European Journal of Medicinal Chemistry Reports最新文献

{"title":"Dicentrine and its N-oxide derivatives induces apoptotic and necrotic cell death in prostate cancer cell lines","authors":"Ranyelison S. Machado ,&nbsp;Daniela C. Tristão ,&nbsp;Natália M. Araújo ,&nbsp;Elias Jorge Muniz Seif ,&nbsp;Kayo Alexandre S. da Cruz ,&nbsp;Mirian G. Morale ,&nbsp;Ileana Gabriela S. de Rubio ,&nbsp;João Henrique G. Lago ,&nbsp;Rodrigo E. Tamura","doi":"10.1016/j.ejmcr.2025.100257","DOIUrl":"10.1016/j.ejmcr.2025.100257","url":null,"abstract":"<div><div>As part of our continuous research for the discovery of anticancer natural products, the effects of alkaloid (6a<em>S</em>)-dicentrine (<strong>1</strong>) and its respective (6a<em>S</em>,6<em>S</em>)- (<strong>1a</strong>) and (6a<em>S</em>,6<em>R</em>)-(<strong>1b</strong>) <em>N</em>-oxides against two prostate cancer cell lines (PC3 and DU145) were evaluated for the first time. Alkaloid <strong>1</strong> exhibited IC₅₀ values of 18.43 and 23.53 μM for both tested cells. On the other hand, <strong>1a</strong> demonstrated higher IC₅₀ values (46.36 and 33.85 μM) whereas <strong>1b</strong> displayed reduced activity (IC₅₀ &gt; 50 μM) for both cells. These results suggest that the stereochemistry of the <em>N</em>-oxide moiety plays an important role in the antitumor activity. Molecular docking indicated differential residue interactions between compounds <strong>1</strong>, <strong>1a</strong>, and <strong>1b</strong> with EGFR and TP53 which could result in their differential modulation. Alkaloid <strong>1</strong> induced strong necrotic and apoptotic cell death in all tested cell lines, while <strong>1a</strong> caused reduced necrotic and apoptotic cell death in PC3, a TP53-null cell line, moderate necrotic cell death in DU145, a mutant TP53 cell line, and strong necrotic death in HEK293, an embryonic kidney cell line with wild-type TP53. Alkaloid <strong>1b</strong> did not induce the death of PC3, but induced necrotic cell death in both DU145 and HEK293. The alkaloids were shown to efficiently modulate gene and protein expression and activate TP53 and EGFR pathways with potential implications for targeting tumors with specific TP53 mutations. Altogether, the obtained results showed that (6a<em>S</em>)-dicentrine (<strong>1</strong>) and its N-oxide derivatives, especially <strong>1a</strong>, displayed potential as antitumor agents and justify its continued investigation as a therapeutic candidate.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100257"},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143528732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential of apitherapy in the management of cardiovascular diseases","authors":"Rimpa Karmakar,&nbsp;Sakshi Soni,&nbsp;Vandana Soni,&nbsp;Umesh Kumar Patil","doi":"10.1016/j.ejmcr.2025.100256","DOIUrl":"10.1016/j.ejmcr.2025.100256","url":null,"abstract":"<div><div>Apitherapy has been used as an adjunctive medical practice in several countries, and bee products or apitherapeutic agents are being consistently utilized for millennia by humanity to treat and prevent an assortment of illnesses. This review sought to explore the relationship between apitherapy and scientific research and experimental trials utilizing bee products within the domain of cardiology. Numerous studies conducted <em>in vivo</em> along with <em>in vitro</em> indicate that these products may have potential benefits in the prevention and management of cardiovascular diseases (CVDs). This concise review of research reveals new facets of the biological activities of many bee products: honey, propolis, bee venom, pollen, royal jelly, beeswax, and bee bread, as naturally occurring and intriguing remedies for common CVDs. There are undoubtedly some intriguing mechanisms in bee products that aid in the treatment and prevention of CVDs. Future research with larger sample sizes and improved techniques is needed to validate the relationship between bee products and CVD risk factors. Conclusively, bee products seem to have the potential to lower cardiovascular disease risk factors; however, more research is required to fully grasp these benefits. Even if our knowledge of bee products has greatly expanded, it is still crucial to fully utilize its potential, standardize its use, and share the results in academic and non-academic settings to further investigate its potential in the area of cardiology.