Anti-cancer agents in medicinal chemistry最新文献

{"title":"Computational Design, Synthesis, and In Vitro Evaluation of Novel Piperazine-Based HDAC Inhibitors as Potential Breast Cancer Therapeutics.","authors":"Sehija Dizdarevic, Dusan Ruzic, Tatjana Srdic-Radic, Zorica Vujić","doi":"10.2174/0118715206448039260114072721","DOIUrl":"https://doi.org/10.2174/0118715206448039260114072721","url":null,"abstract":"<p><strong>Introduction: </strong>Limited treatment options and poor prognosis create a need for new therapies for triplenegative breast cancer. Modulating lysine acetylation of histone and non-histone proteins via histone deacetylase inhibitors is a promising strategy in cancer therapy. This study aimed to design, synthesize, and test novel panHDAC inhibitors in vitro, building on our previous research.</p><p><strong>Methods: </strong>Compound design was based on a previously validated diphenylmethyl piperazine scaffold, used as a template for further modifications. In silico studies included molecular docking and pharmacokinetic profiling for absorption, distribution, metabolism, excretion, and toxicity. Compounds identified from these analyses were synthesized, tested for in vitro enzymatic inhibition, and evaluated for cytotoxicity on cancer cell lines using the MTT assay.</p><p><strong>Results: </strong>Compound 8o had the strongest HDAC inhibitory profile. It was highly potent against HDAC6 (IC50 = 18.5 nM) and active against HDAC1 and HDAC8 (IC50 = 430 nM and 1620 nM, respectively). Compound 8p also inhibited HDAC6 (IC50 = 54 nM) but was less potent against the nuclear isoforms. Both compounds were less active than trichostatin A. In the cytotoxicity assay, 8o and 8p reduced the viability of triple-negative breast cancer cells in a dosedependent manner. Compound 8o was the most active (IC50 = 6.74 μM on MDA-MB-231), exceeding the effect of tubastatin A. Moderate activity was seen on MDA-MB-468 cells.</p><p><strong>Discussion: </strong>In vitro enzymatic assays showed that compound 8o strongly inhibited HDAC6, similar to the reference compound 8b. However, its cellular activity did not exceed 8b, suggesting that factors other than target engagement may limit its cell efficacy. These findings show the need to combine biochemical and physicochemical data when optimising HDAC inhibitors for triple-negative breast cancer.</p><p><strong>Conclusion: </strong>Compounds 8o and 8p were identified as potent panHDAC inhibitors. They demonstrated cytotoxicity against triple-negative breast cancer cells. This provides a promising foundation for future structural optimization and preclinical development.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970041","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":"Advancing in Acute Promyelocytic Leukemia Therapy Research: The Role of 3-Alkylpyridine Alkaloid Analogs in Overcoming Genetic and Molecular Barriers.","authors":"Tulio R Freitas, Tâmara D de Almeida, Fernanda C G Evangelista, Cristina de M G Loures, Camila de S Barbosa, Vinicius G Maltarollo, Gustavo H R Viana, Fernando de P Varotti, Adriano de P Sabino","doi":"10.2174/0118715206413951251125050732","DOIUrl":"https://doi.org/10.2174/0118715206413951251125050732","url":null,"abstract":"<p><strong>Introduction: </strong>Acute leukemias are malignant clonal disorders of blood cells, originating in the bone marrow. Acute Promyelocytic Leukemia (APL), when left untreated, progresses unfavorably, often resulting in severe hemorrhaging. Chemotherapy remains a key therapeutic strategy; however, the need for discovering new antitumor agents is critical. This study aims to evaluate the cytotoxic effects of 16 synthetic analogs of 3-alkylpyridine alkaloids (3-APA) on various APL cell lines and Peripheral Blood Mononuclear Cells (PBMCs), with the goal of identifying promising new therapeutic candidates for APL treatment.</p><p><strong>Materials and methods: </strong>The cytotoxic effects of 16 synthetic 3-APA analogs were assessed on APL cell lines (NB4, NB4-LR2, and HL-60) and PBMC. The MTT assay was used to evaluate the cytotoxic profiles of the compounds. Apoptosis induction and cell cycle arrest were analyzed using flow cytometry. Gene expression changes related to apoptosis (TP53, p21, BAK, Bcl-2, AKT) and oxidative stress (NOX-1, NOX-2, NOX-4, P47-phox) were measured through RT-qPCR. Additionally, chemical similarity analysis via ChEMBL was performed to predict potential molecular targets, including ROS1 and PARP1.