Molecular Diversity最新文献

{"title":"Design, synthesis, and biological evaluation of glycyrrhetinic acid-cinnamamide derivatives as HMGB1/TLR4 pathway inhibitors for sepsis-induced liver injury.","authors":"Jiao Wang, Tian Guo, Zhe Zheng, Yaping Zhang, Zhian Zha, Xiaohan Zhang, Jie Song, Dongyi Wei, Jianbin Yang","doi":"10.1007/s11030-026-11596-1","DOIUrl":"10.1007/s11030-026-11596-1","url":null,"abstract":"<p><p>Sepsis-associated systemic inflammation represents a predominant etiology of acute liver injury, with the high-mobility group box 1(HMGB1)-mediated late-phase inflammatory response playing a central pathogenic role. As a key damage-associated molecular pattern molecule, HMGB1 activates downstream pro-inflammatory cascades through binding to Toll-like receptor 4(TLR4), triggering early-phase cytokine release (TNF-α, IL-1β) and upregulating inflammatory effectors(iNOS, COX-2), thereby establishing a self-amplifying cycle of inflammatory signaling and oxidative stress. Guided by this pathological framework, we developed a series of novel 3-aminoglycyrrhetinic acid derivatives through rational drug design targeting the HMGB1/TLR4 axis. Structural optimization of glycyrrhetinic acid involved C-30 benzyl esterification, C-3 amination, and subsequent conjugation with differentially substituted cinnamic acids, yielding 18 novel analogs. Through systematic pharmacological screening, compound 18 (featuring a 3',4'-dihydroxycinnamamide pharmacophore) emerged as a superior multi-target therapeutic candidate in LPS-challenged RAW264.7 and HepG2 models. It demonstrated concentration-dependent suppression of the upstream mediators TNF-α, IL-1β, HMGB1, and TLR4, while concurrently inhibiting downstream effectors iNOS and COX-2, achieving potent NO reduction (IC₅₀ = 1.13 µM). Notably, compound 18 exhibited dual mechanistic activity by significantly attenuating intracellular ROS generation and restoring mitochondrial membrane integrity, indicating synchronized control of inflammatory and oxidative pathways. Molecular docking analysis indicates that the 3',4'-dihydroxy structure of compound 18 exhibits significantly higher binding affinity with HMGB1 compared to the monohydroxy-substituted compounds 17 and GA. In a murine sepsis model, treatment with compound 18 resulted in remarkable amelioration of hepatic histopathological damage, showing significantly enhanced efficacy compared to the parent compound GA. Mechanistic investigation confirmed that its hepatoprotective effects are mediated through suppression of the hepatic HMGB1/TLR4 signaling axis and subsequent modulation of iNOS/COX-2 expression. Pharmacokinetic studies demonstrated that compound 18 exhibited an oral bioavailability of 39.47%, significantly superior to GA, and showed enriched distribution in liver tissue (accounting for 42.0%). These findings establish compound 18 as a promising lead candidate for developing targeted therapeutics against HMGB1/TLR4-driven acute liver injury in sepsis, providing new strategic insights for inflammatory liver pathology intervention.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"8395-8421"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and anti-glioblastoma multiforme activity of N-methoxy-2-(pyrimidin-4-ylamino)benzamide derivatives as focal adhesion kinase inhibitors.","authors":"Yang Chen, Ting Wu, Haolin Yang, Aoxiang Fan","doi":"10.1007/s11030-026-11670-8","DOIUrl":"10.1007/s11030-026-11670-8","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) remains a lethal brain cancer with poor prognosis, largely due to the limitations of current therapies. Focal adhesion kinase (FAK) is a promising therapeutic target, given its central role in driving GBM progression, invasion, and microenvironment adaptation. While several FAK inhibitors, such as TAE-226, have entered clinical trials, none have achieved approval, underscoring the need for novel, more effective agents. Through a structure-based molecular hybridization strategy that integrated key pharmacophores from TAE-226 and the clinical candidate GSK2256098, a novel series of N-methoxy-2-(pyrimidin-4-ylamino)benzamide derivatives were designed and synthesized. Among the eighteen synthesized compounds, 7h emerged as the most potent compound. It demonstrated superior enzymatic and cellular activity, with FAK inhibitory activity (IC₅₀ = 3.62 nM) and potent anti-proliferative activity against U87-MG glioblastoma cell line (IC₅₀ = 71 nM), outperforming the positive control TAE-226 (IC₅₀ = 4.81 nM and 0.49 µM, respectively). Furthermore, in the PAMPA-BBB assay, the passive permeability (Pe) of 7h reached 25.97 × 10^-6 cm∙s⁻¹, which was comparable to and slightly higher than TAE-226 (24.80 × 10^-6 cm∙s⁻¹), suggesting favorable passive permeation potential that warrants further in vivo brain distribution studies. Mechanistic studies in U87-MG cells revealed that compound 7h induced apoptosis and pronounced G2/M cell cycle arrest compared to TAE-226 at equivalent