Organic & Biomolecular Chemistry最新文献

{"title":"Regulating H2S release from self-assembled peptide H2S-donor conjugates using cysteine derivatives","authors":"Zhao Li, Marius Thomas, Christian M. Berač, Oliver S. Stach, Pol Besenius, John B. Matson","doi":"10.1039/d4ob01148a","DOIUrl":"https://doi.org/10.1039/d4ob01148a","url":null,"abstract":"Self-assembled peptides provide a modular and diverse platform for drug delivery, and innovative delivery methods are needed for delivery of hydrogen sulfide (H<small>₂</small>S), an endogenous signaling molecule (gasotransmitter) with significant therapeutic potential. Of the available types of H<small>₂</small>S donors, peptide/protein H<small>₂</small>S donor conjugates (PHDCs) offer significant versatility. Here we discuss the design, synthesis, and in-depth study of a PHDC containing three covalently linked components: a thiol-triggered H<small>₂</small>S donor based on an <em>S</em>-aroylthiooxime (SATO), a GFFF tetrapeptide, and a tetraethylene glycol (TEG) dendron. Conventional transmission electron microscopy showed that the PHDC self-assembled into spherical structures without heat or stirring, but it formed nanofibers with gentle heat (37 °C) and stirring. Circular dichroism (CD) spectroscopy data collected during self-assembly under nanofiber-forming conditions suggested an increase in β-sheet character and a decrease in organization of the SATO units. Release of H<small>₂</small>S from the nanofibers was studied through triggering with various thiols. The release rate and total amount of H<small>₂</small>S released over both short (5 h) and long (7 d) time scales varied with the charge state: negatively charged and zwitterionic thiols (<em>e.g.</em>, Ac-Cys-OH and H-Cys-OH) triggered release slowly while a neutral thiol (Ac-Cys-OMe) showed ∼10-fold faster release, and a positively charged thiol (H-Cys-OMe) triggered H<small>₂</small>S release nearly 50-fold faster than the negatively charged thiols. CD spectroscopy studies monitoring changes in secondary structure over time during H<small>₂</small>S release showed similar trends. This study sheds light on the driving forces behind self-assembling nanostructures and offers insights into tuning H<small>₂</small>S release through thiol charge state modulation.","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrochemical sulfonylation/Truce–Smiles rearrangement of N-allylbenzamides: toward sulfone-containing β-arylethylamines and Saclofen analogues","authors":"Sébastien Meyer, Alexandre Neuhut, Aurélie Claraz","doi":"10.1039/d4ob01327a","DOIUrl":"https://doi.org/10.1039/d4ob01327a","url":null,"abstract":"The β-arylethylamine pharmacophore is commonly found in medications for central nervous system disorders, prompting the need for safe and efficient methods to endow this motif with relevant functional groups for drug discovery. In this context, herein, we have established electrochemical radical sulfonylation reactions of <em>N</em>-allylbenzamides followed by Truce–Smiles rearrangement to produce sulfone- and sulfonate ester-containing β-arylethylamines. Electricity enables this transformation to occur under mild and oxidant-free conditions. Simple sources of sulfonyl radicals and SO<small>₂</small> surrogates were employed to form sulfones and sulfonate esters, respectively. This practical and operationally robust method exhibited a broad substrate scope with good to high yields. The prospective pharmaceutical utility of the process was further demonstrated by removing the <em>N</em>-protecting groups and hydrolysing the sulfonate ester moiety to provide γ-sulfonyl-β-arylamines and Saclofen.","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapid diazotransfer for selective lysine labelling","authors":"Susannah H. Calvert, Tomasz Pawlak, Gary Hessman, Joanna F. McGouran","doi":"10.1039/d4ob01094a","DOIUrl":"https://doi.org/10.1039/d4ob01094a","url":null,"abstract":"Azide functionalization of protein and peptide lysine residues allows selective bioorthogonal labeling to introduce new, site selective functionaltiy into proteins. Optimised diazotransfer reactions under mild conditions allow aqueous diazotransfer to occur in just 20 min at pH 8.5 on amino acid, peptide and protein targets. In addition, conditons can be modified to selectively label a single lysine residue in both protein targets investigated. Finally, we demonstrate selective modification of proteins containing a single azidolysine using copper(<small>I</small>)-catalyzed triazole formation.","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetraasteranes as homologues of cubanes: effective scaffolds for drug discovery","authors":"Xiaokun Zhang, Chaochun Wei, Keli Zong, Qidi Zhong, Hong Yan","doi":"10.1039/d4ob01043d","DOIUrl":"https://doi.org/10.1039/d4ob01043d","url":null,"abstract":"Classical hydrocarbon scaffolds have long assisted in bringing new molecules to the market for a variety of applications, but one notable omission is that of tetraasteranes, which are homologues of cubanes belonging to a class of polycyclic hydrocarbon cage compounds. Tetraasteranes exhibit potential as scaffolds in drug discovery due to their identical cyclobutane structures and rigid conformation resembling cubanes. Based on the studies of the physical and chemical properties of