Pub Date : 2025-01-02DOI: 10.1016/j.ejmech.2024.117234
Katja Stefan, Sachin Puri, Muhammad Rafehi, Ganesh Latambale, Maria Neif, Franziska Tägl, Nike Sophia Arlt, Zeinab Nezafat Yazdi, Éva Bakos, Xiang Chen, Bohan Zhang, Wouroud Ismail Al-Khalil, Hauke Busch, Zhe-Sheng Chen, Csilla Özvegy-Laczka, Vigneshwaran Namasivayam, Kapil Juvale, Sven Marcel Stefan
Despite the significant roles of solute carrier (SLC) and ATP-binding cassette (ABC) transporters in human health and disease, most remain poorly characterized as intrinsic and/or xenobiotic ligands are unknown, rendering them as ‘undruggable’. Polypharmacology, defined as the simultaneous engagement of multiple targets by a single ligand, offers a promising avenue for discovering novel lead compounds addressing these emerging pharmacological challenges – a major focus in contemporary medicinal chemistry. While common structural motifs among phylogenetically diverse proteins have been proposed to underlie polypharmacology through the concept of 'multitarget binding sites', a comprehensive analysis of these functional and structural aspects from a medicinal chemistry perspective has yet to be undertaken. In our study, we synthesized 65 distinct indazole derivatives and evaluated their activity across a broad biological assessment platform encompassing 17 specific and polyspecific SLC and ABC transporters. Notably, ten indazole compounds exhibited cross-target activity against challenging transporter targets associated with neurodegeneration (ABCA1), metabolic reprogramming (MCT4), and cancer multidrug resistance (ABCC10). One lead molecule demonstrated exceptional potency against these assessed targets. Furthermore, molecular blind docking experiments and advanced binding site analyses revealed, for the first time, conserved binding motifs across MCTs, organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs), and ABC transporters, characterized by specific and recurring residues of tyrosine, phenylalanine, serine, and threonine. These findings highlight not only the potential of polypharmacology in drug discovery but also provide insights into the structural underpinnings of ligand binding across membrane transporters.
{"title":"Functional and Structural Polypharmacology of Indazole-based Privileged Ligands to Tackle the Undruggability of Membrane Transporters","authors":"Katja Stefan, Sachin Puri, Muhammad Rafehi, Ganesh Latambale, Maria Neif, Franziska Tägl, Nike Sophia Arlt, Zeinab Nezafat Yazdi, Éva Bakos, Xiang Chen, Bohan Zhang, Wouroud Ismail Al-Khalil, Hauke Busch, Zhe-Sheng Chen, Csilla Özvegy-Laczka, Vigneshwaran Namasivayam, Kapil Juvale, Sven Marcel Stefan","doi":"10.1016/j.ejmech.2024.117234","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117234","url":null,"abstract":"Despite the significant roles of solute carrier (SLC) and ATP-binding cassette (ABC) transporters in human health and disease, most remain poorly characterized as intrinsic and/or xenobiotic ligands are unknown, rendering them as ‘undruggable’. Polypharmacology, defined as the simultaneous engagement of multiple targets by a single ligand, offers a promising avenue for discovering novel lead compounds addressing these emerging pharmacological challenges – a major focus in contemporary medicinal chemistry. While common structural motifs among phylogenetically diverse proteins have been proposed to underlie polypharmacology through the concept of 'multitarget binding sites', a comprehensive analysis of these functional and structural aspects from a medicinal chemistry perspective has yet to be undertaken. In our study, we synthesized 65 distinct indazole derivatives and evaluated their activity across a broad biological assessment platform encompassing 17 specific and polyspecific SLC and ABC transporters. Notably, ten indazole compounds exhibited cross-target activity against challenging transporter targets associated with neurodegeneration (ABCA1), metabolic reprogramming (MCT4), and cancer multidrug resistance (ABCC10). One lead molecule demonstrated exceptional potency against these assessed targets. Furthermore, molecular blind docking experiments and advanced binding site analyses revealed, for the first time, conserved binding motifs across MCTs, organic anion transporting polypeptides (OATPs), organic cation transporters (OCTs), and ABC transporters, characterized by specific and recurring residues of tyrosine, phenylalanine, serine, and threonine. These findings highlight not only the potential of polypharmacology in drug discovery but also provide insights into the structural underpinnings of ligand binding across membrane transporters.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"93 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142911574","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}
The development of potent glycogen synthase kinase-3β (GSK-3β) inhibitor has been increasingly recognized as the candidate treatment against the multifactorial pathogenic mechanism of Alzheimer’s disease (AD). This study prepared various new pyrrolo[2,3-b]pyridine derivatives, evaluated the anti-AD activities and detected the security based on the structure-guided rational design. Our results indicated that many pyrrolo[2,3-b]pyridine derivatives had strong GSK-3β inhibitory activities, particularly compounds 41, 46 and 54, with the half maximal inhibitory concentrations (IC50) of 0.22, 0.26 and 0.24 nM, respectively, and each of them generally possessed GSK-3β selectivity over 24 structurally similar kinases. In addition, further targeting studies at the cellular level revealed that compound 41 increased GSK-3β phosphorylation at Ser9 site dose-dependently for inhibiting GSK-3β activity, therefore inhibiting the hyperphosphorylation of tau protein by decreasing the p-tau-Ser396 abundance. Moreover, 41 up-regulated β-catenin and neurogenesis-related markers (GAP43 and MAP-2), thereby promoting neurite outgrowth of neurons in SH-SY5Y cells. According to the in vitro cells assay, 41 showed the lower cytotoxicity to SH-SY5Y cells with a survival rate of over 70% at the concentration of 100 μM. In vivo efficacy and acute toxicity experiments showed that, 41 effectively ameliorated the dyskinesia in AlCl3-induced zebrafish AD models and exhibited its low‐toxicity nature in C57BL/6 mice. Overall, the pyrrolo[2,3-b]pyridine derivative 41 could serve as a promising GSK-3β inhibitor for treating AD.
