European Journal of Medicinal Chemistry最新文献

{"title":"First-in-class dual inhibitors of MASTL and Aurora A kinase: Discovery of selective cyclohexa[b]thiophenes with potent anticancer activity","authors":"Somaya A. Abdel-Rahman ,&nbsp;Hossam Nada ,&nbsp;Moustafa T. Gabr","doi":"10.1016/j.ejmech.2025.117729","DOIUrl":"10.1016/j.ejmech.2025.117729","url":null,"abstract":"<div><div>The dysregulation of mitotic kinases, particularly Microtubule Associated Serine/Threonine Kinase Like (MASTL) and Aurora A kinase, play pivotal roles in tumor progression and resistance to therapy. Herein, we report cyclohexa[<em>b</em>]thiophenes as first-in-class dual inhibitors of MASTL and Aurora A kinase. The lead compound, <strong>MA4</strong>, demonstrated potent inhibition of both kinases with IC₅₀ values of 0.16 ± 0.01 μM for Aurora A and 0.56 ± 0.16 μM for MASTL. Kinase selectivity profiling against a panel of 277 kinases revealed a high degree of specificity against both targets. In vitro antiproliferative screening using the NCI-60 human cancer cell line panel revealed broad-spectrum cytotoxicity, with <strong>MA4</strong> exhibiting submicromolar GI₅₀ values across multiple malignancies, outperforming previously reported cyclohexa[<em>b</em>]thiophenes in the multidose screening. Mechanistic studies, including microscale thermophoresis (MST) and NanoBRET target engagement assays, confirmed direct binding to both kinases. Computational studies, including molecular docking and molecular dynamics simulations, revealed key interactions stabilizing <strong>MA4</strong> within the ATP-binding sites of both kinases. We demonstrated the potent anticancer activity of <strong>MA4</strong> in 3D tumor spheroids, along with its favorable pharmacokinetic profile. Additionally, <strong>MA4</strong> exhibited no inhibitory activity against hERG and demonstrated selectivity toward cancer cells over normal cell lines, further supporting its potential for in vivo applications. These findings establish cyclohexa[<em>b</em>]thiophenes as promising dual kinase inhibitors with high selectivity, offering a compelling strategy for targeting mitotic dysregulation in cancer therapy.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117729"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920642","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":"The anti-neoplastic potency of epoxy-substituted polyaromatic platinum(II) and platinum(IV) complexes against A549 lung cancer cells","authors":"Rouba Al Sayegh ,&nbsp;Aleen Khoury ,&nbsp;Maria George Elias ,&nbsp;Najwa Mansour ,&nbsp;Stephanie Mehanna ,&nbsp;Amjad Slika ,&nbsp;Costantine F. Daher ,&nbsp;Janice R. Aldrich-Wright ,&nbsp;Robin I. Taleb","doi":"10.1016/j.ejmech.2025.117734","DOIUrl":"10.1016/j.ejmech.2025.117734","url":null,"abstract":"<div><div>A novel platinum(II) complex, <strong>Pt^II56O<em>SS</em></strong>, coordinated to 5,6-epoxy-5,6-dihydro-1,10-phenanthroline and its platinum(IV) di-hydroxido derivative (<strong>Pt^IV56O<em>SS</em></strong>) were synthesized and successfully characterised via NMR spectroscopy, HPLC, ESI-MS, UV, and CD spectroscopy. The cytotoxic activity of <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong> against A549, A375 and MDA-MB-231 cancer cells was investigated, and the results showed that both complexes exhibit dose dependent growth inhibition against all three cancer cell lines. In addition, <strong>Pt^IV56O<em>SS</em></strong> displayed significantly less toxicity against mesenchymal cells (MCs; &gt;100 μM) compared to both <strong>Pt^II56O<em>SS</em></strong> (6.5 μM) and cisplatin (2.0 μM). A Dose Escalation Study on Balb/c mice showed that the most tolerated dose (MTD) for <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong> were 140 and 200 mg/kg.b.w., respectively (which were ∼23-fold and 33-fold more tolerated than cisplatin). Cellular uptake experiments in A549 cells after 1, 3, 6, 12, 24 and 30 h of incubation, showed that both complexes are actively transported into the