Archiv der Pharmazie最新文献_第10页

Peperomia pellucida (L.) Kunth suppresses glycation-induced inflammatory response in human retinal pigment epithelial cell line ARPE-19 via JAK-STAT3 signaling Peperomia pellucida (L.) Kunth 通过 JAK-STAT3 信号传导抑制糖化诱导的人视网膜色素上皮细胞 ARPE-19 株的炎症反应。

IF 4.3 3区医学

Archiv der Pharmazie Pub Date : 2024-07-22 DOI: 10.1002/ardp.202400299

Keat Lam Ho, Phaik Har Yong, Siew Huah Lim, Zhi Xiang Ng

{"title":"Peperomia pellucida (L.) Kunth suppresses glycation-induced inflammatory response in human retinal pigment epithelial cell line ARPE-19 via JAK-STAT3 signaling","authors":"Keat Lam Ho, Phaik Har Yong, Siew Huah Lim, Zhi Xiang Ng","doi":"10.1002/ardp.202400299","DOIUrl":"10.1002/ardp.202400299","url":null,"abstract":"The formation of advanced glycation end product (AGE) is a risk factor for diabetic retinopathy. Since the current treatment for diabetic retinopathy is accompanied by side effects, preliminary findings have suggested Peperomia pellucida (L.) Kunth as a potential alternative therapeutic option for diabetic retinopathy. This study aimed to elucidate the anti-inflammatory mechanism of P. pellucida in the AGE-stimulated human retinal pigment epithelial cell line ARPE-19. Phytochemical analysis revealed phenylpronanoids, terpenes, and fatty acids in P. pellucida. Through in vitro cell viability assay, the P. pellucida methanolic extract (IC50 = 8.70 mg/mL) and ethyl acetate fraction (IC50 = 7.34 mg/mL) were considered as non toxic for ARPE-19. AGE induced an inflammatory response in ARPE-19 by upregulating the gene (2.4–5.8-fold) and protein (1.4–2.3-fold) expression of signal transducer and activator of transcription 3 (STAT3), interleukin-8 (IL-8), monocyte chemoattractant protein-1, matrix metalloproteinase 2, and vascular endothelial growth factor. At 1.5 mg/mL, P. pellucida methanolic extract suppressed IL-8 expression (p < 0.05), implying its anti-inflammatory action at the early inflammatory stage through the Janus kinase (JAK)-STAT3 pathway. The methanolic extract also restored the ARPE-19 viability under AGE-induced inflammatory stress. The downregulation of inflammatory biomarkers along the JAK-STAT3 pathway suggested P. pellucida as a promising anti-inflammatory source for diabetic retinopathy.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141746926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel 1,2,4-triazole derivatives containing the naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, and biological evaluation 含有萘分子的新型 1,2,4- 三唑衍生物作为选择性丁酰胆碱酯酶抑制剂：设计、合成和生物学评价。

IF 4.3 3区医学

Archiv der Pharmazie Pub Date : 2024-07-21 DOI: 10.1002/ardp.202400406

Ebru Koçak Aslan, Aysima Sezer, Tuba Tüylü Küçükkılınç, Erhan Palaska

{"title":"Novel 1,2,4-triazole derivatives containing the naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, and biological evaluation","authors":"Ebru Koçak Aslan, Aysima Sezer, Tuba Tüylü Küçükkılınç, Erhan Palaska","doi":"10.1002/ardp.202400406","DOIUrl":"10.1002/ardp.202400406","url":null,"abstract":"Butyrylcholinesterase (BChE) is considered a promising therapeutic target for treating Alzheimer's disease due to the increase in the levels and activity of BChE in the late stage of the disease. In this study, a series of novel 1,2,4-triazole derivatives bearing the naphthalene moiety linked to the benzothiazole, thiazole, and phenyl scaffolds via amid chain were designed and synthesized as potential and selective BChE inhibitors. The results of the inhibitory activity studies revealed that most of these compounds exhibited significant inhibitor potency on BChE. Compounds 35a (0.025 ± 0.01 μM) and 37a (0.035 ± 0.01 μM) displayed the most potent inhibitory activity, with excellent selectivity against BChE over acetylcholinesterase (SIBChE, 23,686 and 16,936, respectively) among the target compounds. The kinetics studies revealed that these compounds behaved with noncompetitive BChE inhibitors. Molecular docking studies indicated that 35a and 37a fit well into the active side of BChE. In addition, 35a and 37a also had the lowest cytotoxicity for human neuroblastoma cells (SH-SY5Y), potential antioxidant capacity, moderate inhibition potency on amyloid-β1-42 aggregation, and significant neuroprotective effect against SH-SY5Y cell injury induced by H2O2 and amyloid-β1-42. All results suggest that these compounds might be considered as promising new lead compounds in the drug discovery process for the treatment of late-stage Alzheimer's disease.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 11","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400406","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141732875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A critical review of therapeutic interventions in sickle cell disease: Progress and challenges 镰状细胞病治疗干预的重要回顾：进展与挑战。