{"title":"Synthesis and biological evaluation of novel pyrrolo[2,3-b]pyridine derivatives as potent GSK-3β inhibitors for treating Alzheimer’s disease","authors":"Qing-Qing Xun, Jing Zhang, Yan-Peng Li, Ying Li, Yu-Ying Ma, Zhao-Bin Chen, Le-Ping Ding, Xiao-Long Shi","doi":"10.1016/j.ejmech.2025.117236","DOIUrl":"https://doi.org/10.1016/j.ejmech.2025.117236","url":null,"abstract":"The development of potent glycogen synthase kinase-3β (GSK-3β) inhibitor has been increasingly recognized as the candidate treatment against the multifactorial pathogenic mechanism of Alzheimer’s disease (AD). This study prepared various new pyrrolo[2,3-<em>b</em>]pyridine derivatives, evaluated the anti-AD activities and detected the security based on the structure-guided rational design. Our results indicated that many pyrrolo[2,3-<em>b</em>]pyridine derivatives had strong GSK-3β inhibitory activities, particularly compounds <strong>41</strong>, <strong>46</strong> and <strong>54</strong>, with the half maximal inhibitory concentrations (IC<sub>50</sub>) of 0.22, 0.26 and 0.24 nM, respectively, and each of them generally possessed GSK-3β selectivity over 24 structurally similar kinases. In addition, further targeting studies at the cellular level revealed that compound <strong>41</strong> increased GSK-3β phosphorylation at Ser9 site dose-dependently for inhibiting GSK-3β activity, therefore inhibiting the hyperphosphorylation of tau protein by decreasing the p-tau-Ser396 abundance. Moreover, <strong>41</strong> up-regulated β-catenin and neurogenesis-related markers (GAP43 and MAP-2), thereby promoting neurite outgrowth of neurons in SH-SY5Y cells. According to the <em>in vitro</em> cells assay, <strong>41</strong> showed the lower cytotoxicity to SH-SY5Y cells with a survival rate of over 70% at the concentration of 100 μM. <em>In vivo</em> efficacy and acute toxicity experiments showed that, <strong>41</strong> effectively ameliorated the dyskinesia in AlCl<sub>3</sub>-induced zebrafish AD models and exhibited its low‐toxicity nature in C57BL/6 mice. Overall, the pyrrolo[2,3-<em>b</em>]pyridine derivative <strong>41</strong> could serve as a promising GSK-3β inhibitor for treating AD.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"82 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142917786","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}
Pub Date : 2025-01-01DOI: 10.1016/j.ejmech.2024.117226
Fedor Nikulenkov, Benoit Carbain, Raktim Biswas, Stepan Havel, Jana Prochazkova, Alexandra Sisakova, Magdalena Zacpalova, Melita Chavdarova, Victoria Marini, Vit Vsiansky, Veronika Weisova, Kristina Slavikova, Dhanraj Biradar, Prashant Khirsariya, Marco Vitek, David Sedlak, Petr Bartunek, Lukas Daniel, Jan Brezovsky, Jiri Damborsky, Lumir Krejci
MRE11 nuclease is a central player in signaling and processing DNA damage, and in resolving stalled replication forks. Here, we describe the identification and characterization of new MRE11 inhibitors MU147 and MU1409. Both compounds inhibit MRE11 nuclease more specifically and effectively than the relatively weak state-of-the-art inhibitor mirin. They also abrogate double-strand break repair mechanisms that rely on MRE11 nuclease activity, without impairing ATM activation. Inhibition of MRE11 also impairs nascent strand degradation of stalled replication forks and selectively affects BRCA2-deficient cells. Herein, we illustrate that our newly discovered compounds MU147 and MU1409 can be used as chemical probes to further explore the biological role of MRE11 and support the potential clinical relevance of pharmacological inhibition of this nuclease.