</p><p><strong>Results: </strong>The results demonstrated distinct cytotoxic responses among the tested cell lines. All 16 compounds induced apoptosis in the APL cell lines, leading to a notable decrease in the expression of antiapoptotic genes, including p21, Bcl-2, and AKT, which contributed to cell death. Gene expression analysis revealed an increase in oxidative stress markers, particularly NOX-2 and p47-phox in the NB4 cell line, and NOX-1 and NOX-4 in the NB4-LR2 lineage, suggesting potential mechanisms of cellular damage and resistance.</p><p><strong>Discussion: </strong>The 3-APA analogs showed significant cytotoxic effects against APL cell lines, with distinct selectivity profiles. The induction of apoptosis and the downregulation of anti-apoptotic genes underscore the potential of these compounds as promising therapeutic agents. The observed changes in oxidative stress gene expression further suggest a mechanism of action involving oxidative damage, which could contribute to the efficacy of the compounds, especially in overcoming resistance in the ATRA-resistant NB4-LR2 cell line. Additionally, the prediction of ROS1 and PARP1 as potential molecular targets opens new avenues for further investigation.</p><p><strong>Conclusion: </strong>This study highlights the potential of 3-APA analogs as effective cytotoxic agents in the treatment of APL. The compounds demonstrated significant apoptotic activity and altered gene expression, particularly in apoptosis regulation and oxidative stress pathways. These findings suggest that 3-APA analogs may serve as valuable candidates for future therapeutic development in APL treatment, warranting further research into their molecular mechanisms and clinical applicability.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970059","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":"Preparation and Characterization of Raloxifene- and Rutin-Co-loaded Chitosan Nanoparticles for the Treatment of Colon Cancer.","authors":"Farah Al-Sahlawi, Ali Al-Samydai, Aya Yaseen Mahmood Alabdali, Simone Carradori, Marwan Abdel Mahmoud Abdelkarim Maki, Sasikala Chinnappan","doi":"10.2174/0118715206417467251031064022","DOIUrl":"https://doi.org/10.2174/0118715206417467251031064022","url":null,"abstract":"<p><strong>Introduction: </strong>Colorectal cancer is a significant health concern with high incidence and mortality rates. Raloxifene (RLX) is a selective estrogen receptor modulator that blocks estrogen receptors, reducing the risk of estrogen-dependent cancer growth. Rutin (RT), a naturally occurring flavonoid found in medicinal plants, has attracted attention for its potential role in cancer prevention and treatment, including colon cancer.</p><p><strong>Methods: </strong>In this study, the nanoparticles were prepared by the ionic gelation method. The synthesized nanoparticles were characterized by release assays and FTIR, SEM, and TEM, while their cytotoxic effects were assessed on the HT-29 colon cancer cell line.</p><p><strong>Results: </strong>The drug loading percentage of RLX/RT/CsNPs was found to be 84% at a 1:2 w/w ratio. SEM and TEM analyses revealed that the RLX/RT/CsNPs exhibited an average size of 57.23 nm with a spherical morphology. Thermogravimetric analysis of the nanoparticles revealed a two-stage weight loss pattern, and the drug release study showed RLX/CsNPs = 44.12%, RLX = 10.68%, and RLX/RT/CsNPs = 47.12% drug release at 24 hrs.</p><p><strong>Discussion: </strong>The IC50 value of RLX/RT/CsNPs was 23.51 ± 0.60 μM, which was significantly lower compared with the IC50 of RLX/CsNPs (IC50 = 252.20 ± 7.80 μM, p < 0.001) and RT/CsNPs (IC50 = 300.51 ± 52.05 μM, p < 0.001) against the HT-29 colon cancer cell lines.</p><p><strong>Conclusion: </strong>In conclusion, we developed a new nanoparticle system combining RLX and RT showing favorable physicochemical characteristics and synergistic effects in colon cancer cell lines. The designed NPs can be used as a promising drug therapy against colon cancer.