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100256"},"PeriodicalIF":0.0,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New heterocyclic A1/A3 adenosine receptor ligands through molecular simplification strategies","authors":"Letizia Crocetti ,&nbsp;Abigail Pearce ,&nbsp;Venkat S. Vege ,&nbsp;Qi Xu ,&nbsp;Jing Xu ,&nbsp;Hannes Buthmann ,&nbsp;Maria Paola Giovannoni ,&nbsp;Gabriella Guerrini ,&nbsp;Francesca Catarzi ,&nbsp;Silvia Selleri ,&nbsp;Xianglin Huang ,&nbsp;Aneesh Chandran ,&nbsp;Graham Ladds ,&nbsp;Agostino Cilibrizzi","doi":"10.1016/j.ejmcr.2025.100253","DOIUrl":"10.1016/j.ejmcr.2025.100253","url":null,"abstract":"<div><div>In this paper we report the synthesis of new A₁/A₃ adenosine receptor antagonists designed as simplification products of the A₁ antagonists with pyrazolo[1′,5′:1,6]pyrimido [4,5-d]pyridazin-4(3H)-one scaffold previously developed by us. Notably, selective A₁R antagonists are promising therapeutic agents in Alzheimer's disease and for the treatment of cognitive deficits, while A₃R antagonists are potentially useful in the treatment of ischemia and certain types of cancer. Initial screening with NanoBRET competition binding assay revealed a number of products with pKi ≥5 for A₁R and A₃R. For some representative compounds the antagonist profiles, as well as their selectivity versus A_2AR and A_2BR, have been also validated by antagonizing NECA in cAMP accumulation. The most interesting compounds resulted the A₁/A₃ mixed antagonist <strong>3b</strong> (pKi = 6.41 and 6.29 for A₁R and A₃R respectively, pKb = 5.00 and 5.27 for the A_2aR and A_2bR) and the selective A₃R antagonist <strong>5c</strong> (pKi = 6.40, pKb values of 4.44, 6.17, 4.16, and 4.78 for the A₁R, A₃R, A_2aR and A_2bR, respectively). Furthermore, <em>in silico</em> simulations were carried out to study the molecular mechanism of the high affinity of <strong>3b</strong> for A₁/A₃Rs as well as the selectivity of <strong>5c</strong> for A₃R over A₁R. Overall, this work highlights new series of bicyclic small-molecules as valid candidates for further structural optimization towards the development of therapeutically relevant A₁/A₃ adenosine receptor antagonists.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100253"},"PeriodicalIF":0.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indoles in drug design and medicinal chemistry","authors":"Benjamin A. Babalola ,&nbsp;Monika Malik ,&nbsp;Olanike Olowokere ,&nbsp;Ayomide Adebesin ,&nbsp;Lekhnath Sharma","doi":"10.1016/j.ejmcr.2025.100252","DOIUrl":"10.1016/j.ejmcr.2025.100252","url":null,"abstract":"<div><div>Indole derivatives represent a significant class of compounds in medicinal chemistry due to their diverse biological activities and structural versatility. These compounds are central to the design of drugs targeting a wide array of diseases, including cancer, diabetes, cardiovascular disorders, neurological diseases, and infections. The indole scaffold facilitates interactions with biological macromolecules, enhancing its utility in drug development. This review summarizes the latest advancements in the synthesis, biological efficacy, and therapeutic potential of indole derivatives. Classical methods, such as Fischer, Bartoli, and Reissert indole synthesis, continue to serve as foundational techniques, while modern advancements in combinatorial methods, transition-metal catalysis, cyclization methods, nanoparticles-mediated synthesis, heterogenous catalysis, microwave-aided catalysis, ultrasound-aided approach, and green chemistry offer more efficient, sustainable approaches. Notably, indole derivatives exhibit potent antifungal, antiprotozoal, antidiabetic, antioxidant, antimalarial, antibacterial, anti-inflammatory, and anticancer activities. Recent studies highlight the role of structural modifications in