{"title":"Discovery of new inhibitors of nuclease MRE11","authors":"Fedor Nikulenkov, Benoit Carbain, Raktim Biswas, Stepan Havel, Jana Prochazkova, Alexandra Sisakova, Magdalena Zacpalova, Melita Chavdarova, Victoria Marini, Vit Vsiansky, Veronika Weisova, Kristina Slavikova, Dhanraj Biradar, Prashant Khirsariya, Marco Vitek, David Sedlak, Petr Bartunek, Lukas Daniel, Jan Brezovsky, Jiri Damborsky, Lumir Krejci","doi":"10.1016/j.ejmech.2024.117226","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117226","url":null,"abstract":"MRE11 nuclease is a central player in signaling and processing DNA damage, and in resolving stalled replication forks. Here, we describe the identification and characterization of new MRE11 inhibitors <strong>MU147</strong> and <strong>MU1409</strong>. Both compounds inhibit MRE11 nuclease more specifically and effectively than the relatively weak state-of-the-art inhibitor mirin. They also abrogate double-strand break repair mechanisms that rely on MRE11 nuclease activity, without impairing ATM activation. Inhibition of MRE11 also impairs nascent strand degradation of stalled replication forks and selectively affects BRCA2-deficient cells. Herein, we illustrate that our newly discovered compounds <strong>MU147</strong> and <strong>MU1409</strong> can be used as chemical probes to further explore the biological role of MRE11 and support the potential clinical relevance of pharmacological inhibition of this nuclease.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"29 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908660","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}
Pub Date : 2025-01-01DOI: 10.1016/j.ejmech.2024.117199
Yu-Lin Liu, Qian Zhang, Bing-Qian Li, Di Zhang, Rui-Hao Chui, Lin-Lin Zhang, Qi Zhang, Li-Ying Ma
Pyrimidines are aromatic, heterocyclic organic compounds characterized by a six-membered ring that contains four carbon atoms and two nitrogen atoms. They have been reported to exhibit a variety of biological activities such as antifungal, antiviral, and anti-Parkinsonian effects. Recently, there has been an increased focus on their potential anti-Alzheimer's properties. Several pyrimidine-based drugs and their analogues are currently undergoing various phases of clinical trials, indicating pyrimidine as a promising chemical structure for drug development. Notably, modifications to the pyrimidine structure significantly influence their activity against Alzheimer's disease. For instance, the introduction of heteroatoms into the pyrimidine ring or alternations in the length of the linkage region have been shown to enhance therapeutic efficacy. This review provides a comprehensive overview of pyrimidine derivatives as potential therapeutics for Alzheimer's disease, with a focus on structure-activity relationship (SAR) studies, design strategies, and binding mechanisms. These insights could pave the way for the development of more effective anti-Alzheimer's medications.
