{"title":"Unveiling the Structure of Anhydrous Sodium Valproate with 3D Electron Diffraction and a Facile Sample Preparation Workflow.","authors":"Jiaoyan Xu, Vivek Srinivas, Rohit Kumar, Laura Pacoste, Yiwang Guo, Taimin Yang, Changquan Calvin Sun, Martin Högbom, Xiaodong Zou, Hongyi Xu","doi":"10.1021/acscentsci.5c00412","DOIUrl":"10.1021/acscentsci.5c00412","url":null,"abstract":"<p><p>Understanding the structure of an active pharmaceutical ingredient is essential for gaining insights into its physicochemical properties. Sodium valproate, one of the most effective antiepileptic drugs, was first approved for medical use in 1967. However, the structure of its anhydrous form has remained unresolved. This is because it was difficult to grow crystals of sufficient size for single-crystal X-ray diffraction (SCXRD). Although 3D electron diffraction (3D ED) can be used for studying crystals that are too small for SCXRD, the crystals of anhydrous sodium valproate are extremely sensitive to both humidity and electron beams. They degrade quickly both in air and under an electron beam at room temperature. In this study, we developed a glovebox-assisted cryo-transfer workflow for the preparation of EM grids in a protected atmosphere to overcome the current challenges for studying air- and beam-sensitive samples using 3D ED. Using this technique, we successfully determined the structure of anhydrous sodium valproate, revealing the formation of Na-valproate polyhedral chains. Our results provide a robust framework for the 3D ED analysis of air-sensitive crystals, greatly enhancing its utility across various scientific disciplines.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 6","pages":"960-966"},"PeriodicalIF":12.7,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-05-19eCollection Date: 2025-06-25DOI: 10.1021/acscentsci.5c00840
Louisa Dalton
{"title":"A Conversation with Elaine Bearer, Neuropathologist.","authors":"Louisa Dalton","doi":"10.1021/acscentsci.5c00840","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00840","url":null,"abstract":"<p><p>Microplastics in dementia-affected brains resisted identification until she lit them up.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 6","pages":"816-818"},"PeriodicalIF":12.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-05-19eCollection Date: 2025-06-25DOI: 10.1021/acscentsci.5c00549
Aishanee Sur, David C Powers
{"title":"<i>In Crystallo</i> Photochemistry: Reimagining Synthetic Tractability with Transparent Single-Crystalline Flasks.","authors":"Aishanee Sur, David C Powers","doi":"10.1021/acscentsci.5c00549","DOIUrl":"10.1021/acscentsci.5c00549","url":null,"abstract":"<p><p>Expanding the boundaries of synthetic tractability of what molecules can be synthesized and isolated is an eternal challenge for synthetic chemists. The development of new synthetic methods and strategies enables the properties and potential functions of novel molecular targets to be experimentally evaluated. In the context of catalysis, predictable synthetic strategies are often available to access kinetically persistent intermediates such as catalyst resting states. In contrast, synthesis and characterization of the reactive intermediates are often not possible due to the fleeting lifetimes of these species. <i>In crystallo</i> photochemistry combines single-crystal matrix isolation with cryogenic photochemistry to enable reactive intermediates to be synthesized under conditions in which they are persistent and can be (crystallographically) characterized. This Outlook highlights key achievements of <i>in crystallo</i> photochemistry as well as discusses opportunities and challenges that confront realization of the potential of <i>in crystallo</i> synthesis to redefine the boundaries of synthetic tractability.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 6","pages":"834-842"},"PeriodicalIF":12.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12220827/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Multicatalysis-Enabled Multicomponent Reactions Generate a PTP1B Inhibitor.","authors":"Taoda Shi, Yukai Li, Jiying Yang, Weining Weng, Mengchu Zhang, Jirong Shu, Yu Qian, Tianyuan Zhang, Wenhao Hu","doi":"10.1021/acscentsci.5c00041","DOIUrl":"10.1021/acscentsci.5c00041","url":null,"abstract":"<p><p>Multicomponent reactions are powerful tools for expanding the chemical space in drug discovery, yet achieving selectivity remains a formidable challenge. Here, we introduce a multicatalytic strategy to enable a multicomponent reaction, utilizing a cooperative system of rhodium, copper, Brønsted acid, and magnesium catalysts. This approach achieves excellent chemo-, diastereo-, and enantioselectivity (up to 99% yield, >20:1 dr, and 99% ee). Mechanistic studies, combining experimental and computational analyses, reveal a cascade sequence involving cyclopropenation, desilylation, cyclization, isomerization, aldol addition, and hydrolysis. This highly selective method exhibits broad substrate generality, producing 50 diverse CHBOs. Virtual screening and rapid biological evaluation led to the discovery of (<i>S</i>, <i>S</i>)-<b>3ak</b>, a potent PTP1B inhibitor with a submicromolar IC<sub>50</sub> value. Notably, (<i>S</i>, <i>S</i>)-<b>3ak</b> demonstrated 3-fold higher potency than its enantiomer, underscoring the critical role of chirality. Molecular docking studies elucidated the enantioselective binding mechanism, revealing key interactions responsible for activity differences. In summary, this MMCR strategy enables efficient access to enantiopure bioactive molecules and facilitates drug discovery, exemplified by a novel chiral PTP1B inhibitor.