Bioorganic Chemistry最新文献

{"title":"Design, synthesis and biological evaluation of novel pyrazoline derivatives as dual EGFR/VEGFR-2 inhibitors for targeted cancer therapy.","authors":"Michael M Sawiris, Omneya M Khalil, Peter A Halim, Marwa S A Hassan","doi":"10.1016/j.bioorg.2025.109075","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109075","url":null,"abstract":"<p><p>Three series of pyrazoline compounds (3a-f, 4a-f and 5a-f) were designed and synthesized as antiproliferative agents and potential dual EGFR/VEGFR-2 inhibitors for targeted cancer therapy. All the synthesized compounds were screened by National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines. Compounds 2f, 3b, 3c, 3e, 3f, 4b and 4e were selected for further antiproliferative activity investigation via MTT assay. Compounds 2f, 3e and 3f demonstrated better IC₅₀ results than doxorubicin in breast T47D and MCF7 cancer cells. Compound 3e was the most potent against EGFR and VEGFR2 with IC₅₀ values of 0.142 and 0.071 μM compared to erlotinib and axitinib with IC₅₀ values of 0.064 and 0.050 μM, respectively. Moreover, it reduced VEGFR2 phosphorylation and total VEGFR2 concentration in T47D cells by approximately 3.8 and 2.9-fold, respectively. Compound 3e also caused cell cycle arrest at G0/G1 phase and demonstrated significant increase in early and late apoptosis. Additionally, it upregulated pro-apoptotic genes (caspase-3, p53 and Bax) and downregulated anti-apoptotic gene (BCL-2). Boyden chamber and wound healing assays demonstrated that compound 3e could impair cell migration and invasion in T47D cells. The selectivity indices of compound 3e towards T47D or MCF7 breast cancer cells over the normal breast cell line MCF10A were approximately 46 and 25, respectively. In-silico studies revealed that compound 3e has a bioavailability score of 0.55 and did not violate Lipiniski's rule. Also, the molecular docking studies and molecular dynamics simulations confirmed that compound 3e could interact with EGFR (PDB: 1M17) and VEGFR2 (PDB: 4AG8) analogously to erlotinib and axitinib, respectively.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109075"},"PeriodicalIF":4.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of isatin-triazole-benzenesulfonamide hybrids as dual hCA IX/XII and c-met inhibitors with hypoxia-mediated chemo-sensitizing activity","authors":"Wagdy M. Eldehna ,&nbsp;Mohamed R. Elnagar ,&nbsp;Simone Giovannuzzi ,&nbsp;Amr Tayel ,&nbsp;Maha-Hamadien Abdulla ,&nbsp;Noura S. Alhassan ,&nbsp;Moataz A. Shaldam ,&nbsp;Alessio Nocentini ,&nbsp;Claudiu T. Supuran ,&nbsp;Haytham O. Tawfik","doi":"10.1016/j.bioorg.2025.109071","DOIUrl":"10.1016/j.bioorg.2025.109071","url":null,"abstract":"<div><div>One of the main factors contributing to treatment resistance and a poor prognosis in colorectal cancer is hypoxia. Eleven isatin-based hybrids comprising 1,2,3-triazole and benzenesulfonamide fragments (<strong>5a-f</strong> and <strong>7a-e</strong>) were logically designed and synthesized in this study to investigate their dual inhibitory potential against carbonic anhydrases IX and XII (CA IX/XII) and receptor tyrosine kinase c-Met, two hypoxia-related targets. Strong nanomolar inhibition of CA IX/XII and sub-micromolar to low-micromolar inhibition of c-Met were shown by a number of drugs (<strong>5c</strong>, <strong>5d</strong>, <strong>5e</strong>, <strong>5f</strong>, and <strong>7e</strong>). Compound <strong>5d</strong> had the highest activity (IC₅₀ = 1.57 μM under hypoxia <em>vs.</em> 9.57 μM under normoxia), according to a subsequent cytotoxicity assay in HCT-116 colorectal cancer cells, which showed improved potency of all lead compounds under hypoxic conditions. In the cell lines HT-29 and SW-620, the better profile of <strong>5d</strong> was further validated. Mechanistic investigations revealed that <strong>5d</strong> triggered apoptosis and caused G₂/M phase arrest, confirming its function in hypoxia-driven cytotoxicity. Additionally, in hypoxic conditions, <strong>5d</strong> significantly increased the effectiveness of 5-fluorouracil (5-FU) and oxaliplatin (OXP), increasing its potency by more than 10 times. Positive pharmacokinetic and drug-like characteristics were validated through <em>in silico</em> ADME profiling. Molecular docking investigations revealed that <strong>5d</strong> exhibited strong binding interactions within the c-Met and CA IX/XII active sites. Compound <strong>5d</strong> could be a promising dual-targeting option for overcoming hypoxia-associated resistance in colorectal cancer, as indicated by these data.