{"title":"Progress in the study of anti-Alzheimer's disease activity of pyrimidine-containing bioactive molecules","authors":"Yu-Lin Liu, Qian Zhang, Bing-Qian Li, Di Zhang, Rui-Hao Chui, Lin-Lin Zhang, Qi Zhang, Li-Ying Ma","doi":"10.1016/j.ejmech.2024.117199","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117199","url":null,"abstract":"Pyrimidines are aromatic, heterocyclic organic compounds characterized by a six-membered ring that contains four carbon atoms and two nitrogen atoms. They have been reported to exhibit a variety of biological activities such as antifungal, antiviral, and anti-Parkinsonian effects. Recently, there has been an increased focus on their potential anti-Alzheimer's properties. Several pyrimidine-based drugs and their analogues are currently undergoing various phases of clinical trials, indicating pyrimidine as a promising chemical structure for drug development. Notably, modifications to the pyrimidine structure significantly influence their activity against Alzheimer's disease. For instance, the introduction of heteroatoms into the pyrimidine ring or alternations in the length of the linkage region have been shown to enhance therapeutic efficacy. This review provides a comprehensive overview of pyrimidine derivatives as potential therapeutics for Alzheimer's disease, with a focus on structure-activity relationship (SAR) studies, design strategies, and binding mechanisms. These insights could pave the way for the development of more effective anti-Alzheimer's medications.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"3 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908662","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}
Pub Date : 2024-12-31DOI: 10.1016/j.ejmech.2024.117233
Chunyan Yang, Peiyun Yu, Jinxia Chen, Runxin Lu, Li Hai, Zhongzhen Yang, Li Guo, Yong Wu
Chemotherapy, a primary method of cancer treatment, has been limited in clinical application due to its lack of specificity and tumor multidrug resistance, resulting in numerous undesired side effects. Herein, a small molecule conjugate, TDK-HCPT, was designed and synthesized, which could target tumor cells and prolong the retention of chemotherapy agents within tumor cells. Moreover, a similarly designed control system, TDK-Nap, has been developed as well to enable cancer cell imaging. Two design elements are incorporated into TDK-HCPT: the thiamine disulfide (TDS) and the thioketal subunit (tk). TDS can be reduced in the high glutathione (GSH) conditions within cancer cell to form thiazolium salt, and the resulting enhanced positive charge and lipophobicity make the system difficult to be pumped out of tumor cells, thereby effectively “locking” the chemotherapy drug HCPT inside the tumor cells. Additionally, the tk subunit serves as a ROS trigger, within the tumor cells, the “locked” HCPT were then released and activated by the high ROS conditions, optimizing its targeted potential. This allows TDK-HCPT to serve as a redox-liable molecular platform that targets cancer cells selectively which decreases cancer cell migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a cancer cell “lock in” has been shown to prevent tumorigenesis in an animal model.
{"title":"An Oxidation-Reduction-Triggered Thiamine Disulfide-Based Prodrug of 10-Hydroxycamptothecin for Selective Tumor Cell Locking and Therapeutic Delivery","authors":"Chunyan Yang, Peiyun Yu, Jinxia Chen, Runxin Lu, Li Hai, Zhongzhen Yang, Li Guo, Yong Wu","doi":"10.1016/j.ejmech.2024.117233","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117233","url":null,"abstract":"Chemotherapy, a primary method of cancer treatment, has been limited in clinical application due to its lack of specificity and tumor multidrug resistance, resulting in numerous undesired side effects. Herein, a small molecule conjugate, TDK-HCPT, was designed and synthesized, which could target tumor cells and prolong the retention of chemotherapy agents within tumor cells. Moreover, a similarly designed control system, TDK-Nap, has been developed as well to enable cancer cell imaging. Two design elements are incorporated into TDK-HCPT: the thiamine disulfide (TDS) and the thioketal subunit (tk). TDS can be reduced in the high glutathione (GSH) conditions within cancer cell to form thiazolium salt, and the resulting enhanced positive charge and lipophobicity make the system difficult to be pumped out of tumor cells, thereby effectively “locking” the chemotherapy drug HCPT inside the tumor cells. Additionally, the tk subunit serves as a ROS trigger, within the tumor cells, the “locked” HCPT were then released and activated by the high ROS conditions, optimizing its targeted potential. This allows TDK-HCPT to serve as a redox-liable molecular platform that targets cancer cells selectively which decreases cancer cell migration, retards tumor growth, and lowers tumorigenesis rates as evidenced by a combination of in vitro and in vivo studies. To the best of our knowledge, this is the first time a cancer cell “lock in” has been shown to prevent tumorigenesis in an animal model.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"69 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905535","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}
Pub Date : 2024-12-31DOI: 10.1016/j.ejmech.2024.117215
Yuqi Tang, Xinhua Pan, Fan-Fan Shang, Yang Li, Chaojun Zhang, Hexin Ma, Ao Zhang, Xu Wang, Chunyong Ding, Wantao Chen
Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors, but clinical drug treatments are limited. The natural product diphyllin was identified as a lead compound suppressing the proliferation of HNSCC cells through phenotypic screening of natural product library. However, further developments of diphyllin as an anti-HNSCC agent were restricted by the weak bioactivity and poor metabolic stability. Herein, we designed and synthesized two series of novel diphyllin derivatives that were achieved by introducing various pyranose rings or hydrophilic groups to block the easily metabolic C-4 site with the aim to improve antitumor activity and drug-like properties. Among these compounds, compound A3 showed the most potent inhibitory effects against HNSCC cells with IC50 values ranging from 4.37 to 77.81 nM and much less potent cytotoxicity against normal cells (IC50 > 10 μM). Mechanistically, it effectively inhibited cell proliferation and migration and induced the cell cycle arrest and apoptosis in a concentration-dependent manner. Besides, A3 possessed greatly improved pharmacokinetic properties including over 10-fold higher plasma exposure (AUC0-t: 541 vs 43.6 h*ng/mL) and better oral bioavailability (F: 20.85% vs 2.70%), lower systemic plasma clearance (CL:1897 vs 24523 mL/h/kg), as well as longer half-life (T1/2: 0.530 vs 0.108 h) when compared to diphyllin. In a tumor cell xenograft model, A3 significantly suppressed the CAL27 tumor growth with a TGI of 42.2% without obvious safety concern, which is superior to that of diphyllin (TGI = 23.3%), suggesting great potential for treatment of HNSCC.
