ACS Pharmacology and Translational Science最新文献_第4页

Thermal Stability, Plasma Pharmacokinetics, and Tumor Response Modeling of a Cell-Penetrating Protein That Cleaves RAS Family GTPases 裂解RAS家族gtp酶的细胞穿透蛋白的热稳定性、血浆药代动力学和肿瘤反应模型

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2026-09-11 Epub Date: 2026-08-20 DOI: 10.1021/acsptsci.6c00339

Takanari Sugawara, Teiko Komori Nomura, Ryo Honda

{"title":"Thermal Stability, Plasma Pharmacokinetics, and Tumor Response Modeling of a Cell-Penetrating Protein That Cleaves RAS Family GTPases","authors":"Takanari Sugawara, Teiko Komori Nomura, Ryo Honda","doi":"10.1021/acsptsci.6c00339","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00339","url":null,"abstract":"RRSP–RBD–TATis a cell-penetrating fusionproteincomposed of a RAS/Rap1-specific endopeptidase (RRSP), a RAS-bindingdomain (RBD), and a transactivator-of-transcription (TAT) cell-permeablepeptide. It catalytically and irreversibly cleaves RAS family proteinsand has shown potent antitumor activity. To advance this unconventionalintracellular protein therapeutic toward translation, we characterizedits thermal stability, developed a capillary-based Simple Westernimmunoassay for quantitative blood analysis, measured plasma pharmacokineticsand tumor-associated exposure, and linked these measurements to intratumoralsignaling and tumor response. RRSP–RBD–TAT retainedits secondary structure and anticancer activity for 3 days at 20–37°C, whereas temperatures above approximately 50 °C causedrapid unfolding, aggregation, and irreversible loss of activity. TheSimple Western assay separated immunoreactive RRSP–RBD–TATfrom the albumin-rich region of serum and plasma, enabling quantitativeconcentration–time profiling after intravenous administration.Following a single 50 mg/kg dose, plasma concentrations declined rapidlywith a biexponential profile, whereas apparent micromolar tumor-associatedconcentrations were detected at 3 and 6 h. Tumors showed near-completedepletion of intact RAS and prolonged suppression of ERK phosphorylation,which persisted after tumor-associated drug levels had declined belowthe practical detection range. An integrated semimechanistic pharmacokinetic–pharmacodynamic–tumorgrowth inhibition model reproduced the observed dose-dependent responses.Exploratory human-scaled simulations revealed dose- and schedule-dependenteffects and suggested that both improved intracellular potency andprolonged systemic persistence could lower the projected effectivedose, with potency enhancement producing the larger shift under thecurrent model assumptions.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2639–2653"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Direct Quantification of Complement Biomarkers Using Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS) 液相色谱-串联质谱（LC-MS /MS）直接定量补体生物标志物

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2026-09-11 Epub Date: 2026-06-18 DOI: 10.1021/acsptsci.5c00784

Cong Wu, Jianhui Zhu, Tiffany Wong, Racquel Corpuz, Tiffany Wu, William J. Meilandt, Anne Biever, Norbert LeClair, Kelly Loyet, Jesse Hanson, John Chen, Chengjie Ji, John C. Tran, Luis F. Schachner

{"title":"Direct Quantification of Complement Biomarkers Using Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS)","authors":"Cong Wu, Jianhui Zhu, Tiffany Wong, Racquel Corpuz, Tiffany Wu, William J. Meilandt, Anne Biever, Norbert LeClair, Kelly Loyet, Jesse Hanson, John Chen, Chengjie Ji, John C. Tran, Luis F. Schachner","doi":"10.1021/acsptsci.5c00784","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00784","url":null,"abstract":"The classical complement pathway is a critical therapeutictargetfor numerous diseases, but the lack of robust, translatable biomarkershinders drug development. Here, we report the development and qualificationof a quantitative liquid chromatography-tandem mass spectrometry (LC–MS/MS)platform to measure key classical pathway proteins─C1q, C 1s(total and active), and the native C1q/C 1s complex. The platformwas established across human, cynomolgus monkey, and mouse samples,including serum, plasma, cerebrospinal fluid, and brain homogenates.We employed two complementary workflows: an affinity capture LC–MS/MSmethod to quantify the intact C1q/C 1s complex and a direct digestionstrategy to differentiate total C 1s from its active form. The assaysmet rigorous qualification standards for accuracy, reproducibility(CV ≤15%) and freeze–thaw stability. Applying this platform,we established that cynomolgus monkeys exhibit complement profileshighly similar to those in healthy humans, validating their use asa translational model. In contrast, mice display markedly higher baselinelevels of active C 1s, revealing a critical species-specific differencein complement regulation. This qualified, cross-species platform providesan essential tool for bridging preclinical and clinical research andenabling reliable pharmacodynamic assessment of complement-targetingtherapeutics.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2426–2437"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fibrinogen as a Molecular Bridge Linking SARS-CoV-2 Immune Evasion and Endothelial Access? 纤维蛋白原是连接SARS-CoV-2免疫逃避和内皮通路的分子桥梁？