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"166 ","pages":"Article 109071"},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Binding and ubiquitination-mediated degradation of ACKR3 by the novel Scutellarein derivative TBS6b potently suppresses hepatocellular carcinoma","authors":"Xing Jiang ,&nbsp;Ying Liang ,&nbsp;Guotao Tang ,&nbsp;Haiyan Quan ,&nbsp;Lijun Ruan ,&nbsp;Mengli Zhang ,&nbsp;Zhijun Song ,&nbsp;Min Ou ,&nbsp;Zhien Tan ,&nbsp;Na Lu ,&nbsp;Fangfang Wu ,&nbsp;Xiaonan Yang","doi":"10.1016/j.bioorg.2025.109073","DOIUrl":"10.1016/j.bioorg.2025.109073","url":null,"abstract":"<div><div>Scutellarein, a flavonoid compound from the traditional Chinese herb <em>Scutellaria baicalensis</em>, exhibits inhibitory effects against hepatocellular carcinoma (HCC), but its clinical application is limited by relatively weak potency. To enhance its antitumor activity, we synthesized a novel derivative, 5,6,7-trimethoxy-4′-benzimidazolyl scutellarein 6b (TBS6b), by introducing antitumor pharmacophores—trimethoxyphenyl and benzimidazole—into the scutellarein scaffold. TBS6b demonstrated significantly improved anti-HCC activity both in vitro and in vivo. Cell-based assays, including colony formation, EdU staining, wound healing, transwell migration, and western blot analysis, demonstrated that TBS6b significantly inhibits HCC cell proliferation, migration, and invasion. Mechanistically, we employed proteomic and transcriptomic sequencing, along with western blot and qRT-PCR experiments, to predict and validate atypical chemokine receptor 3 (ACKR3) as the target of TBS6b. Molecular docking studies confirmed that TBS6b binds tightly to the ACKR3 protein. Additionally, with the aid of pharmacological tools, we established that TBS6b promotes the ubiquitination and degradation of ACKR3. Tissue microarray analysis and queries of public databases revealed that ACKR3 expression is elevated in HCC tissues compared to adjacent non-cancerous tissues, correlating closely with patient survival. By constructing cell lines with either silenced or overexpressed <em>ACKR3</em>, we confirmed that ACKR3 promotes the proliferation, migration, and invasion of HCC. Finally, rescue experiments indicated that TBS6b exerts its anticancer effects primarily through targeting ACKR3<em>.</em> These findings establish ACKR3 as a critical target through which TBS6b mediates its anticancer activity against HCC.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"166 ","pages":"Article 109073"},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Utility of carbon dots for diabetes treatment and management: A mini review.","authors":"Neha Sharma, Anshul Sharma, Hae-Jeung Lee","doi":"10.1016/j.bioorg.2025.109074","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109074","url":null,"abstract":"<p><p>Diabetes mellitus is among the most prevalent and challenging diseases worldwide. Its global prevalence continues to rise despite considerable advances in therapeutic options and management strategies, highlighting the urgent need for novel therapeutic agents with minimal side effects. Carbon dots (CDs) have emerged as versatile and promising nanomaterials for diabetes treatment and monitoring, owing to their excellent biological, physicochemical, and photophysical properties. This mini-review highlights recent progress in CD research for diabetes, beginning with an overview of their synthesis via top-down and bottom-up methods. It then examines their roles in carbohydrate- and incretin-metabolizing enzyme inhibition, reduction of glucose uptake and reactive oxygen species in vitro, in vivo investigations in rodent models, and modulation of amyloid aggregation. This review further explores the role of CDs in diabetes monitoring, including sensor-based detection of disease-associated volatile organic compounds and lactic acid in blood, breath, and sweat. Additionally, it highlights their potential in drug delivery and in in vitro bioassays screening anti-diabetic drugs or drug candidates. Although the potential of CDs as anti-diabetic agents has been demonstrated, translation to clinical application requires standardized production methods, advanced physicochemical characterization, comprehensive toxicological and pharmacokinetic evaluations, and long-term animal studies in diverse diabetes models. These efforts will be essential for establishing the safety, efficacy, and reliability of CDs as viable therapeutic and diagnostic tools for diabetes management.