optimizing these compounds for enhanced pharmacological outcomes. For instance, indole-triazole conjugates show impressive antifungal activity, while indole-thiazolidine-2,4-dione inhibitors exhibit strong antidiabetic effects. Additionally, indole derivatives have demonstrated efficacy in targeting key oncogenic pathways, with some compounds exhibiting potent anticancer properties against various cell lines. These promising findings are supported by computational modelling studies that reveal strong interactions with target proteins. Emerging trends in indole-based drug discovery, including the integration of computational modelling and molecular docking, are expected to drive the development of next-generation therapeutics. As research in this area progresses, indole derivatives are poised to remain integral to the development of innovative treatments for a broad range of diseases.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100252"},"PeriodicalIF":0.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural products combating EGFR-TKIs resistance in cancer","authors":"Li Xia ,&nbsp;Gaohui Zhu ,&nbsp;Qiyao Peng ,&nbsp;Xiuyang Li ,&nbsp;Xinrong Zou ,&nbsp;Wanping Zhang ,&nbsp;Lulu Zhao ,&nbsp;Xiong Li ,&nbsp;Ping Wu ,&nbsp;Aimin Luo ,&nbsp;Teng Yang ,&nbsp;Meizi Chen ,&nbsp;Teng Liu ,&nbsp;Yongbo Peng","doi":"10.1016/j.ejmcr.2025.100251","DOIUrl":"10.1016/j.ejmcr.2025.100251","url":null,"abstract":"<div><div>The role of natural products in cancer treatment has received substantial attention. Significantly, natural products can interact with multiple targets, which is meaningful in overcoming drug resistance synergistically. Resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). In this review, we summarize the main resistance mechanisms to EGFR-TKIs and present that 67 reported natural products (from 2005 to 2024) demonstrate the potential to combat EGFR-TKIs resistance in cancer via at least 30 pathways, mainly including ROS, PD-L1, EGFR, MAPK, mTOR, HSP90, JNK, PTEN, and FOXO. Based on the rule of five evaluation of druggability, we can obtain 37 natural products suitable for further development. This review aims to systematically summarize recent advances of natural products in overcoming EGFR-TKIs resistance, and provide some inspirations for novel drug discovery in cancer including NSCLC.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100251"},"PeriodicalIF":0.0,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and evaluation of quinazoline-chalcone hybrids as inducers of cell-cycle arrest and apoptosis in breast cancer via DNA damage and CDK2/ATR inhibition","authors":"Giulia Rodrigues Stringhetta ,&nbsp;Eduardo Bustos Mass ,&nbsp;Izabela Natalia Faria Gomes ,&nbsp;Maria Clara Fonseca Peixoto ,&nbsp;Amanda Helena Tejada ,&nbsp;Luciane Susucchi ,&nbsp;Aryel José Alves Bezerra ,&nbsp;Pedro Victor Silva Resende ,&nbsp;Vinicius Vendrúsculo ,&nbsp;Rui Manuel Reis ,&nbsp;Dennis Russowsky ,&nbsp;Renato José Da Silva Oliveira","doi":"10.1016/j.ejmcr.2025.100250","DOIUrl":"10.1016/j.ejmcr.2025.100250","url":null,"abstract":"<div><div>In this study, a series of novel hybrid compounds, 2-arylquinazolinechalcones, were synthesized and their antitumoral activities were evaluated. Among them, compounds <strong>7b</strong> and <strong>7n</strong> exhibited the highest cytotoxicity and selectivity rates for the triple-negative breast cancer cell line MDA-MB-231. In 3D spheroid culture, <strong>7b</strong> and <strong>7n</strong> decreased viability and increased cell death. Both compounds induced cell death primarily through the extrinsic pathway and promoted cell cycle arrest in G0/G1, possibly through increased expression of p27 and subsequent reduction in CDK2 levels. Additionally, they may trigger oxidative stress and DNA damage, as evidenced by elevated levels of H2AX activation, and compromise DNA repair pathways mediated by ATR and CHK1. To further explore the mechanism behind the observed cell cycle arrest, we performed phospho-RTK and phospho-MAPK Reverse Phase Protein Arrays to investigate changes in the expression of activated RTKs and MAPKs after treatment with <strong>7b</strong> and <strong>7n</strong>, compared to the negative control. These findings suggest that <strong>7b</strong> and <strong>7n</strong> are promising candidates for further development as targeted therapies for triple-negative breast cancer.