tetraasteranes by density functional theory, three series of compounds were designed as homologues of cubanes by the substitution of cubane scaffolds in pharmaceuticals with tetraasteranes. Their potential for pharmaceutical applications was evaluated <em>in silico</em> by molecular docking and dynamics simulations. Their pharmacokinetic and physicochemical properties were studied by the ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The results indicate that tetraasteranes may be scaffolds as novel bioisosteres of cubanes, as well as hydrogen bond donors or acceptors, which enhance the affinity between ligands and receptors with more stable binding behavior and feasible tolerability in ADMET. All these findings provide new opportunities for tetraasteranes to serve as effective pharmaceutical scaffolds for drug discovery and to accelerate the drug discovery process by repurposing both new and old commercial compounds.","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorescein-switching-based lateral flow assay for the detection of microRNAs","authors":"Ji Young Ryu, Tae Su Choi, Ki Tae Kim","doi":"10.1039/d4ob01311e","DOIUrl":"https://doi.org/10.1039/d4ob01311e","url":null,"abstract":"Lateral flow assays (LFAs) are a cost-effective and rapid colorimetric technology that can be effectively used for nucleic acid tests (NATs) in various fields such as medical diagnostics and biotechnology. Given their importance, developing more diverse LFAs that operate through novel working mechanisms is essential for designing highly selective and sensitive NATs and providing insights for designing various practical point-of-care testing (POCT) systems. Herein we report a new type of lateral flow assay (LFA) based on fluorescein-switching, enabled by nucleic acid-templated photooxidation of reduced fluorescein by riboflavin tetraacetate (RFTA). The LFA design leverages the fact that a reduced form of fluorescein, which weakly binds to gold nanoparticle (GNP)-conjugated anti-fluorescein antibodies, is oxidized in the presence of target nucleic acids to yield its native state, which then strongly binds to the antibodies. The study involved designing and optimizing probe sequences to detect miR-6090 and miR-141, which are significant markers for prostate cancer. To minimize background signals of LFAs, sodium borohydride (NaBH<small>₄</small>) was specifically introduced as a reducing agent, and detailed procedures were established. The developed LFA system accurately identified low fmol levels of target microRNAs with minimal false positives, all detectable with the naked eye, making the system a promising tool for point-of-care diagnostics.","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Facile access to α-silylmethylamidines by BF3-catalyzed hydroamination of silylynamides with amines","authors":"Fei Lu, Zengzeng Li, Yulu Wang, Guoliang Liu, Guangguo Niu, Guanghui Wang, Ximei Zhao","doi":"10.1039/d4ob01314j","DOIUrl":"https://doi.org/10.1039/d4ob01314j","url":null,"abstract":"The metal-free BF<small>₃</small>-catalyzed hydroamination of silylynamides with amines allows facile and efficient synthesis of α-silylmethylamidines in moderate to excellent yields (up to 99%) with a broad substrate scope and excellent functional group compatibility under mild reaction conditions. This protocol offers the first synthetic route to silyl-incorporated amidine compounds, which features the use of Lewis acid BF<small>₃</small> as the catalyst and easily available silylynamides as the silicon source. Considering the biological importance of amidine scaffolds and silyl groups, the easy incorporation of these two structural units should make great sense for medicinal chemistry. Notably, with this strategy, the installation of amidine scaffolds to drug-like molecules celecoxib and estrone is realized for the first time. A plausible mechanism involves the formation of vinyl-boron intermediates from BF<small>₃</small>-activated ynamides, which after protodeboronation and tautomerization afford the desired products.","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enantioselective organocatalyzed one-pot synthesis of N-phenyl thioether-tethered tetrasubstituted dihydropyrrole-3-carbaldehydes","authors":"Solai Pandidurai, Govindasamy Sekar","doi":"10.1039/d4ob01411a","DOIUrl":"https://doi.org/10.1039/d4ob01411a","url":null,"abstract":"An efficient method for the asymmetric one-pot synthesis of <em>N</em>-phenyl thioether-tethered tetrasubstituted chiral 4,5-dihydropyrrole-3-carbaldehydes have been developed using readily available benzothiazolium salts and α,β-unsaturated aldehydes as starting materials in the presence of the chiral organocatalyst (<em>R</em>)-diphenylprolinol trimethylsilyl ether. The protocol afforded various functionally enantioenriched chiral tetrasubstituted 4,5-dihydropyrrole-3-carbaldehydes in high yields, with excellent enantio- and diastereoselectivity (≤90% yield, ≤98% ee, and &gt;20 : 1 d.r.). This asymmetric one-pot reaction starts with the reaction of azomethine ylides with dipolarophiles to yield pyrrolo-thiazine-2-carbaldehydes as intermediates. Subsequently, the electrophile alkyl halide is attacked by the sulfur atom of the intermediate, followed by C–S bond cleavage (ring-opening), which furnishes the desired chiral tetrasubstituted 