cells with <strong>Pt^II56O<em>SS</em></strong> exhibiting a similar uptake rate to cisplatin and approximately a 3-fold higher uptake than <strong>Pt^IV56O<em>SS</em></strong>. Intracellular distribution showed that while <strong>Pt^II56O<em>SS</em></strong> resides primarily in the Cytoplasmic Fraction) while (CF), the <strong>Pt^IV56O<em>SS</em></strong> resides heavily in the nucleus and cytoskeleton (NC) fraction. A549 cells treated with <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong> also showed a significant increase in the production of cellular ROS at all-time points (24, 48 and 72 h). Flow cytometry results demonstrated that <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong> caused significant increase in apoptotic cell death. Western blot assays exhibited an upregulation of cytochrome c, cleaved Parp, and the ratio of Bax/Bcl-2 when A549 cells were treated with either <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong>. These results distinguish <strong>Pt^II56O<em>SS</em></strong> and <strong>Pt^IV56O<em>SS</em></strong> as promising candidates for further investigation both <em>in vitro</em> and <em>in vivo</em> against several cancer models with the platinum(IV) analogue showing more promise due to its low cytotoxicity against normal cells coupled with its high <em>in vivo</em> tolerability.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117734"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920619","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":"Design, synthesis, and biological evaluation of isoxazole-dihydropyrimidinone hybrids as potential modulators of adipogenesis and dyslipidemia","authors":"Alisha Ansari ,&nbsp;Nilesh Khandelwal ,&nbsp;Jay Gupta ,&nbsp;Prashant Rai ,&nbsp;Arvind Kumar Jaiswal ,&nbsp;Astha Singh ,&nbsp;Sarita Katiyar ,&nbsp;Ajay Kishor Kushawaha ,&nbsp;Vinita Kushwaha ,&nbsp;Anuradha Vishwakarma ,&nbsp;Divyanshi Singh ,&nbsp;Arpon Biswas ,&nbsp;Ravi Kumar ,&nbsp;Rabi Sankar Bhatta ,&nbsp;Anil Nilkanth Gaikwad ,&nbsp;Koneni V. Sashidhara","doi":"10.1016/j.ejmech.2025.117746","DOIUrl":"10.1016/j.ejmech.2025.117746","url":null,"abstract":"<div><div>The prevalence of obesity and its accompanying metabolic disorders necessitates innovative strategies to modulate adipocyte energy homeostasis. Adipose tissue, vital in energy metabolism, influences various physiological processes. Excessive energy storage leading to obesity exacerbates conditions like insulin resistance, dyslipidemia, and type-2 diabetes. Targeting adipogenic processes becomes crucial in mitigating obesity associated health risks. In this study, a series of 35 compounds integrating isoxazole and dihydropyrimidinone pharmacophores were synthesized and evaluated for their anti-adipogenic potential. Further refinement using structure-activity relationship led to the design of additional compounds, revealing promising anti-adipogenic properties. Among these, compound <strong>10g</strong> demonstrated notable efficacy and was studied for further mechanistic investigation. Compound <strong>10g</strong> targets the early stage of adipogenesis, including mitotic clonal expansion to inhibit the differentiation. It activates the AMPK pathway to exert anti-adipogenic potential and improve mitochondrial function and fatty acid oxidation in mature adipocytes. Treatment of compound <strong>10g</strong> in HFD-fed hamsters results in reduced adipose mass and body weight without altering the calorie intake. Compound <strong>10g</strong> ameliorated dyslipidemia by activating the reverse cholesterol transport machinery in hamsters. These results highlight isoxazole-dihydropyrimidinone hybrids, as a potential pharmacophore for developing drugs for obesity and dyslipidemia.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117746"},"PeriodicalIF":6.