IF 4.3 3区医学

Archiv der Pharmazie Pub Date : 2024-07-19 DOI: 10.1002/ardp.202400381

Chandu Ala, Renuka Parshuram Joshi, Pragya Gupta, Sangam Giri Goswami, Sivaprakash Ramalingam, Chandra Sekhar Kondapalli Venkata Gowri, Murugesan Sankaranarayanan

{"title":"A critical review of therapeutic interventions in sickle cell disease: Progress and challenges","authors":"Chandu Ala, Renuka Parshuram Joshi, Pragya Gupta, Sangam Giri Goswami, Sivaprakash Ramalingam, Chandra Sekhar Kondapalli Venkata Gowri, Murugesan Sankaranarayanan","doi":"10.1002/ardp.202400381","DOIUrl":"10.1002/ardp.202400381","url":null,"abstract":"Sickle cell disease (SCD) is an autosomal recessive genetic disorder that occurs due to the point mutation in the β-globin gene, which results in the formation of sickle hemoglobin (HbS) in the red blood cells (RBCs). When HbS is exposed to an oxygen-depleted environment, it polymerizes, resulting in hemolysis, vaso-occlusion pain, and impaired blood flow. Still, there is no affordable cure for this inherited disease. Approved medications held promise but were met with challenges due to limited patient tolerance and undesired side effects, thereby inhibiting their ability to enhance the quality of life across various individuals with SCD. Progress has been made in understanding the pathophysiology of SCD during the past few decades, leading to the discovery of novel targets and therapies. However, there is a compelling need for research to discover medications with improved efficacy and reduced side effects. Also, more clinical investigations on various drug combinations with different mechanisms of action are needed. This review comprehensively presents therapeutic approaches for SCD, including those currently available or under investigation. It covers fundamental aspects of the disease, such as epidemiology and pathophysiology, and provides detailed discussions on various disease-modifying agents. Additionally, expert insights are offered on the future development of pharmacotherapy for SCD.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 11","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400381","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural characterization and bioactivity profiling of the fungal peptaibiotic tolypin reveal protective effects against influenza viruses 真菌eptaibiotic tolypin 的结构特征和生物活性分析揭示了其对流感病毒的保护作用。

IF 4.3 3区医学

Archiv der Pharmazie Pub Date : 2024-07-19 DOI: 10.1002/ardp.202400384

Johanna Eichberg, Markus Oberpaul, Christoph Hartwig, Andrea Helga Geißler, Carsten Culmsee, Andreas Vilcinskas, Eva Böttcher-Friebertshäuser, Hans Brückner, Thomas Degenkolb, Kornelia Hardes

{"title":"Structural characterization and bioactivity profiling of the fungal peptaibiotic tolypin reveal protective effects against influenza viruses","authors":"Johanna Eichberg, Markus Oberpaul, Christoph Hartwig, Andrea Helga Geißler, Carsten Culmsee, Andreas Vilcinskas, Eva Böttcher-Friebertshäuser, Hans Brückner, Thomas Degenkolb, Kornelia Hardes","doi":"10.1002/ardp.202400384","DOIUrl":"10.1002/ardp.202400384","url":null,"abstract":"In a bioprospection for new antivirals, we tested nonribosomally biosynthesized polypeptide antibiotics in MDCK II cells for their actions on influenza A and B viruses (IAV/IBV). Only tolypin, a mixture of closely related 16-residue peptaibiotics from the fungus Tolypocladium inflatum IE 1897, showed promising activity. It was selected for further investigation and structural characterization by ultrahigh performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HR-MS/MS) and ultrahigh performance liquid chromatography coupled to in-source collision-induced dissociation tandem mass spectrometry (UHPLC-isCID-HR-MS/MS), revealing 12 partially co-eluting individual peptides that were fully sequenced. Since tolypin-related efrapeptins are potent inhibitors of F1/Fo-ATPase, we screened tolypin for its toxicity against MDCK II cells and larvae of the greater wax moth Galleria mellonella. We found that a nontoxic concentration of tolypin (1 µg/mL) reduced the titer of two IBV strains by 4–5 log values, and that of an H3N2 strain by 1–2 log values, but the H1N1pdm strain was not affected. The higher concentrations of tolypin were cytostatic to MDCK II cells, shifted their metabolism from oxidative phosphorylation to glycolysis, and induced paralysis in G. mellonella, supporting the inhibition of F1/Fo-ATPase as the mode of action. Our results lay the foundations for future work to investigate the interplay between viral replication and cellular energy metabolism, as well as the development of drugs that target host factors.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400384","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New labdane diterpenoids from Alpinia galanga: A new type of GLP-1 secretagogues targeting the PKA-CREB and PI3K-Akt signaling axes 从高良姜中提取的新拉布烷二萜：针对 PKA-CREB 和 PI3K-Akt 信号轴的新型 GLP-1 促泌剂。