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109074"},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural diterpenoids isolated-interaction-phenotypic target characterization: An idea performed with Daphne genkwa and Wikstroemia chamaedaphne bud extract.","authors":"Shi-Fei Li, De-Ling Chen, Ya-Ting Li, Li-Wei Zhang","doi":"10.1016/j.bioorg.2025.109065","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109065","url":null,"abstract":"<p><p>In this study, twenty-two diterpenoids (including two unreported structures) were isolated and identified from the buds of Daphne genkwa and Wikstroemia chamaedaphne. Molecular docking analysis revealed that this series of compounds could stably bind to the active site of Cdc42 protein (-6.47 to -10.39 kcal/mol), with their binding energies showing significant correlation to structural features. Spectroscopic experiments confirmed that the compounds could bind to Cdc42 and alter its microenvironment. Cellular assays demonstrated that some compounds exhibited selective cytotoxicity against RAW264.7/HepG2/4T1 cells (lowest IC₅₀ 2.25 μM). CETSA verification showed that compound 6 could enhance the thermal stability of Cdc42 (∆Tm >5 °C), suggesting Cdc42 as a potential antitumor target for this compound. In conclusion, the interactions between these 22 compounds and Cdc42 protein were systematically investigated by using an \"isolated-interaction-phenotypic target characterization\" strategy. These findings not only established a crucial foundation for elucidating the antitumor mechanisms mediated by diterpenoid-Cdc42 interactions but also provided a practical methodological framework for natural product-based drug discovery.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109065"},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel dihydropyridines as potential calcium-channel and P-glycoprotein blockers applicable for chemotherapy sensitization.","authors":"Gang Chen, Shiyi Zhong, Chunxu Zhong, Hongmin Zhang, Ali Raza Ishaq, Yanrong Li, Liuxin Yang, Kai Wang, Jie Pan, Xiang Li","doi":"10.1016/j.bioorg.2025.109072","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109072","url":null,"abstract":"<p><p>P-glycoprotein (P-gp)-mediated multidrug resistance in tumors is one of the main reasons for chemotherapy failure. For hypertensive patients undergoing long-term chemotherapy, antihypertensive drugs with P-gp inhibitory effects are expected to substantially reduce the dosage of chemotherapeutic agents. 1,4-Dihydropyridines (DHPs), as classical calcium channel blockers, have been widely used in clinical hypertension treatment. In this study, novel dihydropyridines, namely HCAs, were designed and evaluated for their ability to reverse multidrug resistance. HCAs exerted synergistic effects on calcium channels and P-gp, potentially alleviating hypertension while sensitizing tumors to chemotherapy. Low concentrations of HCAs significantly enhanced the sensitivity of tumor cells to cisplatin; notably, 2 μM HCA-6 increased the inhibitory effect of cisplatin on HeLa cells by 61.21 %. Overall, HCAs hold promises for benefiting hypertensive patients with long-term cancer conditions and reducing reliance on high-dose chemotherapeutic agents.