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2026-09-11 Epub Date: 2026-08-13 DOI: 10.1021/acsptsci.6c00452

Saroj Kumar Panda, Shashi Singh, Parth Sarthi Sen Gupta

引用次数: 0

The Emergence of Isotryptamine Analogs as Novel Serotonergic Agents with Psychotherapeutic Potential 异色胺类似物作为具有心理治疗潜力的新型血清素能药物的出现

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2026-09-11 Epub Date: 2026-08-18 DOI: 10.1021/acsptsci.6c00288

Richard A. Glennon, Małgorzata Dukat

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Nesfatin-1 Deficiency Exacerbates Calcium Oxalate Monohydrate–Induced Cellular Injury in Renal Epithelial Cells Nesfatin-1缺乏可加重草酸钙诱导的肾上皮细胞损伤

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2026-09-11 Epub Date: 2026-08-17 DOI: 10.1021/acsptsci.6c00200

Ganesh Panditrao Lahane, Arti Dhar

{"title":"Nesfatin-1 Deficiency Exacerbates Calcium Oxalate Monohydrate–Induced Cellular Injury in Renal Epithelial Cells","authors":"Ganesh Panditrao Lahane, Arti Dhar","doi":"10.1021/acsptsci.6c00200","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00200","url":null,"abstract":"Calciumoxalate monohydrate (COM) crystals are majorcontributorsto nephrolithiasis-associated renal tubular injury, primarily throughmechanisms involving oxidative stress, inflammation, apoptosis, andepithelial–mesenchymal transition (EMT). While nesfatin-1 isknown for its antioxidant and cytoprotective actions, the specificrole of endogenous nesfatin-1 in regulating COM-induced epithelialinjury has not been fully defined. In this study, nesfatin-1 was silencedusing antisense oligonucleotides in NRK-52E and primary renal tubularepithelial cells to examine how loss of endogenous nesfatin-1 peptideinfluences cellular susceptibility to COM. COM exposure reduced nesfatin-1levels, and this decline was markedly greater in the nesfatin-1 silenced+ COM group. Silencing nesfatin-1 intensified COM-driven oxidativestress, as reflected by reduced catalase activity and increased levelsof malondialdehyde, nitric oxide, and ROS. Pro-inflammatory markersincluding NF-κB, TNF-α, IL-6, and IL-1β were upregulated,whereas IL-10 was decreased. Apoptotic indicators such as elevatedintracellular Ca2+, diminished Bcl-2, increased caspase-3activation, and higher proportions of apoptotic and necrotic cellswere also evident. EMT and fibrotic markers (TGF-β1, α-SMA,Smad2/3, Smad4, vimentin) were increased, alongside reduced E-cadherinexpression. Exogenous nesfatin-1 mitigated oxidative, inflammatory,apoptotic, and fibrotic responses in COM-treated cells; however, theseprotective effects were minimal in nesfatin-1 silenced + COM cells.Overall, the findings demonstrate that endogenous nesfatin-1 is indispensablefor maintaining epithelial stability under COM-induced stress, andits absence amplifies cellular injury while diminishes responsivenessto exogenous peptide. Nesfatin-1 thus emerges as a potential therapeutictarget for limiting crystal-induced renal cells damage.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2544–2559"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Topiramate Impairs Spermatogenesis, Sperm Parameters, and Epididymal Duct Contractility in Rats 托吡酯损害大鼠精子发生、精子参数和附睾管收缩性