IF 4.3 3区医学

Archiv der Pharmazie Pub Date : 2024-07-19 DOI: 10.1002/ardp.202400383

Pei Liu, Pianchou Gongpan, Sheng-Li Wu, Xin-Yu Li, Xiao-Yan Huang, Yun-Bao Ma, Chang-An Geng

{"title":"New labdane diterpenoids from Alpinia galanga: A new type of GLP-1 secretagogues targeting the PKA-CREB and PI3K-Akt signaling axes","authors":"Pei Liu, Pianchou Gongpan, Sheng-Li Wu, Xin-Yu Li, Xiao-Yan Huang, Yun-Bao Ma, Chang-An Geng","doi":"10.1002/ardp.202400383","DOIUrl":"10.1002/ardp.202400383","url":null,"abstract":"Glucagon-like peptide-1 (GLP-1) secretagogues are fascinating pharmacotherapies to overcome the defects of GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors in treating diabetes and obesity. To discover new GLP-1 secretagogues from natural sources, alpigalangols A-Q (1–17), 17 new labdane diterpenoids including four unusual nor-labdane and N-containing ones, were isolated from the fruits of Alpinia galanga. Most of the isolates showed GLP-1 promotive effects in NCl-H716 cells, of which compounds 3, 4, 12, and 14–17 were revealed with high promoting rates of 246.0%–413.8% at 50 µM. A mechanistic study manifested that the most effective compound 12 upregulated the mRNA expression of Gcg and Pcsk1, and the protein phosphorylation of PKA, CREB, and GSK3β, but was inactive on GPBAR and GPR119 receptors. Network pharmacology analysis indicated that the PI3K-Akt pathway was involved in the GLP-1 stimulation of 12, which was highly associated with AKT1, CASP3, PPARG, and ICAM1 proteins. This study suggests that A. galanga is rich in diverse labdane diterpenoids with GLP-1 promoting effects, representing a new type of antidiabetic candidates from natural sources.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141730836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Caffeic acid and its derivative caffeic acid phenethyl ester as potential therapeutic compounds for cardiovascular diseases: A systematic review 咖啡酸及其衍生物咖啡酸苯乙酯作为治疗心血管疾病的潜在化合物：系统综述。

IF 4.3 3区医学

Archiv der Pharmazie Pub Date : 2024-07-15 DOI: 10.1002/ardp.202400240

Arya Nasimi Shad, Iman Akhlaghipour, Atefeh Babazadeh Baghan, Vahid Reza Askari PharmD, PhD, Vafa Baradaran Rahimi PharmD, PhD

{"title":"Caffeic acid and its derivative caffeic acid phenethyl ester as potential therapeutic compounds for cardiovascular diseases: A systematic review","authors":"Arya Nasimi Shad, Iman Akhlaghipour, Atefeh Babazadeh Baghan, Vahid Reza Askari PharmD, PhD, Vafa Baradaran Rahimi PharmD, PhD","doi":"10.1002/ardp.202400240","DOIUrl":"10.1002/ardp.202400240","url":null,"abstract":"Cardiovascular diseases (CVDs) contribute to major public health issues. Some studies have found that caffeic acid (CA) and caffeic acid phenethyl ester (CAPE) may effectively prevent or treat CVDs. However, there is a major need to sum up our current understanding of the possible beneficial or detrimental effects of CA and CAPE on CVDs and related mechanisms. Therefore, this study aimed to summarize the data on this topic. A methodical search was carried out on key databases, including Pubmed, Google Scholar, Scopus, and Web of Science, from the beginning to June 2024. Studies were then assessed for eligibility based on inclusion and exclusion criteria. Treatment with CA and CAPE significantly and positively affected cardiovascular health in various aspects, including atherosclerotic diseases, myocardial infarction, hypertension, cardiac arrhythmias, and hypercoagulation state. Several mechanisms were proposed to mediate these effects, including transcription factors and signaling pathways associated with antioxidant, cytostatic, and anti-inflammatory processes. CA and CAPE were found to have several beneficial effects via multiple mechanisms during the prevention and treatment of various CVDs. However, these promising effects were only reported through in vitro and animal studies, which reinforces the need for further evaluation of these effects via human clinical investigations.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis, and biological evaluation of naphthalene imidazo[1,2-b]pyridazine hybrid derivatives as VEGFR selective inhibitors 作为血管内皮生长因子受体选择性抑制剂的萘咪唑并[1,2-b]哒嗪混合衍生物的设计、合成和生物学评价。