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109072"},"PeriodicalIF":4.7,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145256980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innovative design and synthesis of dual-acting hCA IX/CDK-2 inhibitors through hetero ring fused pyrimidine utilization for cutting-edge anticancer therapy: Zein nanoparticles for in vivo lung cancer treatment","authors":"Heba M. Abosalim ,&nbsp;Tarek F. El-Moselhy ,&nbsp;Nabaweya Sharafeldin ,&nbsp;Simone Giovannuzzi ,&nbsp;Paloma Begines ,&nbsp;Mohamed S. Nafie ,&nbsp;Sherif Ashraf Fahmy ,&nbsp;Mohamed K. Diab ,&nbsp;Asaad Babker ,&nbsp;Claudiu T. Supuran ,&nbsp;Mervat H. El-Hamamsy ,&nbsp;Haytham O. Tawfik","doi":"10.1016/j.bioorg.2025.109057","DOIUrl":"10.1016/j.bioorg.2025.109057","url":null,"abstract":"<div><div>A dual-targeting strategy is anticipated to enhance cancer therapy efficacy. Accordingly, a series of fused pyrimidine analogues (<strong>5a-h</strong> and <strong>8a-f</strong>) was rationally designed and synthesized as potential inhibitors towards carbonic anhydrase IX (hCA IX) and cyclin-dependent kinase-2 (CDK-2). The enzyme inhibition results revealed that compounds <strong>5c</strong> and <strong>5d</strong> exhibited potent inhibitory activity, with IC₅₀ values of 0.29 μM and 0.32 μM and <em>K</em>_I values of 39 nM and 42.2 nM, respectively. Unfortunately, compounds <strong>5c</strong> and <strong>5d</strong> revealed non-promising cell growth inhibition (GI%) against A549 cancer cells (3 % and 9 %, respectively). Impressively, their Zein-nanoparticles (NPs) significantly promoted the GI% to 94.8 % and 96.5 % respectively. The nanoformulations of <strong>5c</strong> and <strong>5d</strong> significantly induced apoptotic lung cancer cell death, leading to total apoptosis that was 62.35 % and<!--> <!-->62.7 % of the control, 17.2 %, respectively. Gene expressions revealed significant upregulation of apoptosis-associated genes P53,<!--> <!-->Bax, and caspases 3, 8, 9; however, the anti-apoptotic gene Bcl-2 was downregulated in the A549 cancer cells. In addition, the average particle sizes, polydispersity index (PDI), zeta potential, and encapsulation efficiency (EE%) of <strong>5c</strong>@Zein NPs and <strong>5d</strong>@Zein NPs were investigated. Both formulations showed monodispersed nanosized particles of 151.6 ± 9.2 and 162.4 ± 10.7 nm, with zeta potential values of −30.9 ± 1.8 and − 24.6 ± 2.1 mV, respectively. Moreover, <strong>5c</strong> and <strong>5d</strong> were highly encapsulated within the Zein NPs and showed a pH-triggered <em>in vitro</em> release manner. Validating the <em>in vivo</em> cancer model, <strong>5c</strong>-Zein NPs significantly ameliorated the induced changes by decreasing the lung index and inhibiting the CDK-2 and hCA IX proteins. Furthermore, molecular docking studies revealed specific and favorable interactions of compounds <strong>5c</strong> and <strong>5d</strong> within the binding pockets of hCA IX and CDK-2, which support their potential as dual-target inhibitors.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"166 ","pages":"Article 109057"},"PeriodicalIF":4.7,"publicationDate":"2025-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Small-molecule mTOR inhibitors in the clinic: From bench to bedside.","authors":"Chen Yang, Xiaofei Sun, Zhong Yu, Dan Liu, Rong Hu","doi":"10.1016/j.bioorg.2025.109048","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109048","url":null,"abstract":"<p><p>As a central modulator of cellular proliferation, metabolic processes, and immunological functions, the mechanistic target of rapamycin (mTOR) signaling pathway has emerged as an attractive therapeutic focus for managing diverse pathological conditions, including cancer, autoimmune disorders, and organ transplant rejection. mTOR inhibitors, initially identified in the context of cancer therapy, have shown efficacy in regulating immune responses and preventing abnormal cell proliferation. Pharmacological investigations spanning preclinical models to human subjects reveal mTOR-targeting agents possess immunomodulatory properties concurrent with antitumor effects, evidenced by multicenter clinical studies documenting improved progression-free survival rates and delayed oncological recurrence in epithelial-derived and hematopoietic malignancies. This review explores the development of mTOR inhibitors, tracing their journey from early laboratory discoveries to clinical application, and emphasizes their role in transforming the therapeutic landscape for a range of diseases.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109048"},"PeriodicalIF":4.