDA-MB-231 cancer cells. Moreover, compound <b>15</b> exerted cell cycle arrest at both the G0-G1 and G2-M phases. The in vivo efficacy of compound <b>15</b> as an antitumor agent was further investigated in female mice bearing Solid Ehrlich Carcinoma. Notably, administration of compound <b>15</b> resulted in a marked decrease in both tumor weight and volume, accompanied by improvements in biochemical, hematological, histological, and immunohistochemical parameters that verified the repression of both angiogenesis and inflammation as additional Anticancer mechanisms. Moreover, the binding interactions of compounds <b>15</b> and <b>17</b> within the binding sites of all three target receptors (EGFR, FGFR3, and VEGF) were clearly illustrated using molecular docking.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141476176","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":"Enriching iPSC research diversity: Harnessing human biobank collections for improved ethnic representation","authors":"David Gurwitz,&nbsp;Rachel Steeg","doi":"10.1002/ddr.22227","DOIUrl":"10.1002/ddr.22227","url":null,"abstract":"<p>Biobanks of human biosamples and cell lines are indispensable for biomedical research on human health and disease and for drug development projects. Many human cell line biobanks worldwide hold collections of lymphoblastoid cell lines (LCLs), representing thousands of affected and control donors from diverse ethnic/ancestry groups. In recent years, induced human pluripotent stem cells (iPSCs) and differentiated human cells derived from these iPSCs have become indispensable for applied biomedical research. Establishing iPSCs remains a laborious and costly step towards generating differentiated human cells. To address this research need, several non-profit and commercial biobanks have established iPSC collections for distribution to researchers, thereby serving as a resource for generating differentiated human cells. The most common starting materials for generation of iPSCs are a skin biopsy for harvesting fibroblasts, or a blood sample for collection of peripheral blood mononuclear cells. However untapped resources include the large established collections of biobanked human LCLs which can be reprogrammed to iPSCs using a variety of published protocols including the use of non-integrating episomal vectors. Many biobanks curate LCLs from diverse ethnic/ancestry populations, an aspect largely absent in most established iPSC biobanks which tend to primarily reflect populations from developed countries. Here, we call upon researchers across the breadth of iPSC research to tap the unique resource of existing and diverse human LCL collections for establishing biobanked iPSC panels that better represent the varied human ethnic (and hence genomic) diversity, thereby benefiting precision medicine and drug development research on a global scale.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 5","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22227","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466876","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":"SEP-363856 exerts neuroprotection through the PI3K/AKT/GSK-3β signaling pathway in a dual-hit neurodevelopmental model of schizophrenia-like mice","authors":"Mengdie Li,&nbsp;Yunxiao Liu,&nbsp;Meng Sun,&nbsp;Yating Yang,&nbsp;Ling Zhang,&nbsp;Yuexia Liu,&nbsp;Fujin Li,&nbsp;Huanzhong Liu","doi":"10.1002/ddr.22225","DOIUrl":"10.1002/ddr.22225","url":null,"abstract":"<p>Schizophrenia (SZ) is a serious, destructive neurodevelopmental disorder. Antipsychotic medications are the primary therapy approach for this illness, but it's important to pay attention to the adverse effects as well. Clinical studies for SZ are currently in phase ΙΙΙ for SEP-363856 (SEP-856)-a new antipsychotic that doesn't work on dopamine D₂ receptors. However, the underlying action mechanism of SEP-856 remains unknown. This study aimed to evaluate the impact and underlying mechanisms of SEP-856 on SZ-like behavior in a perinatal MK-801 treatment combined with social isolation from the weaning to adulthood model (MK-SI). First, we created an animal model that resembles SZ that combines the perinatal MK-801 with social isolation from weaning to adulthood. Then, different classical behavioral tests were used to evaluate the antipsychotic properties of SEP-856. The levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1β), apoptosis-related genes (Bax and Bcl-2), and synaptic plasticity-related genes (brain-derived neurotrophic factor [BDNF] and PSD-95) in the hippocampus were analyzed by quantitative real-time PCR. Hematoxylin and eosin staining were used to observe the morphology of neurons in the hippocampal DG subregions. Western blot was performed to detect the protein expression levels of BDNF, PSD-95, Bax, Bcl-2, PI3K, p-PI3K, AKT, p-AKT, GSK-3β, p-GSK-3β in the hippocampus. MK-SI neurodevelopmental disease model studies have shown that compared with