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100250"},"PeriodicalIF":0.0,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143420481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct conversion of peptides into diverse peptidomimetics using a transformer-based chemical language model","authors":"Atsushi Yoshimori ,&nbsp;Jürgen Bajorath","doi":"10.1016/j.ejmcr.2025.100249","DOIUrl":"10.1016/j.ejmcr.2025.100249","url":null,"abstract":"<div><div>The design of pharmaceutically relevant compounds that mimic bioactive peptides or secondary structure elements in proteins is an important task in medicinal chemistry. Over time, various chemical strategies have been developed to convert natural peptide ligands into so-called peptidomimetics. This process is supported by computational approaches to identify peptidomimetic candidate compounds or design templates mimicking active peptide conformations. However, generating peptidomimetics continues to be challenging. Chemical language models (CLMs) offer new opportunities for molecular design. Therefore, we have revisited computational design of peptidomimetics from a different perspective and devised a CLM to directly transform input peptides into peptidomimetic candidates, without requiring intermediate states. A critically important aspect of the approach has been the generation of training data for effective learning that was guided by a quantitative measure of peptide-likeness such that the CLM could implicitly capture transitions from peptides or peptide-like molecules to compounds with reduced or eliminated peptide character. Herein, we introduce the CLM for peptidomimetics design and establish proof-of-principle for the approach. For given input peptides, both the general model and a version fine-tuned for a specific application were shown to produce a spectrum of candidate compounds with varying similarity, gradually changing chemical features, and diminishing peptide-likeness. As a part of our study, the CLM and data are provided.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100249"},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143160281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biological evaluation of novel 5-((1H-indol-3-yl) methyl)-2-(4-chlorobenzyl)-6-phenyl-imidazo[2,1-b][13,4]thiadiazole derivatives as novel BCL-2 specific inhibitors","authors":"Shivangi Sharma ,&nbsp;Sadashivamurthy Shamanth ,&nbsp;Humaira Siddiqua ,&nbsp;Laijau Goyary ,&nbsp;Kunigal S. Sagar ,&nbsp;Susmita Kumari ,&nbsp;Divya Sathees ,&nbsp;Gudapureddy Radha ,&nbsp;Bibha Choudhary ,&nbsp;Sathees C. Raghavan ,&nbsp;Kempegowda Mantelingu","doi":"10.1016/j.ejmcr.2025.100247","DOIUrl":"10.1016/j.ejmcr.2025.100247","url":null,"abstract":"<div><div>Antiapoptotic protein BCL2 is known to be upregulated in several cancer cells and therefore, it is an excellent target for cancer therapy. Previously, we reported a novel BCL2 inhibitor, Disarib, which inhibited BCL2 by predominantly binding to its BH1 domain and exhibited platelet-sparing ability like ABT199, the only FDA-approved BCL2 inhibitor. Here, we have synthesized the novel Disarib derivatives where oxindole moiety in Disarib was replaced with indole and evaluated their biological activity. We report several derivatives of Disarib and the identification of DSR 43 and 4-OCH₃, as the most potent among them. Treatment of cancer cell lines with the Disarib derivatives, DSR 43 and 4-OCH₃ led to the activation of the apoptotic pathway without generating any ROS or disrupting the mitochondrial membrane potential within the cells, leading to cell death. Western blot analysis in tandem with Annexin V/PI staining confirmed the activation of apoptosis. <em>In silico</em> studies, using derivatives suggests a promising therapeutic window with less off-target effects. Furthermore, their efficacy across different cancer cell lines highlights their broad potential as anticancer agents. Taken together, our results suggest that Disarib derivatives may have the potential to be developed as cancer therapeutic.