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 6","pages":"938-949"},"PeriodicalIF":12.7,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203432/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Submolecular Resolution of β‑Sheet Plasticity: Decoding Mutations and PTMs in Protein Aggregation Disorders.","authors":"Ruonan Wang, Zhongyi Jian, Yanlian Yang, Chen Wang, Lanlan Yu, Mingzhan Wang, Chenxuan Wang","doi":"10.1021/acscentsci.5c00421","DOIUrl":"10.1021/acscentsci.5c00421","url":null,"abstract":"<p><p>The functional diversity of proteins often arises from the remodeling of conformational ensembles, particularly through mutations and post-translational modifications (PTMs). However, experimentally characterizing such ensembles remains challenging due to their heterogeneous and transient nature. Here, we report the determination of the conformational substates of β-sheets and the effect associated with mutations and PTMs in human islet amyloid polypeptide (hIAPP) via scanning tunneling microscopy (STM). Thanks to the ultrahigh resolution of STM, the β-sheets formed by the assembly of hIAPP were revealed to be conformationally diverse, including 17 types of conformational substates concomitant with 60 types of interconformation interactions. These conformational substates are highly heterogeneous in the folding structures but close in energy. Four mutations and PTMs were carried out with hIAPP to investigate the evolvability of the β-sheet assembly. Regulation effects accomplished by the mutations and PTMs on the conformational ensembles of β-sheets have been identified, including the number of conformational substates, the most probable substates, and the topography of the energetic landscapes of inter-β-strand interactions. Different types of variations show divergence in the influences on the β-sheet conformational ensembles, which is correlated with the divergent aggregation propensity. Our results highlight the plasticity of conformational ensembles upon mutations and PTMs.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 6","pages":"927-937"},"PeriodicalIF":12.7,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203261/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-05-14DOI: 10.1021/acscentsci.5c0081310.1021/acscentsci.5c00813
Katarina Zimmer,
{"title":"A Conversation with Matthias Rillig, Soil Ecologist","authors":"Katarina Zimmer, ","doi":"10.1021/acscentsci.5c0081310.1021/acscentsci.5c00813","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00813https://doi.org/10.1021/acscentsci.5c00813","url":null,"abstract":"<p >Rillig uncovers how microplastics are transforming soil.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 5","pages":"642–644 642–644"},"PeriodicalIF":12.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00813","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-05-14eCollection Date: 2025-05-28DOI: 10.1021/acscentsci.5c00813
Katarina Zimmer
{"title":"A Conversation with Matthias Rillig, Soil Ecologist.","authors":"Katarina Zimmer","doi":"10.1021/acscentsci.5c00813","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00813","url":null,"abstract":"<p><p>Rillig uncovers how microplastics are transforming soil.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 5","pages":"642-644"},"PeriodicalIF":12.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-05-13eCollection Date: 2025-06-25DOI: 10.1021/acscentsci.5c00468
Prakash Chandra Tiwari, Antonio Pulcinella, Emil Hodžić, Timothy Noël
{"title":"Late-Stage Heteroarene Alkylation via Minisci Reaction with Gaseous Alkanes Enabled by Hydrogen Atom Transfer in Flow.","authors":"Prakash Chandra Tiwari, Antonio Pulcinella, Emil Hodžić, Timothy Noël","doi":"10.1021/acscentsci.5c00468","DOIUrl":"10.1021/acscentsci.5c00468","url":null,"abstract":"<p><p>The late-stage functionalization of complex molecules is a pivotal strategy in drug discovery, enabling the rapid optimization of lead compounds. However, the use of gaseous alkanes as alkylating agents in these processes remains underexplored due to their inertness and handling challenges. Here we present a photocatalytic platform that facilitates the alkylation of heteroarenes using abundant gaseous C1-C4 hydrocarbons under continuous-flow conditions. Through hydrogen atom transfer (HAT) catalysis, we achieve the efficient alkylation of pharmaceutically relevant compounds without the need for prefunctionalized reagents. Our method is not only scalable and sustainable but also extends to the functionalization of marketed drugs and natural products.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 6","pages":"910-917"},"PeriodicalIF":12.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12203263/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-05-12eCollection Date: 2025-05-28DOI: 10.1021/acscentsci.5c00779
Marta Zaraska
{"title":"Pollution Confuses Pollinators. Can Scientists Retrain Them?","authors":"Marta Zaraska","doi":"10.1021/acscentsci.5c00779","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00779","url":null,"abstract":"<p><p>As VOCs cause flower aromas to break down, bees may need to learn new tricks.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 5","pages":"649-652"},"PeriodicalIF":12.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
ACS Central SciencePub Date : 2025-05-12DOI: 10.1021/acscentsci.5c0077910.1021/acscentsci.5c00779
Marta Zaraska,
{"title":"Pollution Confuses Pollinators. Can Scientists Retrain Them?","authors":"Marta Zaraska, ","doi":"10.1021/acscentsci.5c0077910.1021/acscentsci.5c00779","DOIUrl":"https://doi.org/10.1021/acscentsci.5c00779https://doi.org/10.1021/acscentsci.5c00779","url":null,"abstract":"<p >As VOCs cause flower aromas to break down, bees may need to learn new tricks.</p>","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 5","pages":"649–652 649–652"},"PeriodicalIF":12.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.5c00779","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144146491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}