concentrations, suggesting a potent anti-proliferative effect associated with FAK inhibition. In a U87-MG xenograft mouse model, 7h exhibited favorable in vivo dose-dependent antitumor efficacy with this specific model. At 10 mg/kg/day, its tumor growth inhibition (TGI = 54.1%) exceeded that of TAE-226 (TGI = 50.1%), while a dose of 20 mg/kg/day achieved enhanced TGI of 83.44%. Molecular docking simulations suggested that 7h combined within the ATP pocket of FAK, facilitated by synergistic hydrophobic interactions and key hydrogen bonds with residues ILE-428 and CYS-502. Overall, as a preliminary proof-of-concept, compound 7h represents a novel and promising FAK inhibitor, demonstrating potential for overcoming current therapeutic limitations in GBM.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7531-7549"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, biological activity and in silico evaluation of phenylthiazole derivatives as multifunctional skin-whitening agents.","authors":"Yang Xu, Xuhui Liang, Chang-Gu Hyun","doi":"10.1007/s11030-026-11522-5","DOIUrl":"10.1007/s11030-026-11522-5","url":null,"abstract":"<p><p>Excessive melanin accumulation causes hyperpigmentation, a skin pathophysiology that highlights the need for safe and multifunctional skin-whitening agents. Building on the reported tyrosinase inhibitory potential of phenylthiazole derivatives, a series of compounds was designed and synthesized to investigate the structural determinants of their multi-functional activities. The biological evaluation included mushroom tyrosinase (mTYR) inhibition, as well as anti-melanogenic, anti-inflammatory, and antioxidant assays. Among the series, compound 3c exhibited the most potent multi-functional profile, showing mTYR inhibition (IC₅₀ = 30.8 ± 2.7 µM) with a mixed-type inhibitory mechanism (K_i = 20 µM), a 34% reduction in melanin content at 40 µM, significant nitric oxide inhibition (IC₅₀ = 33.7 ± 2.0 µM), and strong antioxidant activity (SC₅₀ = 29.0 ± 0.8 µM). Density Functional Theory (DFT) calculations and predicted physicochemical properties indicate that 3c possesses favorable molecular stability and promising potential for skin penetration. Molecular docking and molecular dynamics (MD) simulations further demonstrated that 3c stably occupies the active pocket of human tyrosinase-related protein 1 (TYRP1, PDB ID: 5M8M), forming key interactions with Zn²⁺-coordinating residues and maintaining a stable energetic profile. Collectively, these findings indicate that 3c exhibits the most balanced multi-functional activity within the series and holds promise as a lead compound for topical skin-whitening applications.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"8297-8312"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147873023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational design of triazole tyrosinase inhibitors via integrated free energy calculations.","authors":"Nathália Luiza Oliveira Costa, Cláudio Nahum Alves, Lucas Sousa Martins, José Rogério A Silva","doi":"10.1007/s11030-026-11601-7","DOIUrl":"10.1007/s11030-026-11601-7","url":null,"abstract":"<p><p>Tyrosinase (TYR) is a copper-containing metalloenzyme involved in melanin biosynthesis and is an important target in the development of treatments for hyperpigmentation disorders, including melasma, post-inflammatory hyperpigmentation, and melanoma. Among the scaffold classes investigated for TYR inhibition, 1,2,4-triazole derivatives have attracted increasing interest. In this study, we evaluated a structurally diverse series of triazole derivatives using an integrated computational workflow that included absorption, distribution, metabolism, excretion and toxicity (ADMET) profiling, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations based on Linear Interaction Energy (LIE) and Free Energy Perturbation (FEP). Using Bacillus megaterium TYR as the model enzyme, the triazole derivatives generally produced more favorable docking scores than kojic acid and established recurring interactions with hydrophobic residues such as Met215, Val217, Ala221, and Phe227, as well as hydrogen-bonding contacts with Gly216. The free energy calculations reproduced the experimental binding affinities with high accuracy (FEP: R² = 0.91, MAE = 0.20 kcal/mol; LIE: R² = 0.93, MAE = 0.54 kcal/mol). Residue-level energy analysis indicated that interactions involving Arg209, Gly216 and Val218 play a major role in ligand binding across the series, with aromatic and halogenated substituents favoring stronger van der Waals contacts in this region. Overall, these results provide a consistent structural and energetic framework for understanding triazole-based TYR inhibition and may support the rational design of improved inhibitors for cosmetic and therapeutic applications.