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939955","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":"Morusin Attenuates Cancer Stemness and Modulates CSC-driven Macrophage Polarization in Cervical Cancer.","authors":"Tanya Tripathi, Udit Joshi, Apoorva Chaudhary, Divya Janjua, Shivam Kumar, Neha Tanwar, Aastha Mittal, Anna Senrung, Alok Chandra Bharti","doi":"10.2174/0118715206442035260118215116","DOIUrl":"https://doi.org/10.2174/0118715206442035260118215116","url":null,"abstract":"<p><strong>Introduction: </strong>Cancer stem cells (CSC) role in treatment resistance is well established. CSCs promote M2 macrophage polarization within the tumor microenvironment, creating a pro-tumorigenic feedback loop that sustains CSC homeostasis. Therefore, disrupting this cross-talk can be an effective therapeutic strategy. In the present study, we identified Morusin as a potent inhibitor that could impact both cancer stemness and CSCinduced macrophage polarization.</p><p><strong>Methods: </strong>In silico screening was performed to assess the druggability of Morusin and its binding to stemness markers. Molecular Docking and simulation were performed to check the stability of Morusin binding with markers. To evaluate its effect on cancer stemness, low-adhesion spheroids were treated with Morusin at IC50, followed by qPCR and western blot for stemness markers. To investigate Morusin's influence on CSC-mediated macrophage polarization, innovative transwell co-culture systems were employed to assess the impact of tumor spheroids on macrophage phenotype.</p><p><strong>Result: </strong>Molecular docking identified Morusin as a binder of the stemness factors Oct4, Sox2, and Nanog, with MD simulations confirming stable interactions and the strongest binding to Oct4. In an in vitro system, Morusin reduced spheroid size, disrupted spheroidal integrity and self-renewal, and lowered Oct4 and Sox2 levels, proving to be an effective anti-CSC agent. In a transwell system, activated THP1 cells co-cultured with 3D tumorspheres showed enhanced M2 polarization compared to monolayers, whereas Morusin-treated tumorspheres shifted THP1 cells toward an M1 phenotype.</p><p><strong>Discussion: </strong>These findings indicate that Morusin targets both Cervical-CSC stemness and prevents CSCinduced M2 polarization, thus dampening CSC-Macrophage crosstalk.</p><p><strong>Conclusion: </strong>These findings indicate that Morusin targets both Cervical-CSC stemness and prevents CSCinduced M2 polarization, thus dampening CSC-Macrophage crosstalk.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147939992","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":"Nucleobase Ionic Liquids (NBILs) Induced Apoptosis via Caspase 3 Activation and in silico Regulation of the IRE1a Pathway in Pancreatic Cancer PANC-1 Cells.","authors":"Pradnya Patil, Prakash Bansode, Gaurang Telang, Smriti Mishra, Deepti Kurhe, Dipak Mali, Namdeo Jadhav, Dilip Dagade, Dattaprasad Pore, Gajanan Rashinkar","doi":"10.2174/0118715206415118251205220038","DOIUrl":"https://doi.org/10.2174/0118715206415118251205220038","url":null,"abstract":"<p><strong>Introduction: </strong>Globally rising incidences of pancreatic cancer, a leading cause of death, have made it imperative to explore new chemotherapeutic agents, such as ionic liquids (ILs), as an emerging class of anticancer agents. Nucleobase ionic liquids (NBILs) have shown great promise against pancreatic cancer PANC-1 cells. This study aims to synthesize purine and pyrimidine nucleobase ionic liquids (NBILs) and evaluate their in vitro anticancer activity on PANC-1 cells to gain valuable insights into the anticancer potential of NBILs.</p><p><strong>Methods: </strong>Comprehensive in vitro studies, including flow cytometric apoptosis analysis, reverse transcription polymerase chain reaction (RT-PCR), gene expression studies, and molecular docking analysis, were performed to demonstrate the potent anticancer effects of NBILs.</p><p><strong>Results: </strong>A series of nucleobase ionic liquids (NBILs) was synthesized using a multi-step protocol. Significant anti-pancreatic cancer activity was observed for the synthesized NBILs against PANC-1 cells, with compound 14b showing high expression of CASP3 and a high percentage of apoptosis.</p><p><strong>Discussion: </strong>Molecular mechanism and in silico studies demonstrated remarkable anti-pancreatic cancer activity of NBILs via activation of CASP3 and regulation of the IRE1a pathway. The research highlights the future potential for utilizing NBILs against pancreatic cancer PANC-1 cells.