sham group, MK-SI group exhibit higher levels of autonomic activity, stereotyped behaviors, withdrawal from social interactions, dysregulated sensorimotor gating, and impaired recognition and spatial memory. These findings imply that the MK-SI model can mimic symptoms similar to those of SZ. Compared with the MK-SI model, high doses of SEP-856 all significantly reduced increased activity, improved social interaction, reduced stereotyping behavior, reversed sensorimotor gating dysregulation, and improved recognition memory and spatial memory impairment in MK-SI mice. In addition, SEP-856 can reduce the release of proinflammatory factors in the MK-SI model, promote the expression of BDNF and PSD-95 in the hippocampus, correct the Bax/Bcl-2 imbalance, turn on the PI3K/AKT/GSK-3β signaling pathway, and ultimately help the MK-SI mice's behavioral abnormalities. SEP-856 may play an antipsychotic role in MK-SI “dual-hit” model-induced SZ-like behavior mice by promoting synaptic plasticity recovery, decreasing death of hippocampal neurons, lowering the production of pro-inflammatory substances in the hippocampal region, and subsequently initiating the PI3K/AKT/GSK-3β signaling cascade.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22225","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327355","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":"Validating linalool as a potential drug for breast cancer treatment based on machine learning and molecular docking","authors":"Qian Zhang,&nbsp;Dengfeng Chen","doi":"10.1002/ddr.22223","DOIUrl":"10.1002/ddr.22223","url":null,"abstract":"<p>Breast cancer (BC) is a common cancer for women. This study aims to construct a prognostic risk model of BC and identify prognostic biomarkers through machine learning approaches, and clarify the mechanism by which linalool exerts tumor-suppressive function. Three mRNA microarray/RNA sequencing data sets (GSE25055, GSE103091, and TCGA-BRCA) were obtained from Gene Expression Omnibus database and The Cancer Genome Atlas database, and prognostic genes were obtained by univariate COX analysis. Multiple machine learning methods were used to screen core genes and construct prognostic risk models. The enrichment analysis of crucial genes was analyzed using the DAVID database. UALCAN, human protein atlas, geneMANIA, and LinkedOmics databases were used to analyze gene expression and co-expressed genes. Molecular docking and molecular dynamics simulation was applied to verify the binding affinity between linalool and phosphoglycerate kinase 1 (PGK1). Cell counting kit 8 (CCK-8, Edu, transwell, flow cytometry, and Western blot assay were used to analyze cell activity, apoptosis, cell cycle and protein expression. Eight prognostic genes were obtained by bioinformatics analysis and machine learning, and prognostic risk models were constructed. This model could well predict the prognosis of patients, and the risk score could be used as an independent risk factor for BC. Overall survival (OS) and immune cell infiltration characteristics were distinct between high and low risk groups. PGK1 was highly expressed in BC and the OS of patients with high PGK1 expression was shorter. PGK1 was related to cell cycle and PPAR signaling pathway. Linalool and PGK1 had good binding activity, and linalool could inhibit the viability, proliferation, migration, and invasion of BC cells, promote cell apoptosis, and induce G0/G1 arrest. In addition, linalool can promote PPARγ protein expression and inhibit PGK1 expression. Machine learning and molecular docking were promising for exploration of new drug targets for BC, and linalool exerts tumor-suppressive effects in BC by inhibiting PGK1 expression and activating PPAR signaling pathway.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327356","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":"2-(Methyl(phenyl)amino)-N-(phenyloxyphenyl)acetamide structural motif representing a framework for selective SIRT2 inhibition","authors":"Selen Gozde Kaya,&nbsp;Gokcen Eren,&nbsp;Alberto Massarotti,&nbsp;Filiz Bakar-Ates,&nbsp;Erva Ozkan,&nbsp;Mahmut Gozelle,&nbsp;Yesim Ozkan","doi":"10.1002/ddr.22224","DOIUrl":"10.1002/ddr.22224","url":null,"abstract":"<p>The mammalian cytoplasmic protein SIRT2, a class III histone deacetylase family member, possesses NAD⁺-dependent lysine deacetylase/deacylase activity. Dysregulation of SIRT2 has been implicated in the pathogenesis of several diseases, including neurological and metabolic disorders and cancer; thus, SIRT2 emerges as a potential therapeutic target. Herein, we identified a series of diaryl acetamides (<b>ST61</b>-<b>ST90</b>) by the structural optimization of our hit <b>STH2</b>, followed by enhanced SIRT2 inhibitory potency and selectivity. Among them, <b>ST72</b>, <b>ST85</b>, and <b>ST88</b> selectively inhibited SIRT2 with IC₅₀ values of 9.97, 5.74, and 8.92 μM, respectively. Finally, the entire study was accompanied by <i>in silico</i> prediction of binding modes of docked compounds and the stability of SIRT2-ligand complexes. We hope our findings will provide substantial information for designing selective inhibitors of SIRT2.