头颈部鳞状细胞癌（HNSCC）是最常见的恶性肿瘤之一，但临床药物治疗有限。通过天然产物文库的表型筛选，鉴定天然产物二黄芪多糖为抑制HNSCC细胞增殖的先导化合物。然而，由于生物活性较弱和代谢稳定性较差，制约了二苯丁醇作为抗鳞状细胞癌药物的进一步发展。在此，我们设计并合成了两个系列的新的二黄芪衍生物，通过引入各种吡喃糖环或亲水性基团来阻断易代谢的C-4位点，以提高抗肿瘤活性和药物样性质。其中，化合物A3对HNSCC细胞的抑制作用最强，IC50值为4.37 ~ 77.81 nM，对正常细胞的细胞毒性较弱(IC50 >；10μM)。机制上，它能有效抑制细胞增殖和迁移，诱导细胞周期阻滞和凋亡，并呈浓度依赖性。此外，A3具有显著改善的药代动力学特性，包括10倍以上的血浆暴露（AUC0-t: 541 vs 43.6 h*ng/mL），更好的口服生物利用度（F: 20.85% vs 2.70%），更低的全身血浆清除率（CL:1897 vs 24523 mL/h/kg），以及更长的半衰期（T1/2: 0.530 vs 0.108 h）。在肿瘤细胞异种移植模型中，A3能显著抑制CAL27肿瘤生长，TGI为42.2%，且无明显安全性问题，优于二苯三酚（TGI = 23.3%），提示其治疗HNSCC的潜力巨大。
{"title":"Synthesis and Pharmacological Evaluation of Natural Product Diphyllin Derivatives against Head and Neck Squamous Cell Carcinoma","authors":"Yuqi Tang, Xinhua Pan, Fan-Fan Shang, Yang Li, Chaojun Zhang, Hexin Ma, Ao Zhang, Xu Wang, Chunyong Ding, Wantao Chen","doi":"10.1016/j.ejmech.2024.117215","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117215","url":null,"abstract":"Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignant tumors, but clinical drug treatments are limited. The natural product diphyllin was identified as a lead compound suppressing the proliferation of HNSCC cells through phenotypic screening of natural product library. However, further developments of diphyllin as an anti-HNSCC agent were restricted by the weak bioactivity and poor metabolic stability. Herein, we designed and synthesized two series of novel diphyllin derivatives that were achieved by introducing various pyranose rings or hydrophilic groups to block the easily metabolic C-4 site with the aim to improve antitumor activity and drug-like properties. Among these compounds, compound <strong>A3</strong> showed the most potent inhibitory effects against HNSCC cells with IC<sub>50</sub> values ranging from 4.37 to 77.81 nM and much less potent cytotoxicity against normal cells (IC<sub>50</sub> > 10 μM). Mechanistically, it effectively inhibited cell proliferation and migration and induced the cell cycle arrest and apoptosis in a concentration-dependent manner. Besides, <strong>A3</strong> possessed greatly improved pharmacokinetic properties including over 10-fold higher plasma exposure (AUC<sub>0-t</sub>: 541 vs 43.6 h*ng/mL) and better oral bioavailability (<em>F</em>: 20.85% vs 2.70%), lower systemic plasma clearance (CL:1897 vs 24523 mL/h/kg), as well as longer half-life (T<sub>1/2</sub>: 0.530 vs 0.108 h) when compared to diphyllin. In a tumor cell xenograft model, <strong>A3</strong> significantly suppressed the CAL27 tumor growth with a TGI of 42.2% without obvious safety concern, which is superior to that of diphyllin (TGI = 23.3%), suggesting great potential for treatment of HNSCC.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"542 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908661","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}
Pub Date : 2024-12-30DOI: 10.1016/j.ejmech.2024.117230
Bo Li, Yibing Chen, Siyuan Wang, Bo Jin, Jinyu Yang, Qun Niu, Guizhou Hao, Ning Wang, Wenchao Zhang, Linxiang Zhao, Jiachen Wen, Dan Liu
Concurrent inhibition of HDAC and BRD4, two well-established epigenetic targets for anti-tumor therapy, demonstrates the potential to enhance anti-tumor effects synergistically. The present study involves the development of a series of novel HDAC3/BRD4 dual inhibitors, followed by evaluation of their antitumor efficacy against several tumor models. Guided by scaffold hopping strategy, key pharmacophore of BRD4 inhibitor I-BET-151 was incorporated into an in-house developed HDAC3-selective inhibitor 17h. A set of twenty-two compounds was synthesized and characterized. Most of these compounds demonstrated significant potency in inhibiting HDAC3 and exhibited selectivity over its closely-related isoform, HDAC1. The potent BRD4 inhibition of these compounds has been further confirmed through HTFR and thermal shift assays. Of which, compounds 26b and 26n demonstrated potent dual inhibition against HDAC3 and BRD4. Compound 26n demonstrated potent antiproliferative effects against a panel of cancer cells, with human pancreatic cancer cell line Capan-1 displaying the highest susceptibility. Compound 26n exhibited significant upregulation of Ac-H3 and downregulation of c-Myc at concentrations as low as 1 μM, suggesting proper target engagement in Capan-1 cells. Compound 26n demonstrated significant antitumor efficacy in Capan-1 CDX model, with a tumor growth inhibition rate of 71% under the given dosing regimen. In summary, this research highlights the promising therapeutic potential of benzodihydroindazole derivatives as HDAC3/BRD4 dual inhibitors, warranting further investigation.