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143927154","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":"Design, synthesis, and in vitro and in vivo biological evaluation of 2-amino-naphtho[2,3-b]thiophene-4,9-dione derivatives as potent anticancer agents.","authors":"Soumen K. Manik, Satyajit Haldar, Ankita Bhattachrya, Utsab Debnath, Sk Asraf Ali, Shraman Jana, Manik Shit, Pallab K. Haldar, Suniti Pradhan, Dipak K. Hazra, Kankan K. Maity, Sudipta Kumar Ghorai, Shubhankar Samanta, Anup K. Misra, Kuladip Jana, Nirmal K. Hazra","doi":"10.1016/j.ejmech.2025.117728","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117728","url":null,"abstract":"This study synthesized a series of substituted 2-amino-naphtho[2,3-b]thiophene 4,9-dione derivatives through multi-component reactions involving Domino and Krapcho strategies. Among the 15 synthesized analogs, compound <strong>4a</strong> emerged as a lead compound with potent anticancer activity against the aggressive triple-negative breast cancer (TNBC) cell line MDA-MB-231. Mechanistic investigations demonstrated that treatment with compound <strong>4a</strong> induced dose-dependent inhibition of cell viability, cell cycle arrest, and robust apoptotic responses in MDA-MB-231 cells. Apoptotic assays confirmed enhanced caspase-3/7 activation and increased reactive oxygen species (ROS) generation. Crucially, immunocytochemistry analysis revealed that compound <strong>4a</strong> significantly suppressed the phosphorylation of Akt at Ser473, a pivotal regulatory event in the PI3K/Akt signaling pathway, which is frequently dysregulated in TNBC. This inhibition disrupted pro-survival signaling, sensitizing MDA-MB-231 cells to apoptosis while sparing normal cells, highlighting compound <strong>4a</strong> as a potential anticancer agent through selective therapeutic targeting of Akt-driven pathways.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"125 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920643","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":"Design, synthesis and characterization of aryl bis-guanyl hydrazones as RNA binders of C9orf72 G4C2 extended repeats","authors":"Alice Maiocchi ,&nbsp;Martina Pedrini ,&nbsp;Veronica Ferrari ,&nbsp;Agata Sofia Assunçao Carreira ,&nbsp;Vincenzo Maria D'Amore ,&nbsp;Federica Santoro ,&nbsp;Anna Di Porzio ,&nbsp;Maddalena Bosetti ,&nbsp;Riccardo Cristofani ,&nbsp;Alessandra Silvani ,&nbsp;Diego Brancaccio ,&nbsp;Luciana Marinelli ,&nbsp;Francesco Saverio Di Leva ,&nbsp;Alessandro Provenzani ,&nbsp;Angelo Poletti ,&nbsp;Pierfausto Seneci","doi":"10.1016/j.ejmech.2025.117736","DOIUrl":"10.1016/j.ejmech.2025.117736","url":null,"abstract":"<div><div>Expanded G₄C₂ repeats derived from mutations of the <em>C9orf72</em> gene are causative factors in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, leading to multiple pathological events. Bis thiophene <em>para</em> dinicotinimidamide <strong>2a</strong> was reported to preferentially stabilize G-quadruplex G₄C₂ RNA structures at sub-micromolar concentrations. We replaced its amidine groups with BBB-compliant guanyl hydrazones, and carried out scaffold variations to improve water solubility. An eight-membered array was built around bis-thiophene- (<strong>4b</strong>-<strong>6a</strong>), bis-oxazole- (<strong>7b</strong>), diphenylurea diamide- (<strong>8b</strong>) and phenyldioxy ditriazolephenyl scaffolds (<strong>9a,b</strong>). Biological profiling of the array identified <strong>4b</strong> as a promising, drug-like hit, active in cellular assays on ALS patient-derived cells.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117736"},"PeriodicalIF":6.