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ddr.22224","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310331","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":"Downregulation of HIGD1B induces mitochondria-mediated apoptosis in gastric cancer cells by inactivating Akt and ERK pathways","authors":"Xiangyu Chen,&nbsp;Binghua Sun,&nbsp;Shuai Li","doi":"10.1002/ddr.22221","DOIUrl":"10.1002/ddr.22221","url":null,"abstract":"<p>Gastric cancer (GC) is one of the most common malignancies worldwide. Hypoxia-inducible domain (HIGD) family members (e.g., HIGD1A) have been linked to tumor progression. However, the role of HIGD1B (another HIGD family member) in GC has yet to be fully understood. Based on data from TCGA_GC, GSE65801, and GSE65801 data sets, HIGD1B levels were evaluated in normal and GC tissues. Next, HIGD1B levels were validated by reverse transcription-quantitative PCR and western blot analysis analyses. Meanwhile, patients with GC in the TCGA_GC cohort were grouped into high- and low-HIGD1B level groups, and overall survival, functional enrichment, and immune infiltration were analyzed. Additionally, gain- and loss-of-function experiments were performed to determine the function of HIGD1B in GC cells. Compared to normal controls, HIGD1B mRNA levels were significantly elevated in GC tissues. Moreover, high HIGD1B levels may be an independent indicator of poor prognosis in patients with GC. Additionally, high HIGD1B levels were correlated with high stromal and ESTIMATE scores and elevated expression of immune checkpoints in patients with GC. Functional analyses showed that HIGD1B deficiency notably suppressed GC cell proliferation, migration, and invasion. Moreover, HIGD1B deficiency significantly induced mitochondria-mediated apoptosis in GC cells by inactivating Akt and ERK pathways. Collectively, HIGD1B may predict the prognosis of patients with GC and may function as an oncogene in GC. These findings suggest that HIGD1B may serve as a prognostic biomarker and potential therapeutic target in GC.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305681","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":"Vicinal diaryl pyrazole with tetrazole/urea scaffolds as selective angiotensin converting enzyme-1/cyclooxygenase-2 inhibitors: Design, synthesis, anti-hypertensive, anti-fibrotic, and anti-inflammatory","authors":"Wael A. A. Fadaly,&nbsp;Yaseen A. M. M. Elshaier,&nbsp;Fares E. M. Ali,&nbsp;Ali H. El-Bahrawy,&nbsp;Khaled R. A. Abdellatif,&nbsp;Mohamed T. M. Nemr","doi":"10.1002/ddr.22217","DOIUrl":"10.1002/ddr.22217","url":null,"abstract":"<p>As a hybrid weapon, two novel series of pyrazoles, <b>16a-f</b> and <b>17a-f</b>, targeting both COX-2 and ACE-1-<i>N</i>-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. <b>In vitro</b>, <b>17b</b> and <b>17f</b> showed <b>COX-2</b> selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and <b>NF-κB</b> (IC₅₀ 1.87 and 2.03 μM, respectively). <b>17b</b> (IC₅₀ 0.078 μM) and <b>17 f</b> (IC₅₀ 0.094 μM) inhibited <b>ACE-1</b> comparable to perindopril (PER) (IC₅₀ 0.048 μM). <b>In vivo</b>, <b>17b</b> decreased systolic blood pressure by 18.6%, <b>17b</b> and <b>17f</b> increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced <b>NF-κB-p65</b> and <b>P38-MAPK</b> expression by −0.62, −0.22, −0.53, and −0.24 folds, respectively compared to \u0000<span>l</span>-NAME (−0.34, −0.45 folds decline in <b>NF-κB-p65</b> and <b>P38-MAPK</b>, respectively). <b>17b</b> reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283204","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":"Oxymatrine attenuates sepsis-induced inflammation and organ injury via inhibition of HMGB1/RAGE/NF-κB signaling pathway","authors":"Junbing He,&nbsp;Wanbing Qin,&nbsp;Shusong Jiang,&nbsp;Yao Lin,&nbsp;Yingying Lin,&nbsp;Ruoxuan Yang,&nbsp;Mingwei Xu,&nbsp;Qinghua Liu","doi":"10.1002/ddr.22219","DOIUrl":"10.1002/ddr.22219","url":null,"abstract":"<p>Sepsis is a life-threatening organ dysfunction that endangers patient lives and is caused by an imbalance in the host defense against infection. Sepsis continues to be a significant cause of morbidity and mortality in critically sick patients. Oxymatrine (OMT), a quinolizidine alkaloid derived from the traditional Chinese herb <i>Sophora flavescens</i> Aiton, has been shown to have anti-inflammatory effects on a number of inflammatory illnesses according to research. In this study, we aimed to evaluate the therapeutic effects of OMT on sepsis and explore the underlying mechanisms. We differentiated THP-1 cells into THP-1 macrophages and studied the anti-inflammatory mechanism of OMT in a lipopolysaccharide (LPS)-induced THP-1 macrophage sepsis model. Activation of the receptor for advanced glycation end