{"title":"Discovery of 4,5-dihydro-benzo[g]indazole-based hydroxamic acids as HDAC3/BRD4 dual inhibitors and anti-tumor agents","authors":"Bo Li, Yibing Chen, Siyuan Wang, Bo Jin, Jinyu Yang, Qun Niu, Guizhou Hao, Ning Wang, Wenchao Zhang, Linxiang Zhao, Jiachen Wen, Dan Liu","doi":"10.1016/j.ejmech.2024.117230","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117230","url":null,"abstract":"Concurrent inhibition of HDAC and BRD4, two well-established epigenetic targets for anti-tumor therapy, demonstrates the potential to enhance anti-tumor effects synergistically. The present study involves the development of a series of novel HDAC3/BRD4 dual inhibitors, followed by evaluation of their antitumor efficacy against several tumor models. Guided by scaffold hopping strategy, key pharmacophore of BRD4 inhibitor I-BET-151 was incorporated into an in-house developed HDAC3-selective inhibitor <strong>17h</strong>. A set of twenty-two compounds was synthesized and characterized. Most of these compounds demonstrated significant potency in inhibiting HDAC3 and exhibited selectivity over its closely-related isoform, HDAC1. The potent BRD4 inhibition of these compounds has been further confirmed through HTFR and thermal shift assays. Of which, compounds <strong>26b</strong> and <strong>26n</strong> demonstrated potent dual inhibition against HDAC3 and BRD4. Compound <strong>26n</strong> demonstrated potent antiproliferative effects against a panel of cancer cells, with human pancreatic cancer cell line Capan-1 displaying the highest susceptibility. Compound <strong>26n</strong> exhibited significant upregulation of Ac-H3 and downregulation of c-Myc at concentrations as low as 1 μM, suggesting proper target engagement in Capan-1 cells. Compound <strong>26n</strong> demonstrated significant antitumor efficacy in Capan-1 CDX model, with a tumor growth inhibition rate of 71% under the given dosing regimen. In summary, this research highlights the promising therapeutic potential of benzodihydroindazole derivatives as HDAC3/BRD4 dual inhibitors, warranting further investigation.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"152 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142905538","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}
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease for which few drugs are available in clinical practice. Here, we identified novel capsaicin analogs by combining in-house chemical library screening and further structural optimization. (E)-1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one (Compound 14) was found to be the most potent in inhibiting TGF-β-induced collagen accumulation, proliferation and migration in fibroblast cells. Furthermore, compound 14 (IC50 = 0.51 ± 0.06 μM) showed over 100-fold increasing antifibrotic activity compared to capsaicin (IC50 = 53.71 ± 4.78 μM). Notably, compound 14 could target TRPV1, thereby affecting the expression of the fibrosis markers Collagen Ⅰ and α-SMA by inhibiting the TGF-β/Smads and MAPK pathways to exert antifibrotic activity in vitro. Compound 14 significantly inhibited collagen deposition in lung tissues, ameliorated alveolar structures, and increased survival rates in mice with bleomycin-induced pulmonary fibrosis. In addition, compound 14 possessed lower cytotoxicity (compared to nitedanib) and no toxicity in mice. Overall, compound 14 promise as a potential drug candidate for the treatment of IPF.