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apigenin and its derivative modulate nitric oxide production and interfere with TLR4-M2: In-vitro and in-silico insights","authors":"Samreen Soomro ,&nbsp;M. Ahmed Mesaik ,&nbsp;Farzana Shaheen ,&nbsp;Sobia Ahsan Halim ,&nbsp;Muhammad Waqas ,&nbsp;Naira Nayeem ,&nbsp;Mashael Alanazi ,&nbsp;Ajmal Khan ,&nbsp;Ahmed Al-Harrasi","doi":"10.1016/j.bioorg.2025.109069","DOIUrl":"10.1016/j.bioorg.2025.109069","url":null,"abstract":"<div><div>The imbalance in reactive oxygen/nitrogen species causes oxidative stress which contributes to chronic inflammation and diseases. In this study, the immunomodulatory potential of the natural product ‘Apigenin (4,5,7-trihydroxyflavone)’ (APG) and its derivative ‘Apigenin-7-O-β-D-(6″-p-coumaroyl)-glucopyranoside’ (APG-7) was elucidated through cell-based spectrophotometry, chemiluminescence, and fluorescent microscopy. Their effects were assessed on the production of superoxide anion, myeloperoxidase-dependent hypochlorite anion, intracellular oxidative stress and nitric oxide (NO). Moreover, their cellular toxicity was investigated on 3 T3 fibroblast cell line. APG significantly reduced superoxide anion (48.2 %) and hypochlorite production (IC₅₀ = 27.2 μg/mL), while APG-7 showed minimal activity in these assays. Both compounds inhibited NO production, with APG showing stronger inhibition (98 %) than APG-7 (55 %). However, APG was more cytotoxic (IC₅₀ = 4.5 μg/mL) as compared to APG-7 (∼25 μg/mL), indicating a safer profile of APG-7. NO is produced by LPS triggered activation of Toll-like receptor 4 (TLR4), therefore <em>in-silico</em> molecular docking and dynamics simulation were performed to deduce the binding affinity of APG and APG-7 at TLR4/MD-2 interface. Our <em>in-silico</em> findings suggest that both the compounds may target TLR4/MD-2 interface to inhibit the production of NO. Overall, the results support the immunomodulatory potential of APG and APG-7, warranting further investigation.</div></div>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"166 ","pages":"Article 109069"},"PeriodicalIF":4.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145265747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oxadiazole derivatives as potent androgen receptor inhibitors: Design, synthesis, and anticancer evaluation.","authors":"Shubham Kumar, Pankaj Wadhwa","doi":"10.1016/j.bioorg.2025.109060","DOIUrl":"https://doi.org/10.1016/j.bioorg.2025.109060","url":null,"abstract":"<p><p>Prostate cancer remains one of the most prevalent malignancies worldwide, necessitating the continuous development of novel therapeutic agents. In this study, a series of novel oxadiazole-based compounds (MS01-MS15) were synthesized and evaluated for their anticancer potential against PC-3 prostate cancer cell lines. The MTT assay revealed significant cytotoxic effects, with percentage inhibition reaching up to 97.32 % and IC₅₀ values ranging from 370.37 nM to 838.14 nM. In comparison, the standard drug bicalutamide exhibited an IC₅₀ value of 158.03 nM. Molecular docking studies using Autodock Vina demonstrated strong interactions between the synthesized compounds and the androgen receptor (PDB ID: 1Z95), with binding affinities ranging from -6.5 to -9.0 kcal/mol. Notably, MS14, featuring a fluorine substituent at the para position, emerged as the most potent compound, exhibiting the highest binding affinity (-9.0 kcal/mol) and the lowest IC₅₀ value (370.37 nM). Moreover, ROS production assay and androgen receptor inhibition assay has shown promising results for MS-14 as compared to standard drug. Structure-activity relationship (SAR) analysis indicated that electron-withdrawing substituents, particularly fluorine and chlorine, enhanced the anticancer efficacy, whereas bulkier and electron-donating groups diminished activity. Importantly, validation in androgen-sensitive LNCaP cells confirmed that MS14 retained significant antiproliferative activity, achieving up to 78.2 % inhibition at 1000 nM, thereby supporting its dual AR-dependent and AR-independent modes of action. These findings underscore the potential of oxadiazole derivatives as promising androgen receptor inhibitors for prostate cancer therapy.</p>","PeriodicalId":257,"journal":{"name":"Bioorganic Chemistry","volume":"165 ","pages":"109060"},"PeriodicalIF":4.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}