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2026-09-11 Epub Date: 2026-08-15 DOI: 10.1021/acsptsci.6c00273

Maele Oliveira de Sena, Maria Santana da Silva, Yanka do Vale Carvalho, Herick Jose Cunha Chaves, Maria Letícia da Costa, Bruna da Silva Figueredo, Jackson Nazareno Gomes de Lima, Renata Souza e Silva, Expedito Silva do Nascimento Junior, Anna Karynna Alves de Alencar Rocha, Elaine Cristina Gavioli, Edilson Dantas da Silva Junior

{"title":"Topiramate Impairs Spermatogenesis, Sperm Parameters, and Epididymal Duct Contractility in Rats","authors":"Maele Oliveira de Sena, Maria Santana da Silva, Yanka do Vale Carvalho, Herick Jose Cunha Chaves, Maria Letícia da Costa, Bruna da Silva Figueredo, Jackson Nazareno Gomes de Lima, Renata Souza e Silva, Expedito Silva do Nascimento Junior, Anna Karynna Alves de Alencar Rocha, Elaine Cristina Gavioli, Edilson Dantas da Silva Junior","doi":"10.1021/acsptsci.6c00273","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00273","url":null,"abstract":"Topiramate is a widely prescribed antiepileptic drugwith a multimodalmechanism of action. However, its effects on male reproductive functionremain poorly characterized. This study was conducted to investigatethe impact of this drug on testicular and epididymal function in adultmale Wistar rats. Animals were treated orally for 21 days with topiramateat 40 or 160 mg/kg. Serum testosterone levels, testicular histomorphology,spermatogenic indices, sperm parameters, and epididymal duct contractilitywere subsequently evaluated. The treatment did not alter serum testosteronelevels at either dose. However, both doses reduced Sertoli cell andround spermatid numbers, increased primary spermatocyte counts, anddecreased meiotic and overall spermatogenic yields, whereas only thehigher dose (160 mg/kg) reduced Sertoli cell efficiency and dailysperm production. The lower dose (40 mg/kg) increased sperm morphologicalabnormalities, whereas the higher dose reduced total and progressivesperm motility and induced both head and tail defects. Additionally,treatment with topiramate at 160 mg/kg prolonged sperm transit timein the cauda epididymis and reduced contractile responses of the distalcauda epididymal duct to KCl, noradrenaline, and carbachol, suggestingimpaired epididymal transport and potential ejaculatory dysfunction.Altogether, these findings demonstrate that topiramate adversely affectsmale reproductive function. Given its widespread use in individualsof reproductive age, these results underscore the need for translationalstudies in humans to assess potential reproductive risks associatedwith this therapy.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2595–2605"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Small-Molecule-Mediated Depletion of the Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1B (DYRK1B) Protein Scaffold 双特异性酪氨酸磷酸化调节激酶1B （DYRK1B）蛋白支架的小分子介导缺失

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2026-09-11 Epub Date: 2026-08-29 DOI: 10.1021/acsptsci.6c00238

Miriam Ems, Mattias F. Lindberg, Till Adhikary, Laurent Meijer, Matthias Lauth

{"title":"Small-Molecule-Mediated Depletion of the Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1B (DYRK1B) Protein Scaffold","authors":"Miriam Ems, Mattias F. Lindberg, Till Adhikary, Laurent Meijer, Matthias Lauth","doi":"10.1021/acsptsci.6c00238","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00238","url":null,"abstract":"Members of the DYRK kinase family have been implicatedin the regulationof key metabolic processes. In particular, DYRK1B plays a centralrole in hepatic lipid metabolism and fatty liver disease. Notably,these functions depend not only on the enzyme’s catalytic activitybut also on scaffolding properties. Consequently, therapeutic ambitionsaiming to target the entire spectrum of DYRK1B functions must inactivateor eliminate the protein itself rather than merely inhibiting itsenzymatic activity, as is achieved by current kinase inhibitors. Inthis study, we describe a small molecule from the leucettinib classof DYRK inhibitors (LCTB-92) that not only suppresses DYRK kinaseactivity but also promotes selective ablation of the DYRK1B proteinwhile sparing the closely related paralog DYRK1A. The identificationof this compound establishes a foundation for the development of selectiveagents capable of targeting the entire DYRK1B protein scaffold, therebyaddressing catalytic-dependent as well as catalytic-independent kinasefunctions.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2419–2425"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Acute Submaximal Running Potentiates the Straub Tail Response to Meperidine in a Dose- and Sex-Dependent Manner in Mice 急性亚极限跑步增强小鼠对哌啶的剂量和性别依赖性的斯特劳布尾反应