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100247"},"PeriodicalIF":0.0,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143160279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, evaluation of the biological activity against Trypanosoma cruzi and Leishmania donovani. Preliminary in silico ADMET studies of 5-nitroimidazole derivatives","authors":"Miguel A. Rodríguez ,&nbsp;Ali Mijoba ,&nbsp;Nereida J. Parra-Giménez ,&nbsp;Zuleyma Blanco ,&nbsp;Katiuska Chávez ,&nbsp;Alirica I. Suárez ,&nbsp;Esteban Fernandez-Moreira ,&nbsp;Hegira Ramírez ,&nbsp;Jaime E. Charris","doi":"10.1016/j.ejmcr.2025.100248","DOIUrl":"10.1016/j.ejmcr.2025.100248","url":null,"abstract":"<div><div>The synthesis and evaluation of the biological activity of a series of 5-nitroimidazole hybrids is described. The structures of the synthesized hybrids were confirmed by spectral analysis FT-IR, ¹H NMR, ¹³C NMR, MS, and by Elemental Analysis. The toxicity (ADME/Tox) assessment study were carried out to predict the molecular properties associated with pharmacokinetic aspects of novel compounds. The trypanocidal and leishmanicidal activities of all synthesized hybrids were evaluated, compounds <strong>7a</strong> and <strong>8b</strong> were active against the epimastigote form of <em>T. cruzi</em>. Compound <strong>10b</strong> showed marginal activity against the promastigote form of <em>L. donovani</em>. Sulfonyl derivative <strong>8b</strong> was the most promising compound with IC₅₀: 9.58 ± 2.02 μM and with a selectivity index (SI) greater than 31.31, that justifies the description as a promising hit for further study as a possible antichagasic agent.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100248"},"PeriodicalIF":0.0,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143264575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"P-glycoprotein-independent cytotoxic effects of 5-aminopyrazole in L1210 leukemia cells","authors":"Lucia Sofrankova ,&nbsp;Jana Spaldova ,&nbsp;Pavol Stefik ,&nbsp;Branislav Pavilek ,&nbsp;Dusan Bortnak ,&nbsp;Lucia Pavlikova ,&nbsp;Ivana Zidekova ,&nbsp;Daniel Vegh ,&nbsp;Viktor Milata ,&nbsp;Albert Breier ,&nbsp;Zdena Sulova","doi":"10.1016/j.ejmcr.2025.100246","DOIUrl":"10.1016/j.ejmcr.2025.100246","url":null,"abstract":"<div><div>We previously investigated the cytotoxic effects of 5-aminopyrazoles (5-APs) on leukemia cells both negative and positive for P-glycoprotein (P-gp) expression, a common contributor to multidrug resistance. Five derivatives (A1-A5), each containing perfluorinated methylbenzene at the N3 nitrogen of the pyrazole ring, were tested on murine lymphoblastic cell line variants: parental S cells (P-gp positive), R cells (vincristine-resistant and P-gp positive), and T cells (human P-gp transfected). Among these, A1 and A4 exhibited the strongest effects, especially in R cells, with lesser but similar effects observed in S and T cells. Cell death assays revealed both apoptosis and necrosis, with apoptosis confirmed by DNA fragmentation and activation of caspases 3/7, 8, and, to a lesser extent, 9, suggesting a predominance of extrinsic apoptosis. The compounds also induced autophagy, identified by LysoTracker Green and monodansylcadaverine staining. All derivatives, except A5, suppressed P-gp activity, though they did not alter P-gp expression at the mRNA or protein level. Cell cycle analysis showed changes in the G0/G1 and S phases. The heightened sensitivity of R cells to 5-AP, despite P-gp expression, likely results from an altered phenotype due to vincristine-induced stress rather than from P-gp inhibition alone. This conclusion is supported by the fact that T cells expressing P-gp are as sensitive to 5-APs as S cells.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"13 ","pages":"Article 100246"},"PeriodicalIF":0.0,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143160278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}