IF 4.3 3区医学

Archiv der Pharmazie Pub Date : 2024-07-15 DOI: 10.1002/ardp.202400411

Shuang Wang, LinLing Gan, Lei Han, Ping Deng, Yihao Li, Dongxiao He, Haoze Chi, Liwei Zhu, Yuehui Li, Rui Long, Zongjie Gan

{"title":"Design, synthesis, and biological evaluation of naphthalene imidazo[1,2-b]pyridazine hybrid derivatives as VEGFR selective inhibitors","authors":"Shuang Wang, LinLing Gan, Lei Han, Ping Deng, Yihao Li, Dongxiao He, Haoze Chi, Liwei Zhu, Yuehui Li, Rui Long, Zongjie Gan","doi":"10.1002/ardp.202400411","DOIUrl":"10.1002/ardp.202400411","url":null,"abstract":"The vascular endothelial growth factor receptor (VEGFR) is a receptor tyrosine kinase that is regarded as an emerging target for abnormal angiogenesis diseases. In this study, novel naphthalene imidazo[1,2-b]pyridazine hybrids as VEGFR selective inhibitors were designed and synthesized using a scaffold hopping strategy based on ponatinib, a multitarget kinase inhibitor. Among the evaluated compounds, derivative 9k (WS-011) demonstrated the most potent inhibitory potency against VEGFR-2 (IC50 = 8.4 nM) and displayed superior VEGFR selectivity over a panel of 70 kinases compared with ponatinib. Furthermore, 9k possessed good cytotoxic effects on various cancer cell lines, especially the colon cancer HT-29 cells, with an acceptable oral bioavailability. Moreover, 9k significantly inhibited the migration and invasion of human umbilical vein endothelial cells (HUVEC) cells and induced apoptosis through the upregulation of apoptotic proteins in HT-29 cells. 9k also effectively suppressed the activation of VEGFR-2 signaling pathways, which in turn inhibited the growth of HT-29 cells and the tube formation of HUVECs in vitro. All of the findings revealed that 9k could be considered a promising antiangiogenesis lead that merits further investigation.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141618727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Soft drug inhibitors for the epigenetic targets lysine-specific demethylase 1 and histone deacetylases 表观遗传靶标赖氨酸特异性去甲基化酶 1 和组蛋白去乙酰化酶的软性药物抑制剂。

IF 4.3 3区医学

Archiv der Pharmazie Pub Date : 2024-07-14 DOI: 10.1002/ardp.202400450

Johannes Seitz, Marina Auth, Tony Prinz, Mirjam Hau, Pavlos Tzortzoglou, Johannes Schulz-Fincke, Karin Schmidtkunz, Adina A. Baniahmad, Dominica Willmann, Eric Metzger, Lutz Hein, Sebastian Preissl, Roland Schüle, Manfred Jung

{"title":"Soft drug inhibitors for the epigenetic targets lysine-specific demethylase 1 and histone deacetylases","authors":"Johannes Seitz, Marina Auth, Tony Prinz, Mirjam Hau, Pavlos Tzortzoglou, Johannes Schulz-Fincke, Karin Schmidtkunz, Adina A. Baniahmad, Dominica Willmann, Eric Metzger, Lutz Hein, Sebastian Preissl, Roland Schüle, Manfred Jung","doi":"10.1002/ardp.202400450","DOIUrl":"10.1002/ardp.202400450","url":null,"abstract":"Epigenetic modulators such as lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) are drug targets for cancer, neuropsychiatric disease, or inflammation, but inhibitors of these enzymes exhibit considerable side effects. For a potential local treatment with reduced systemic toxicity, we present here soft drug candidates as new LSD1 and HDAC inhibitors. A soft drug is a compound that is degraded in vivo to less active metabolites after having achieved its therapeutic function. This has been successfully applied for corticosteroids in the clinic, but soft drugs targeting epigenetic enzymes are scarce, with the HDAC inhibitor remetinostat being the only example. We have developed new methyl ester-containing inhibitors targeting LSD1 or HDACs and compared the biological activities of these to their respective carboxylic acid cleavage products. In vitro activity assays, cellular experiments, and a stability assay identified potent HDAC and LSD1 soft drug candidates that are superior to their corresponding carboxylic acids in cellular models.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400450","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141615333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Utilization of an optimized AlphaFold protein model for structure-based design of a selective HDAC11 inhibitor with anti-neuroblastoma activity 利用优化的 AlphaFold 蛋白模型，基于结构设计具有抗神经母细胞瘤活性的选择性 HDAC11 抑制剂。