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2026-09-11 Epub Date: 2026-08-31 DOI: 10.1021/acsptsci.6c00328

Tatyana Nery, Naiara de Souza Santos, Ana Cristina de Bem Alves, Amanda Leite Bastos-Pereira, Aderbal S. Aguiar, Jr.

{"title":"Acute Submaximal Running Potentiates the Straub Tail Response to Meperidine in a Dose- and Sex-Dependent Manner in Mice","authors":"Tatyana Nery, Naiara de Souza Santos, Ana Cristina de Bem Alves, Amanda Leite Bastos-Pereira, Aderbal S. Aguiar, Jr.","doi":"10.1021/acsptsci.6c00328","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00328","url":null,"abstract":"Physical exerciserecruits endogenous opioid mechanismsin thecentral nervous system, but whether this physiological opioid tonepotentiates the effects of exogenous μ-agonists, and whethersuch interactions differ between sexes, remains unknown. Here, weused the Straub tail response as a behavioral index of central μ2-opioid receptor activity to investigate whether acute submaximalrunning modulates the pharmacodynamic effects of meperidine in maleand female Swiss mice. In resting animals, meperidine produced a dose-and time-dependent Straub tail response across a 12-fold dose range,and the submaximal doses of 8 and 12 mg/kg were selected for treadmillexperiments. Running at approximately 70% of V̇O2 max potentiated the Straub tail response at 12 mg/kg in both sexes,with the effect substantially larger in females, as indicated by asignificant Sex × Exercise interaction. Thermal antinociceptionwas equivalent between sexes at 12 mg/kg, indicating that the dimorphismwas specific to the exercise-opioid interaction rather than to baselinedrug sensitivity. A separate experiment testing whether running aloneelicits a naloxone-sensitive response was inconclusive in both sexes;under opioid receptor blockade, however, females maintained higherrunning-induced scores than males, indicating that the sex differencepersists during naloxone treatment. These findings indicate that acutesubmaximal running potentiates the Straub tail response to meperidinein a dose- and sex-dependent manner. The sexually dimorphic natureof this interaction suggests that biological sex and exercise intensitymay jointly modulate opioid pharmacodynamics during physical activity.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2617–2627"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antiproliferation and Anti-invasion Activity of Binuclear Copper(II) Complex in BRAFi-Resistant Melanoma Cells 双核铜（II）复合物在抗brafi黑色素瘤细胞中的抗增殖和抗侵袭活性

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2026-09-11 Epub Date: 2026-08-10 DOI: 10.1021/acsptsci.6c00033

Manoel Oliveira de Moraes Junior, Larissa Anastácio da Costa Carvalho, Yasmin Catherine da Paz Mendonça, Renaira Oliveira da Silva, Cleia Justino Nunes, Keli Lima, João Agostinho Machado-Neto, Tiago Rodrigues, Vito Rebecca, Corine Bertolotto, Ana Maria da Costa Ferreira, Silvya Stuchi Maria-Engler