</p><p><strong>Conclusion: </strong>NBILs displayed significant anti-pancreatic cancer activity through apoptosis induction via activation of Caspase 3 and in silico regulation of the IRE1a pathway in pancreatic cancer PANC-1 cells.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832751","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":"CAF Heterogeneity in Ovarian Cancer: Implications for Chemoresistance and Treatment Strategies.","authors":"Sambasivam Gopinath, Pavithra Balakrishnan, Yamini Muli, Jubilee Ramasamy, Saranya Puniyakotti, Nithya Varadarajan, Ramaiyan Velmurugan","doi":"10.2174/0118715206434395260409095604","DOIUrl":"https://doi.org/10.2174/0118715206434395260409095604","url":null,"abstract":"<p><strong>Introduction: </strong>Cancer-Associated Fibroblasts (CAFs) are key players in the tumor microenvironment (TME) of ovarian cancer, influencing progression and chemoresistance. Their heterogeneous subtypes contribute distinctly to immune evasion, extracellular matrix (ECM) remodelling, and drug resistance.</p><p><strong>Methods: </strong>This review synthesizes evidence from recent single-cell and proteomic analyses to delineate CAF subtypes, including myCAFs, iCAFs, and apCAFs, and their associated gene signatures (e.g., VCAN, SULF1, COL11A1, CXCL12). The relationship between CAF-mediated pathways and resistance to platinum-based chemotherapies is explored.</p><p><strong>Results: </strong>High expression of CAF-associated genes correlates with platinum resistance in ovarian cancer. VCAN enhances ECM stiffness and immune suppression; SULF1 alters ECM sulfation, affecting drug uptake; COL11A1 activates Src/Akt pathways leading to EMT; and CXCL12 triggers Wnt/β-catenin signalling, increasing resistance. These mechanisms collectively impair treatment efficacy.</p><p><strong>Discussion: </strong>The dynamic and plastic nature of CAFs presents both a challenge and an opportunity in cancer therapy. While some CAF subsets promote chemoresistance, others may exert tumor-suppressive effects. This duality underscores the importance of precise molecular profiling to distinguish between pro-tumor and antitumor CAF populations. Current data suggest that therapeutic approaches targeting CAF-specific genes or pathways, particularly those influencing ECM remodelling and survival signalling, could significantly enhance the efficacy of standard chemotherapy. Personalized treatment strategies that selectively deplete or reprogram tumor- promoting CAFs while preserving supportive stromal elements may improve patient outcomes.</p><p><strong>Conclusion: </strong>Targeting specific CAF subtypes and their molecular pathways offers promise for overcoming chemoresistance. Future therapies should focus on eliminating tumor-promoting CAFs while preserving or reprogramming tumor-suppressive ones.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832761","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":"MicroRNA-21 in Cancer and Fibrosis: Molecular Mechanisms and Therapeutic Progress.","authors":"Anushka Sharma, Awaneet Kaur, Javed Khan, Himani Pandey","doi":"10.2174/0118715206442580260401101941","DOIUrl":"https://doi.org/10.2174/0118715206442580260401101941","url":null,"abstract":"<p><p>MicroRNA-21 (miR-21) is a key regulator of gene expression involved in cancer progression and fibrosis. Its dysregulation promotes cell proliferation, resistance to apoptosis, Epithelial-Mesenchymal Transition (EMT), and Extracellular Matrix (ECM) remodeling, making it one of the most widely studied oncomiRs and fibromiRs. Evidence shows that miR-21 contributes to tumor growth, metastasis, and fibrosis by suppressing tumor suppressors such as PTEN and PDCD4 and activating pro-fibrotic pathways, including TGF-β signaling. Its consistent dysregulation highlights its potential as a biomarker for diagnosis, prognosis, and treatment monitoring. Several therapeutic strategies, such as antagomiRs, locked nucleic acids (LNAs), CRISPR-based inhibition, and nanoparticle- or viral-mediated delivery systems, have shown promising preclinical results. Despite advances, challenges remain in translating miR-21 inhibition to clinical use. Key limitations include off-target effects, delivery inefficiencies, and context-dependent variability in miR-21 function. These issues hinder the development of safe and effective miR-21-targeted therapies. MiR-21 plays a central role in cancer and fibrosis and offers significant potential as both a biomarker and therapeutic target. Future research should focus on precision-based approaches, next-generation gene-editing technologies, and improved preclinical models to optimize miR-21 inhibition for clinical application. This review compiles and evaluates current literature on miR-21 biogenesis, regulation, functional roles, and therapeutic targeting across various cancers and organ-specific fibrotic disorders.