{"title":"Discovery of novel capsaicin analogs as TRPV1 inhibitors for the treatment of idiopathic pulmonary fibrosis","authors":"Yu Cao, Yongju Wen, Zongyuan Zhou, Ruiying Xi, Wen Shuai, Jichao Zhang, Apichart Suksamrarn, Guolin Zhang, Xiao-xia Lu, Fei Wang","doi":"10.1016/j.ejmech.2024.117229","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117229","url":null,"abstract":"Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease for which few drugs are available in clinical practice. Here, we identified novel capsaicin analogs by combining in-house chemical library screening and further structural optimization. (E)-1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one (Compound <strong>14)</strong> was found to be the most potent in inhibiting TGF-β-induced collagen accumulation, proliferation and migration in fibroblast cells. Furthermore, compound <strong>14</strong> (IC<sub>50</sub> = 0.51 ± 0.06 μM) showed over 100-fold increasing antifibrotic activity compared to capsaicin (IC<sub>50</sub> = 53.71 ± 4.78 μM). Notably, compound <strong>14</strong> could target TRPV1, thereby affecting the expression of the fibrosis markers Collagen Ⅰ and α-SMA by inhibiting the TGF-β/Smads and MAPK pathways to exert antifibrotic activity <em>in vitro</em>. Compound <strong>14</strong> significantly inhibited collagen deposition in lung tissues, ameliorated alveolar structures, and increased survival rates in mice with bleomycin-induced pulmonary fibrosis. In addition, compound <strong>14</strong> possessed lower cytotoxicity (compared to nitedanib) and no toxicity in mice. Overall, compound <strong>14</strong> promise as a potential drug candidate for the treatment of IPF.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"9 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901870","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}
Pub Date : 2024-12-28DOI: 10.1016/j.ejmech.2024.117228
Siyuan Ge, Rongchao Jian, Qiwei Xuan, Yingxiang Zhu, Xiaofei Ren, Wenjiao Li, Xiaole Chen, Ruikang Huang, Chi-Sing Lee, Suet C. Leung, Nicoletta Basilico, Silvia Parapini, Donatella Taramelli, Nattapon Pinthong, Svetlana V. Antonyuk, Paul M. O’Neill, Zhaojun Sheng, W. David Hong
Aryl quinolone derivatives can target the cytochrome bc1 complex of Plasmodium falciparum, exhibiting excellent in vitro and in vivo antimalarial activity. However, their clinical development has been hindered due to their poor aqueous solubility profiles. In this study, a series of bioisosteres containing saturated heterocycles fused to a 4-pyridone ring were designed to replace the inherently poorly soluble quinolone core in antimalarial quinolones with the aim to reduce π-π stacking interactions in the crystal packing solid state, and a synthetic route was developed to prepare these alternative core derivatives. One such novel derivate, F14, exhibited significant enhancements in both aqueous solubility (20 μM) and lipophilicity (LogD 2.7), whilst retaining nanomolar antimalarial activity against the W2 strain of P. falciparum (IC50 = 235 nM). The pharmacokinetic studies reported, provide preliminary insights into the in vivo distribution and elimination of F14, while findings from single crystal X-ray diffraction experiment rationalized the enhanced solubility. Protein X-ray crystallography and in silico docking simulations provide insight into the potential mode of action within the cytochrome bc1 complex. These findings demonstrated the viability of this bioisostere replacement strategy and provided support for further exploration of in vivo efficacy in preclinical animal models and valuable insights for new drug design strategies in the fight against malaria.