{"title":"Antiproliferation and Anti-invasion Activity of Binuclear Copper(II) Complex in BRAFi-Resistant Melanoma Cells","authors":"Manoel Oliveira de Moraes Junior, Larissa Anastácio da Costa Carvalho, Yasmin Catherine da Paz Mendonça, Renaira Oliveira da Silva, Cleia Justino Nunes, Keli Lima, João Agostinho Machado-Neto, Tiago Rodrigues, Vito Rebecca, Corine Bertolotto, Ana Maria da Costa Ferreira, Silvya Stuchi Maria-Engler","doi":"10.1021/acsptsci.6c00033","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00033","url":null,"abstract":"Melanoma lethality is driven by high intratumoral heterogeneity,metastatic competence, and phenotypic plasticity, which foster rapidemergence of resistance to targeted therapies such as BRAF inhibitors(BRAFi, e.g. vemurafenib). Copper(II) complexes have emerged as promisinganticancer candidates, yet their activity against BRAFi-resistantmelanoma remains poorly defined. Here, we show that the binuclearcopper(II) complex [Cu2(apyhist)2dpam](ClO4)4 (herein referred to as [Cu(II)L]) displays low-micromolarcytotoxicity and antiproliferative activity in parental and BRAFi-resistantmelanoma models. Binuclear [Cu(II)L] suppresses melanoma migrationand invasion and reduces tumor burden and dermal invasion in a reconstructedhuman skin melanoma model with limited toxicity to normal tissue.Mechanistically, [Cu2(apyhist)2dpam](ClO4)4 triggers a ROS-dependent stress response thatis attenuated by N-acetylcysteine, leading to DNA damage, mitochondrialdepolarization and caspase-independent cell death. Molecular profilingindicates engagement of cell cycle arrest and stress-adaptation programs,with signatures suggesting ferroptotic-associated, necroptotic andautophagy-related signaling, pointing to a redox-driven, diverse mechanismrather than a single dominant death pathway. Different modulationof key markers (PARP1, H2AX, MLKL, GPX4, LC3B-II, and p62) supportsthat its multitarget activity can bypass adaptive resistance mechanisms.Collectively, these findings support binuclear [Cu(II)L] as a candidateto target invasive and drug-resistant melanoma phenotypes.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2454–2468"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Concise Total Synthesis and Pharmacological Evaluation of Procerones A and B 丙孕酮A、B的简明全合成及药理评价

IF 3.7

ACS Pharmacology and Translational Science Pub Date : 2026-09-11 Epub Date: 2026-08-21 DOI: 10.1021/acsptsci.6c00196

Jasmin Janneschütz, Pia B. Gartlgruber, Phila Weissenstein, Christine Aczel, Vinzenz M. Herkner, Cornelia Shtepani, Celina Haller, Yuki Bacowsky, Fatima Aslam, Laureta Gashi, Hasier Eraña, Juan C. Fuentes-Monteverde, Sarah Abel, Stefan Simić, Judith Wackerlig-Damle, Arnold Grünweller, Christian Griesinger, Joaquín Castilla, Sophia Khom, Nina Schützenmeister

{"title":"Concise Total Synthesis and Pharmacological Evaluation of Procerones A and B","authors":"Jasmin Janneschütz, Pia B. Gartlgruber, Phila Weissenstein, Christine Aczel, Vinzenz M. Herkner, Cornelia Shtepani, Celina Haller, Yuki Bacowsky, Fatima Aslam, Laureta Gashi, Hasier Eraña, Juan C. Fuentes-Monteverde, Sarah Abel, Stefan Simić, Judith Wackerlig-Damle, Arnold Grünweller, Christian Griesinger, Joaquín Castilla, Sophia Khom, Nina Schützenmeister","doi":"10.1021/acsptsci.6c00196","DOIUrl":"https://doi.org/10.1021/acsptsci.6c00196","url":null,"abstract":"Procerones are highly brominated marine natural productsthat wereisolated in 2019 from Polycarpa procera. Herein, we report the first total syntheses of procerones A andB, together with their enantiomers, in only three linear steps, startingfrom commercially available acetophenone and benzaldehyde derivatives.The synthesis takes advantage of a chalcone core structure obtainedby Aldol condensation followed by Davis oxidation to implement thechiral α-hydroxy ketone moiety without the use of heavy metals.The effects of all synthesized compounds, including the enantiopurenatural products, on the major inhibitory neurotransmitter receptorin the mammalian brain (GABAA receptor) were determined,and the four enantiopure procerones were additionally tested for antiprionactivity. While no antiprion activity was observed for the testedcompounds, one unprecedented precursor, as well as procerone B andits enantiomer, significantly enhanced GABAA receptor function,suggesting that this scaffold may serve as a starting point for developingnovel GABAA receptor modulators.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"9 9","pages":"2525–2534"},"PeriodicalIF":3.7,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148950903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0