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832847","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":"Overview of Spirooxindoline Scaffolds in Cancer Therapy.","authors":"Kamlesh Sharma","doi":"10.2174/0118715206433392260406050321","DOIUrl":"10.2174/0118715206433392260406050321","url":null,"abstract":"<p><p>Spirooxindoline derivatives have emerged as promising scaffolds in cancer therapy due to their structural diversity and potent cytotoxic effects. This review summarizes progress in the structural design and biological assessment of spirooxindoline derivatives. Modifications at the oxindole and benzene rings markedly enhance potency and selectivity against key cancer cell lines such as HeLa, MCF-7, HepG2, and A549. Several derivatives, including spirooxindole-pyrrolidine hybrids, thiazolo-pyrrolidine-spirooxindolines, and dispirooxindolines, demonstrate superior activity compared with cisplatin and doxorubicin. Mechanistic studies reveal induction of apoptosis, inhibition of proliferation, and interactions with critical targets including EGFR, HER2, and p53. Emerging synthetic strategies, particularly multicomponent reactions and click chemistry, further expand the scope of these molecules. Collectively, current findings underscore their potential as anticancer agents and the importance of future in vivo and pharmacokinetic studies to advance clinical translation.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":2.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832798","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":"Preclinical Evaluation of the Methyl (Z)-2-(isothioureidomethyl)-2-pentenoate Hydrobromide: Antitumor Efficacy and Safety Profile in a Murine Melanoma Model.","authors":"Laura Sartori Assunção, Iara Fabrícia Kretzer, Ana Gabriela Rosa, Mariana Martins Vernaschi, Juliano Andreoli Miyake, Evelise Maria Nazari, Misael Ferreira, Marcus Mandolesi Sá, Tania Beatriz Creczynski-Pasa","doi":"10.2174/0118715206441663260216045255","DOIUrl":"https://doi.org/10.2174/0118715206441663260216045255","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Melanoma is a malignancy often resistant to conventional therapies, highlighting the need for novel agents that effectively target tumor progression and subdue apoptotic resistance. Isothiouronium salts have shown promising anticancer potential; however, their in vivo potential remains largely unexplored. This study aimed to evaluate the preclinical safety and antitumor efficacy of the isothiouronium derivative ISMF08.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;C57BL/6J mice underwent acute and repeated-dose toxicity studies to determine the maximum tolerated dose (MTD) of IS-MF08. Following MTD determination, melanoma-bearing mice inoculated with B16F10 cells were treated intraperitoneally with IS-MF08 for 10 days. Tumor growth, survival, body weight, hematological parameters, and histopathology of liver, kidneys, and tumor tissue were evaluated.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The MTD was defined as 15 mg/kg. Repeated dosing with IS-MF08 at 12 mg/kg was well tolerated and promoted tumor growth inhibition (87%) and increased survival. Treatment also attenuated weight loss and tumor- induced anemia and leukocytosis. Histological analyses of tumors showed reduced neoplastic cell density and signs of collagen deposition. Mild histological changes in the liver and kidneys were observed at higher doses, along with an isolated increase in ALT levels and a slight increase in serum creatinine. In contrast, other liver enzymes (AST, ALT), TB, DB, total protein, albumin, and renal function markers remained within physiological limits.