{"title":"Novel antimalarial 3-substituted quinolones isosteres with improved pharmacokinetic properties","authors":"Siyuan Ge, Rongchao Jian, Qiwei Xuan, Yingxiang Zhu, Xiaofei Ren, Wenjiao Li, Xiaole Chen, Ruikang Huang, Chi-Sing Lee, Suet C. Leung, Nicoletta Basilico, Silvia Parapini, Donatella Taramelli, Nattapon Pinthong, Svetlana V. Antonyuk, Paul M. O’Neill, Zhaojun Sheng, W. David Hong","doi":"10.1016/j.ejmech.2024.117228","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117228","url":null,"abstract":"Aryl quinolone derivatives can target the cytochrome <em>bc</em><sub><em>1</em></sub> complex of <em>Plasmodium falciparum</em>, exhibiting excellent <em>in vitro</em> and <em>in vivo</em> antimalarial activity. However, their clinical development has been hindered due to their poor aqueous solubility profiles. In this study, a series of bioisosteres containing saturated heterocycles fused to a 4-pyridone ring were designed to replace the inherently poorly soluble quinolone core in antimalarial quinolones with the aim to reduce π-π stacking interactions in the crystal packing solid state, and a synthetic route was developed to prepare these alternative core derivatives. One such novel derivate, <strong>F14</strong>, exhibited significant enhancements in both aqueous solubility (20 μM) and lipophilicity (Log<em>D</em> 2.7), whilst retaining nanomolar antimalarial activity against the W2 strain of <em>P. falciparum</em> (IC<sub>50</sub> = 235 nM). The pharmacokinetic studies reported, provide preliminary insights into the <em>in vivo</em> distribution and elimination of <strong>F14</strong>, while findings from single crystal X-ray diffraction experiment rationalized the enhanced solubility. Protein X-ray crystallography and <em>in silico</em> docking simulations provide insight into the potential mode of action within the cytochrome <em>bc</em><sub><em>1</em></sub> complex. These findings demonstrated the viability of this bioisostere replacement strategy and provided support for further exploration of <em>in vivo</em> efficacy in preclinical animal models and valuable insights for new drug design strategies in the fight against malaria.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"151 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888979","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}
Pub Date : 2024-12-28DOI: 10.1016/j.ejmech.2024.117203
Jitendra Chaudhary, Gurdeep Kaur, Iqubal Singh
This study presents a comprehensive exploration of the synthesis of novel compounds targeting Chagas Disease (CD) caused by Trypanosoma cruzi. It is a global health threat with over 6-7 million infections worldwide. Addressing challenges in current treatments, the investigation explores diverse compound classes, including thiazoles, thiazolidinone, imidazole, pyrazole, 1,6-diphenyl-1H-pyrazolo[3,4-b] pyridine, pyrrole, naphthoquinone, neolignan, benzeneacyl hydrazones, and chalcones-based compounds. Highlighting compounds with superior trypanocidal activity compared to standard drugs. The study elucidates structure-activity relationships, emphasizing the impact of substituents, fluorine presence, and substitution patterns. Noteworthy findings include neolignan derivatives demonstrating efficacy against intracellular amastigotes and free-moving trypomastigotes, with unsaturated side chains. Benzeneacylhydrazones and chalcones, as novel classes, showed varied efficacy, with certain compounds surpassing benznidazole. A novel series of triketone compounds exhibited strong anti-parasitic activity, outperforming standard drugs. Docking study revealed that the halogen and methoxy substituted phenyl ring, thiazole, thiazolidine-4-one, quinoline, isoindoline-1,3-dione, pyrrole heterocyclic motifs can play the key role in the designing of effective inhibitors of T. cruzi. Mutually, these insights placed the foundation for the development of innovative and effective treatments for CD, addressing the urgent need for improved therapeutic options.
{"title":"Synthesis Strategies and Anti-parasitic Evaluation of Novel Compounds for Chagas Disease: Advancing Drug Discovery through Structure-Activity Relationships","authors":"Jitendra Chaudhary, Gurdeep Kaur, Iqubal Singh","doi":"10.1016/j.ejmech.2024.117203","DOIUrl":"https://doi.org/10.1016/j.ejmech.2024.117203","url":null,"abstract":"This study presents a comprehensive exploration of the synthesis of novel compounds targeting Chagas Disease (CD) caused by <em>Trypanosoma cruzi</em>. It is a global health threat with over 6-7 million infections worldwide. Addressing challenges in current treatments, the investigation explores diverse compound classes, including thiazoles, thiazolidinone, imidazole, pyrazole, 1,6-diphenyl-1<em>H</em>-pyrazolo[3,4-<em>b</em>] pyridine, pyrrole, naphthoquinone, neolignan, benzeneacyl hydrazones, and chalcones-based compounds. Highlighting compounds with superior trypanocidal activity compared to standard drugs. The study elucidates structure-activity relationships, emphasizing the impact of substituents, fluorine presence, and substitution patterns. Noteworthy findings include neolignan derivatives demonstrating efficacy against intracellular amastigotes and free-moving trypomastigotes, with unsaturated side chains. Benzeneacylhydrazones and chalcones, as novel classes, showed varied efficacy, with certain compounds surpassing benznidazole. A novel series of triketone compounds exhibited strong anti-<em>para</em>sitic activity, outperforming standard drugs. Docking study revealed that the halogen and methoxy substituted phenyl ring, thiazole, thiazolidine-4-one, quinoline, isoindoline-1,3-dione, pyrrole heterocyclic motifs can play the key role in the designing of effective inhibitors of <em>T. cruzi</em>. Mutually, these insights placed the foundation for the development of innovative and effective treatments for CD, addressing the urgent need for improved therapeutic options.","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"20 1","pages":""},"PeriodicalIF":6.7,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888939","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}
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