4,5-dihydropyrroles.","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"(Dimethylamino)methylene hydantoins as building blocks in the synthesis of oxoaplysinopsins and parabanic acids with antifungal activity","authors":"Edson Barrera, Alberto V. Jerezano, Ulises F. Reyes-González, Daniela Martínez-López, Carlos H. Escalante, Julio López, Eder I. Martínez-Mora, Omar Gómez-García, Dulce Andrade-Pavón, Lourdes Villa-Tanaca, Francisco Delgado, Joaquín Tamariz","doi":"10.1039/d4ob01242a","DOIUrl":"https://doi.org/10.1039/d4ob01242a","url":null,"abstract":"A short, efficient, and stereoselective methodology is described for the synthesis of 5-((dimethylamino)methylene)hydantoins and their conversion into oxoaplysinopsins and parabanic acids. A highly convergent one-pot, two-step reaction between methyl <em>N</em>-arylglycinates, isocyanates, and DMFDMA under microwave irradiation provided the corresponding (dimethylamino)methylene hydantoins as a single <em>E</em>-stereoisomer in high overall yields. The synthesis of (<em>S</em>)-1-(1-phenylethyl) chiral hydantoins, which undergo a stereoselective addition of acetic anhydride, aza-heterocycles, and amines, received special attention. The reaction with indole delivered a series of novel oxoaplysinopsins. Meanwhile, parabanic acids were prepared by a new approach, treating (dimethylamino)methylene hydantoins with <em>m</em>CPBA to generate the oxidative fragmentation of the exocyclic methylene. The antifungal evaluation of the prepared products was carried out on a series of <em>Candida</em> spp., finding potent growth inhibition. According to previous docking studies, this activity is probably due to the inhibitory interaction of the derivatives with the active site of the fungal HMGR enzyme.","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A facile access to aliphatic trifluoromethyl ketones via photocatalyzed cross-coupling of bromotrifluoroacetone and alkenes","authors":"Satoshi Mizuta, Tomoko Yamaguchi, Masaharu Iwasaki, Takeshi Ishikawa","doi":"10.1039/d4ob01247j","DOIUrl":"https://doi.org/10.1039/d4ob01247j","url":null,"abstract":"Biological molecules incorporating trifluoromethyl ketones (TFMKs) have emerged as reversible covalent inhibitors, aiding in the management and treatment of inflammatory diseases, cancer, and respiratory conditions. TFMKs, renowned for their versatile binding properties and adaptability, are pivotal in the rational design of novel drugs for diverse diseases. The photocatalytic insertion of alkenes, abundant feedstocks, into the α-carbon of trifluoromethylacetone represents a highly effective and atom-economical method for synthesizing valuable TFMKs. However, these processes typically necessitate high-energy photoirradiation (<em>λ</em> &gt; 300 nm, Hg lamp) and stoichiometric oxidants to generate the acetonyl radical from acetone. In our study, we demonstrate the visible-light photocatalytic radical addition into olefins using bromotrifluoroacetone as the trifluoroacetonyl radical precursor under mild conditions. Aliphatic trifluoromethyl ketones or the corresponding bromo-substituted products can be obtained by selecting an appropriate photocatalyst and solvent. Comprehensive experimental investigations, including cyclic voltammetry, Stern–Volmer quenching studies, and kinetic isotope effects, corroborate the synthesis of trifluoroacetonyl radical species from bromotrifluoroacetone under photoredox conditions. Further, we demonstrate the efficient synthesis of an oseltamivir derivative bearing a trifluoromethylketone moiety, which shows promising biological activity. Hence, this methodology will streamline the direct introduction of trifluoromethyl ketone into biological target molecules during drug discovery.","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142202344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A zero-background fluorescent probe for sensing and imaging of glutathione <i>via</i> the \"covalent-assembly\" approach.","authors":"Zheng Yang, Zhiyao Wang, Ying Peng, Hao Yang, Qian Wang, Xiaodan Jia, Xiangrong Liu","doi":"10.1039/d4ob01181c","DOIUrl":"https://doi.org/10.1039/d4ob01181c","url":null,"abstract":"<p><p>Developing selective and sensitive fluorescent probes for the detection of glutathione (GSH) concentration and intracellular distribution is of great significance for early diagnosis and treatment of diseases such as liver injury and cancer since GSH plays irreplaceable roles in regulating intracellular redox homeostasis. Herein, we present a new fluorescent probe that can be specifically activated by GSH through the conjugate addition and hydrolysis induced covalent-assembly approach for achieving zero-background interference fluorescence off-on sensing. Besides, the probe exhibited prominent selectivity and sensitivity, a low detection limit and cytotoxicity, thus successfully realizing specific real-time monitoring and tracking of GSH levels in living cells. As a consequence, this work might provide a potentially promising candidate for validating the function of GSH in various physiological and pathological processes, which is beneficial for early diagnosis and therapeutics of related diseases.</p>","PeriodicalId":96,"journal":{"name":"Organic & Biomolecular Chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}