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;Preclinical evidence suggests that IS-MF08 is a promising candidate for further development as a multitargeted antineoplastic compound. It has demonstrated selectivity, tumor growth inhibition, and a manageable toxicity profile, positioning it as a potential therapeutic option for melanoma and possibly other solid tumors with similar resistance mechanisms. However, several limitations should be acknowledged. The antitumor activity of ISMF08 was evaluated in a single syngeneic mouse model (B16F10), which may not fully recapitulate the heterogeneity of human tumors. Furthermore, the lack of pharmacokinetic data and long-term toxicity assessments limits conclusions about the compound's safety over prolonged periods. Additionally, histopathological and hematological analyses have provided initial insights into the drug's tolerability. Future studies should expand the range of tumor models, explore immunological interactions, and incorporate molecular assays and bioavailability profiles to better elucidate the therapeutic potential and translational applicability of IS-MF08.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;IS-MF08 demonstrated robust antitumor activity with a safety profile. Despite the limitations of the present study, these findings support its continued development as a potential multi-target chemotherapeutic agent. Further studies are necessary to elucidate the ther","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832771","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":"Anticancer Potential of Eudesmanolides Derived from Sphagneticola trilobata against Colorectal Cancer, by Targeting β-catenin Signalling.","authors":"Remya Johny, Faisal Moossa Athikkavil, Sreekumar U Aiswarya, Amrutha A Nisthul, Meghna Sudhesh, Balan Abhijith, K A Krishnakumar, Ruby J Anto, Ravi S Lankalapalli, Smitha V Bava","doi":"10.2174/0118715206431960260123110937","DOIUrl":"https://doi.org/10.2174/0118715206431960260123110937","url":null,"abstract":"<p><strong>Introduction: </strong>The role of β-catenin signalling in the pathogenesis of Colorectal Cancer (CRC) is indisputable. In this study, we report the identification of a cytotoxic fraction that targets the β-catenin signalling axis in colorectal cancer cells.</p><p><strong>Methods: </strong>Chromatographic and spectrometric techniques were used for the isolation and phytochemical characterization of Eudesmanolides (EDS). Cell-viability assays, flow cytometry, fluorescent microscopy, immunoblot analysis, qRT-PCR, and in silico molecular docking studies were used to analyse the antitumor potential of EDS against CRC cells. Toxicological evaluation of EDS was conducted in Swiss albino mice.</p><p><strong>Results: </strong>We have isolated and characterized the bioactive fraction designated EDS, consisting of the eudesmanolides, namely wedelolide D and prostrolide A, from the Ethyl Acetate (EA) leaf extract of the plant Sphagneticola trilobata (S. trilobata). EDS was found to be highly efficacious against CRC cells and induced an apoptotic mode of cell death in different CRC cell lines. Delineation of the apoptotic pathway induced by EDS revealed extrinsic pathway activation and amplification of the apoptotic signals via the intrinsic pathway through truncated-BID. Molecular investigations revealed EDS-mediated inhibition of β-catenin signalling and PPAR-γ (peroxisome proliferator-activated receptor gamma) activation in HCT116 CRC cells.</p><p><strong>Discussion: </strong>Our study revealed that EDS induced strong apoptotic signals in CRC cells, initiated at the cell surface, resulting in apoptosis involving extrinsic and intrinsic mechanisms irrespective of the p53 status or molecular phenotype of CRC cells. In addition, PPAR-γ activation by EDS resulted in the suppression of β- catenin nuclear accumulation and the subsequent inhibition of proliferative and survival signalling. Moreover, EDS was found to be pharmacologically safe.</p><p><strong>Conclusion: </strong>To summarize, we demonstrate, with mechanism-based evidence, the chemotherapeutic efficacy of EDS, comprising the eudesmanolides, wedelolide D, and prostrolide A, derived from S. trilobata, against CRC. The potential of these lead-structures are worth exploring for their beneficial effects in combination with other therapeutic interventions.</p>","PeriodicalId":7934,"journal":{"name":"Anti-cancer agents in medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832802","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}