IF 4.3 3区医学

Archiv der Pharmazie Pub Date : 2024-07-12 DOI: 10.1002/ardp.202400486

Fady Baselious, Sebastian Hilscher, Sven Hagemann, Sunita Tripathee, Dina Robaa, Cyril Barinka, Stefan Hüttelmaier, Mike Schutkowski, Wolfgang Sippl

{"title":"Utilization of an optimized AlphaFold protein model for structure-based design of a selective HDAC11 inhibitor with anti-neuroblastoma activity","authors":"Fady Baselious, Sebastian Hilscher, Sven Hagemann, Sunita Tripathee, Dina Robaa, Cyril Barinka, Stefan Hüttelmaier, Mike Schutkowski, Wolfgang Sippl","doi":"10.1002/ardp.202400486","DOIUrl":"10.1002/ardp.202400486","url":null,"abstract":"AlphaFold is an artificial intelligence approach for predicting the three-dimensional (3D) structures of proteins with atomic accuracy. One challenge that limits the use of AlphaFold models for drug discovery is the correct prediction of folding in the absence of ligands and cofactors, which compromises their direct use. We have previously described the optimization and use of the histone deacetylase 11 (HDAC11) AlphaFold model for the docking of selective inhibitors such as FT895 and SIS17. Based on the predicted binding mode of FT895 in the optimized HDAC11 AlphaFold model, a new scaffold for HDAC11 inhibitors was designed, and the resulting compounds were tested in vitro against various HDAC isoforms. Compound 5a proved to be the most active compound with an IC50 of 365 nM and was able to selectively inhibit HDAC11. Furthermore, docking of 5a showed a binding mode comparable to FT895 but could not adopt any reasonable poses in other HDAC isoforms. We further supported the docking results with molecular dynamics simulations that confirmed the predicted binding mode. 5a also showed promising activity with an EC50 of 3.6 µM on neuroblastoma cells.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ardp.202400486","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quinazoline-oxindole hybrids as angiokinase inhibitors and anticancer agents: Design, synthesis, biological evaluation, and molecular docking studies 作为血管激酶抑制剂和抗癌剂的喹唑啉-吲哚混合物：设计、合成、生物学评价和分子对接研究。

IF 4.3 3区医学

Archiv der Pharmazie Pub Date : 2024-07-12 DOI: 10.1002/ardp.202300682

Yasmin M. Syam, Somaia S. Abd El-Karim, Heba T. Abdel-Mohsen

{"title":"Quinazoline-oxindole hybrids as angiokinase inhibitors and anticancer agents: Design, synthesis, biological evaluation, and molecular docking studies","authors":"Yasmin M. Syam, Somaia S. Abd El-Karim, Heba T. Abdel-Mohsen","doi":"10.1002/ardp.202300682","DOIUrl":"10.1002/ardp.202300682","url":null,"abstract":"Two new sets of quinazoline-oxindole 8a–l and quinazoline-dioxoisoindoline 10a–d hybrids were designed as type II angiokinase inhibitors and anticancer agents. The design strategy was adjusted to account for the quinazoline scaffold's placement in the target kinases' hinge region, where it would form hydrogen bonding and hydrophobic interactions with the important amino acids to stabilize it, and the amide group's occupation in the gate region, which would direct the oxindole scaffold toward the hydrophobic back pocket. The two sets of quinazolines 8a–l and 10a–d displayed pronounced inhibitory activity on VEGFR-2 (IC50 = 0.46–2.20 µM). The quinazoline-oxindole hybrids 8d, 8f, and 8h displayed IC50 = 0.46, 0.49, and 0.49 µM, respectively. Compound 8f demonstrated potent multikinase activity with IC50 values of 0.95 and 0.67 µM against FGFR-1 and BRAF, respectively. Additionally, compound 8f showed significant anticancer activity against National Cancer Institute's cancer cell lines, with GI50 reaching 1.21 µM. Analysis of the impact of compound 8f on the MDA-MB-231 cell line's cell cycle and apoptosis revealed that 8f stalled the cell cycle at the G2/M phase and promoted its necrosis.","PeriodicalId":128,"journal":{"name":"Archiv der Pharmazie","volume":"357 10","pages":""},"PeriodicalIF":4.3,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0