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920620","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":"Design, synthesis, and structure-activity relationships of selective biphenyl antithrombotic tissue factor/factor VIIa inhibitors","authors":"Pravin L. Kotian,&nbsp;Yahya El-Kattan,&nbsp;Shri Niwas ,&nbsp;Minwan Wu,&nbsp;Tsu-Hsing Lin ,&nbsp;Brent Bourdreaux ,&nbsp;Surendra K. Saini ,&nbsp;Andrew Spaulding,&nbsp;Debra Kellogg-Yelder,&nbsp;Cynthia Parker,&nbsp;Ramanda Chambers-Wilson ,&nbsp;Shanta Bantia ,&nbsp;Zhixin Miao,&nbsp;Jason Williams ,&nbsp;Allison Schmittou,&nbsp;Krishnan Raman,&nbsp;Paul A. Wiget,&nbsp;Pooran Chand ,&nbsp;Y. Sudhakar Babu","doi":"10.1016/j.ejmech.2025.117708","DOIUrl":"10.1016/j.ejmech.2025.117708","url":null,"abstract":"<div><div>The primary initiator for coagulation is the tissue factor (TF)-factor VIIa (FVIIa) cofactor-enzyme complex, TF-FVIIa. This complex leads to subsequent proteolytic activation of clotting factors. The TF-FVIIa complex plays a vital role in thrombosis-related diseases and is an attractive therapeutic target. Herein we report further optimization of our novel series of biphenyl antithrombotic agents as potent and selective TF-FVIIa inhibitors. Using a structure-guided drug design approach to explore the S1 and S′ pockets of the FVIIa active site and building on compounds from earlier investigations of the S2 pocket, 41 new compounds were synthesized, including 24 compounds with TF-FVIIa IC₅₀ values of 30 nM or less. Structure-Activity Relationships (SARs) were evaluated in silico using the R-group decomposition function in StarDrop 7.0®. A sampling of the compounds was screened for selectivity against other human serine proteases. PT and aPTT assays were performed to provide insights of the inhibitor activity in the extrinsic and intrinsic coagulation pathways, respectively. Six compounds were chosen based on the coagulation assays to undergo PK studies. These six were poorly soluble and thus their oral PK profiles in rat models suffered. Future results will include efforts to improve bioavailability. This work represents the campaign that led to the discovery of <strong>BCX-3607</strong> and its aims to improve upon it, identifying new, potent, and selective TF-FVIIa inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"294 ","pages":"Article 117708"},"PeriodicalIF":6.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915796","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":"Design and development of chromene-3-carboxylate derivatives as antidiabetic agents: Exploring the antidiabetic potential via dual inhibition of angiotensin II type 1 receptor and neprilysin enzyme","authors":"Shikha Thakur ,&nbsp;Sandhya Chahal ,&nbsp;Madhav S. Jadhav ,&nbsp;Priyanka Mohanty ,&nbsp;Anil Bhanudas Gaikwad ,&nbsp;Jayant Sindhu ,&nbsp;Hemant R. Jadhav","doi":"10.1016/j.ejmech.2025.117705","DOIUrl":"10.1016/j.ejmech.2025.117705","url":null,"abstract":"<div><div>Diabetes mellitus, particularly type II diabetes mellitus, is a metabolic condition that has a substantial impact on the health of individuals. The implication of diabetes with increased risk of cardiovascular diseases (CVD) and, consequently, myocardial infarction is well established. However, developing new antidiabetic drugs with an established efficacy on cardiovascular health is an underdeveloped area of research. To address this, in the present study, a new series of chromene-3-carboxylate derivatives (<strong>1B1–1B22</strong>) as dual inhibitors of Angiotensin II Type 1 Receptor (AT1R) and Neprilysin (NEP), which are recognized targets in diabetes with CVD, is reported. The compounds were rationally designed and synthesized, considering the pharmacophoric features of these two targets. The evaluation was performed <em>via</em> glucose uptake, α-amylase, AT1R, and NEP inhibition assay. The derivatives were found to increase glucose uptake and inhibit all three targets, of which compound <strong>1B15</strong> was the most active. The most active compound, <strong>1B15,</strong> reduced the oxidative stress and restored the mitochondrial membrane potential. The biological findings were further corroborated by <em>in silico</em> studies, which included molecular modelling and dynamics. It was deduced that <strong>1B15</strong> remains unionized in acidic to weak basic pH and may be passively absorbed. Further, the molecule was found to undergo hydroxylation as a means of Phase I metabolism and glucuronic conjugation in Phase II. The wet lab experiments on <strong>1B15</strong> further validated the <em>in-silico</em> absorption and metabolism prediction. The compounds, particularly <strong>1B15</strong>, could be explored further as a lead for its utility as an antidiabetic with profound implications on cardiovascular health.