products (RAGE), as well as NF-κB, was assessed by Western blot analysis and immunofluorescence staining. ELISA was used to measure the levels of inflammatory factors. We found that OMT significantly inhibited HMGB1-mediated RAGE/NF-κB activation and downstream inflammatory cytokine production in response to LPS stimulation. Finally, an in vivo experiment was performed on septic mice to further study the effect of OMT on injured organs. The animal experiments showed that OMT significantly inhibited HMGB1-mediated RAGE/NF-κB activation, protected against the inflammatory response and organ injury induced by CLP, and prolonged the survival rate of septic mice. Herein, we provide evidence that OMT exerts a significant therapeutic effect on sepsis by inhibiting the HMGB1/RAGE/NF-κB signaling pathway.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283202","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":"Vedolizumab in the treatment of Crohn's disease: A promising therapeutic approach","authors":"Abrar Ahmad Zargar","doi":"10.1002/ddr.22220","DOIUrl":"10.1002/ddr.22220","url":null,"abstract":"<p>Crohn's disease (CD) is a chronic and debilitating inflammatory bowel disease that affects millions of individuals worldwide. Despite the availability of various treatment options, a significant number of patients do not achieve remission or experience adverse effects with conventional therapies. Vedolizumab, a novel therapeutic agent, has emerged as a promising approach in the management of CD. Despite improvements in treatment choices, there is still a demand for medicines that are efficient and well-tolerated. Vedolizumab, a monoclonal antibody targeting α4β7 integrin, has emerged as a promising therapeutic approach for the treatment of CD. The review aims to provide a summary of vedolizumab, current treatment options, impact of vedolizumab on the patient's quality of life, mechanism of action, clinical effectiveness, safety and efficacy of vedolizumab, potential side effects or risks associated with vedolizumab therapy, and potential predictors. Furthermore, we investigate limitations and challenges associated with vedolizumab and possible future developments and medical implications. This review provides a comprehensive examination of the present data supporting vedolizumab as a possible treatment option for CD, highlighting its benefits and outlining prospective directions for future study and clinical practice improvement.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141283203","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":"Glucosyltriazole amphiphile treatment attenuates breast cancer by modulating the AMPK signaling","authors":"Neeraj Kumar Chouhan,&nbsp;Abhisheik Eedara,&nbsp;Mamta N. Talati,&nbsp;Sudha S. S. S. S. Ambadipudi,&nbsp;Sai Balaji Andugulapati,&nbsp;Srihari Pabbaraja","doi":"10.1002/ddr.22215","DOIUrl":"https://doi.org/10.1002/ddr.22215","url":null,"abstract":"<p>Breast cancer is the second most frequent cancer among women. Out of various subtypes, triple-negative breast cancers (TNBCs) account for 15% of breast cancers and exhibit more aggressive characteristics as well as a worse prognosis due to their proclivity for metastatic progression and limited therapeutic strategies. It has been demonstrated that AMP-activated protein kinase (AMPK) has context-specific protumorigenic implications in breast cancer cells. A set of glucosyltriazole amphiphiles, consisting of acetylated (<b>9a-h</b>) and unmodified sugar hydroxyl groups (<b>10a-h</b>), were synthesized and subjected to in vitro biological evaluation. Among them, <b>9h</b> exhibited significant anticancer activity against MDA-MB-231, MCF-7, and 4T1 cell lines with IC₅₀ values of 12.5, 15, and 12.55 μM, respectively. Further, compound <b>9h</b> was evaluated for apoptosis and cell cycle analysis in in vitro models (using breast cancer cells) and antitumour activity in an in vivo model (orthotopic mouse model using 4T1 cells). Annexin-V assay results revealed that treatment with <b>9h</b> caused 34% and 28% cell death at a concentration of 15 or 7.5 μM, respectively, while cell cycle analysis demonstrated that <b>9h</b> arrested the cells at the G2/M or G1 phase in MCF-7, MDA-MB-231 and 4T1 cells, respectively. Further, in vivo, investigation showed that compound <b>9h</b> exhibited equipotent as doxorubicin at 7.5 mg/kg, and superior efficacy than doxorubicin at 15 mg/kg. The mechanistic approach revealed that <b>9h</b> showed potent anticancer activity in an in vivo orthotopic model (4T1 cells) partly by suppressing the AMPK activation. Therefore, modulating the AMPK activation could be a probable approach for targeting breast cancer and mitigating cancer progression.</p>","PeriodicalId":11291,"journal":{"name":"Drug Development Research","volume":"85 4","pages":""},"PeriodicalIF":3.8,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141245702","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}