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117705"},"PeriodicalIF":6.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143910324","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":"Conformational restriction enables discovering a series of chroman derivatives as potent and selective NaV1.8 inhibitors with improved pharmacokinetic properties","authors":"Na Li ,&nbsp;Linlin Wang ,&nbsp;Xinyuan Hu ,&nbsp;Haiyan Xu ,&nbsp;Bowen Yang ,&nbsp;Li Zhan ,&nbsp;Yongjie Cai ,&nbsp;Yueling Gu ,&nbsp;Xueqin Chen ,&nbsp;Yueming Zheng ,&nbsp;Tongchao Liu ,&nbsp;Zhaobing Gao ,&nbsp;Bing Xiong","doi":"10.1016/j.ejmech.2025.117697","DOIUrl":"10.1016/j.ejmech.2025.117697","url":null,"abstract":"<div><div>Voltage-gated sodium channel 1.8 (Na_V1.8) is a promising analgesic target due to its unique biophysical characteristics and specific role in nociceptive sensation. VX-150 initially completed proof-of-concept studies in clinical trials, but with high dosages and frequent administration. Herein, based on VX-150, we report the design, synthesis and structure-activity relationship (SAR) study aiming to identify novel, potent and selective Na_V1.8 inhibitors with improved pharmacokinetic properties. Conformational restriction strategy and subsequent optimization led to the identification of the chroman derivative (<em>R</em>)-<strong>40</strong> as the most promising hNa_V1.8 inhibitor showing an IC₅₀ value of 5.9 ± 1.0 nM and good selectivity over other tested Na_V channels and hERG channel. More importantly, (<em>R</em>)-<strong>40</strong> showed good <em>in vitro</em> metabolic stability in liver microsomes across multiple species and excellent <em>in vivo</em> PK profiles in rats and dogs. Notably, (<em>R</em>)-<strong>40</strong> exerted dose-dependent analgesic activities in both rat models with postoperative and inflammatory pain, and a wide safety margin in neurotoxicity evaluation. Overall, these results confirmed conformational restriction as an effective strategy to improve PK profile, and our detailed study provided a valuable foundation for developing novel Na_V1.8 inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117697"},"PeriodicalIF":6.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915782","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":"Characterization of a Water Soluble Quininib Prodrug that Blocks Metabolic Activity and Proliferation of Multiple Cancer Cell Lines","authors":"Valentina Tonelotto, Alina Qaisar, Eavan C. McLoughlin, Amelia Cassaday, Karishma Kundu, Marzia Pendino, Simone Marcone, Jacintha O'Sullivan, Brendan Twamley, Lasse D. Jensen, Stephen D. Thorpe, Breandan N. Kennedy, Niamh M. O'Boyle","doi":"10.1016/j.ejmech.2025.117727","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117727","url":null,"abstract":"Quininib is a small molecule antagonist of cysteinyl leukotriene receptor 1 (CysLT₁), which is increasingly recognized for its role in cancer progression. Overexpression of CysLT₁ has been documented in colorectal cancer, renal cell carcinoma, breast cancer, and uveal melanoma (UM). However, quininib’s poor aqueous solubility presents a significant barrier to its clinical development. The aim of this study was to overcome this limitation by synthesizing and evaluating novel ester analogues, ace-quininib and its hydrochloride salt, ace-quininib-HCl, as more soluble, bioactive forms of quininib. The objectives were to 1) synthesize and characterize the analogues; 2) evaluate their anti-cancer activity in a panel of cell lines, including UM (OMM2.5) and metastatic pancreatic cancer (SUIT2-007); 3) assess their enzymatic conversion to quininib; 4) determine their aqueous solubility and in vivo suitability; and 5) evaluate preliminary toxicity in zebrafish larvae. Ace-quininib was rapidly converted to quininib in the presence of porcine liver esterase, confirming its function as a prodrug. It exhibited potent anti-cancer activity across the NCI-60 cell line panel, with the strongest effects observed in CCRF-CEM leukemia (GI₅₀ = 0.22 μM) and UO-31 renal cancer cells (GI₅₀ = 0.62 μM). Both ace-quininib and ace-quininib-HCl reduced metabolic activity in OMM2.5 and SUIT2-007 cells in a dose-dependent manner. Notably, ace-quininib-HCl also inhibited long-term colony formation in OMM2.5 cells. Solubility studies revealed that while quininib and ace-quininib remained water-insoluble, ace-quininib-HCl demonstrated excellent aqueous solubility (2.18 ± 0.18 mg/mL). Furthermore, both ace-quininib and quininib were well tolerated in zebrafish larvae, supporting their potential for in vivo application. The novelty of this study lies in the design of a previously unreported hydrochloride salt of an esterified quininib analogue with significantly enhanced solubility and preserved bioactivity. These results suggest that ace-quininib-HCl offers a viable strategy to improve the pharmacokinetic profile of CysLT₁ inhibitors.This work adds value by providing a translational solution to a key limitation in CysLT₁-targeted cancer therapy, supporting further preclinical development of ace-quininib-HCl as a candidate for future clinical application.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"51 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915784","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":"Bicyclic 2-aminopyrimidine derivatives as potent VEGFR-2 inhibitors and apoptosis Inducers: Structure-Guided design, synthesis, anticancer assessment, and in-silico exploration","authors":"Arshma Siddique ,&nbsp;Sadia Shaheen ,&nbsp;Ali Iftikhar ,&nbsp;Amir Faisal ,&nbsp;Hafiz Muzzammel Rehman ,&nbsp;Muhammad Shah ,&nbsp;Ayesha Tahir ,&nbsp;Umer Rashid","doi":"10.1016/j.ejmech.2025.117726","DOIUrl":"10.1016/j.ejmech.2025.117726","url":null,"abstract":"<div><div>Anticancer therapy focuses on VEGFR-2 inhibition to disrupt angiogenesis, a critical process that sustains tumor growth and metastasis. This study outlines the synthesis and biological evaluation of 14 newly designed compounds featuring a bicyclic 2-amino-pyrimidine scaffold. <em>In-vitro</em> VEGFR-2 inhibition showed that compounds <strong>55</strong> and <strong>61</strong> were more potent with IC₅₀ of 0.035 μM and 0.043 μM respectively, compared to the reference drug Sorafenib, and revealed selectivity for VEGFR-2 over EGFR. Consequently, <strong>55</strong> and <strong>61</strong> displayed good antiproliferative activities against the tested cell lines A549 (IC₅₀ = 2.67 and 2.71 μM, respectively) and HCT116 (IC₅₀ = 10.87 and 12.17 μM, respectively). The most active compounds were further assessed for their ability to induce apoptosis and preferential effect on wound closure in A549 cells, investigated <em>via</em> the cell scratch assay. Moreover, these compounds substantially reduced the phosphorylation of ERK and AKT, two downstream targets of VEGFR-2. The CAM assay further verified the antiangiogenic potential of lead compounds, revealing a significant reduction of neovascularization. Molecular docking studies performed for compound <strong>55</strong> showed hydrogen bond interactions with Asp1046, Cys919, and Glu885, similar to FDA-approved sorafenib. Moreover, a 100 ns MD simulation confirmed the complex's stability, while other analyses, such as RMSD, RMSF, PCA, and FEL, were performed to characterize protein conformational variations. Thorough SAR analysis, along with findings of cytotoxic activities and <em>in-vitro</em> inhibition of VEGFR-2, supports the potential of these synthetic compounds as VEGFR-2 inhibitors.</div></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"293 ","pages":"Article 117726"},"PeriodicalIF":6.0,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915783","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}