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"8461-8478"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Total synthesis of the proposed menominin A and its stereoisomers: identification of a highly potent isomer (1a) against RM-1 prostate cancer cells.","authors":"Yu Jiang, Xin Li, Jiayi Li, Yuhan Xiao, Huiling Xu, Junqiu Zhang, Min-Jing Cheng, Junyang Liu, Jia-Lei Yan","doi":"10.1007/s11030-026-11631-1","DOIUrl":"10.1007/s11030-026-11631-1","url":null,"abstract":"<p><p>Menominin A is a natural cyclodepsipeptide isolated from the freshwater sponge-associated cyanobacterium Nostoc sp. UIC 10,607, and exhibits antiproliferative activity against the high-grade serous ovarian cancer cell line OVCAR3. The pronounced biological relevance and limited natural abundance have rendered menominin A a compelling target for total synthesis and biological studies. Herein, we report the total synthesis and cytotoxicity evaluation of the proposed structure of menominin A and its seven isomers. Key features of this synthesis include an Evans aldol reaction to construct the 3-hydroxy-2-methylcarboxylic acid unit, a chiral phosphonic acid-mediated asymmetric allylic addition to establish a chiral alcohol, and a ring-closing metathesis followed by hydrogenation to construct the macrocyclic framework. The mismatch between the NMR spectra of our synthetic samples and those of the natural product suggests that the originally proposed structure is incorrect. Biological evaluation indicated that three compounds (1a, 1b, and 1g) displayed moderate to potent antitumor activity against osteosarcoma, human colon cancer, and prostate cancer. The most active compound 1a exhibited antiproliferative activity against RM-1 cells in a sustained manner, yielding IC₅₀ values of 4.18 µM (48 h) and 1.15 µM (72 h).</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7497-7512"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In silico discovery of natural compounds from Vietnamese essential oils database with target binding to cancer-related proteins.","authors":"Thang Truong Le, Chau Dao Minh Huynh, Nam Hoang Phan, Anh Mai Duong, Nguyen Xuan Hanh Ngo, Phuc Nguyen Thien Dao, Viet Hoang, Thach Phan Van","doi":"10.1007/s11030-026-11597-0","DOIUrl":"10.1007/s11030-026-11597-0","url":null,"abstract":"<p><p>Cancer remains a global health challenge, requiring diverse and multi-targeted therapeutic strategies. In recent years, natural compounds-particularly essential oils (EOs), which are widely available and chemically diverse-have gained growing attention in cancer prevention and treatment. In this study, we employed an in silico approach to identify essential oil-derived compounds with potential against cancer. A chemical library of 2,033 compounds was constructed based on GC-MS profiling of essential oils extracted from Vietnamese plants. Among these, 610 compounds were predicted to exhibit anticancer activity. Following IC₅₀ and ADMET-based filtering, 477 compounds were identified as both cytotoxic and pharmacologically safe. These compounds were further evaluated through molecular docking against five key cancer-related targets: VEGF-A, PARP-1, mTOR, BRAF, and EGFR. 15 candidates showed strong binding affinities across multiple targets, including m-camphorene (- 9.9 kcal/mol with BRAF), β-amyrin (- 7.93 kcal/mol with PARP-1), β-sitostenone (- 9.33 kcal/mol with EGFR), trans-β-elemenone (- 7.67 kcal/mol with VEGF-A), and occidentalol (- 8.3 kcal/mol with mTOR). Molecular dynamics simulations further confirmed the structural stability of m-camphorene-BRAF complex. To evaluate its possible clinical relevance, the prognostic significance of m-camphorene-related gene signatures was analyzed using transcriptomic datasets from TCGA across ten common cancer types. Significant associations between these signatures and patient survival were observed in BRCA, KIRC, and SKCM, suggesting potential translational relevance. Overall, this study highlights the value of natural compound libraries and virtual screening strategies in accelerating drug discovery from traditional medicinal sources and provides a computational foundation for further experimental validation of EO-derived anticancer agents.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"8479-8497"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent progress in the application of CF₃-imidoyl sulfoxonium ylides in transition metal-catalyzed C-H functionalization.","authors":"Xiaoying Zhao, Dulin Kong, Hongliang Wu, Ruirui Zhai, Xun Chen","doi":"10.1007/s11030-026-11604-4","DOIUrl":"10.1007/s11030-026-11604-4","url":null,"abstract":"<p><p>The incorporation of CF₃ groups into molecules represents a significant strategy in medicinal chemistry, as this modification can profoundly enhance their biological activities. CF₃-imidoyl sulfoxonium ylides (TFISYs) have emerged as versatile and stable carbene precursors, demonstrating remarkable utility as CF₃-containing coupling partners for the assembly of diverse CF₃-heterocycles. This review systematically summarizes recent advances in transition metal-catalyzed, directing group-assisted C-H bond activation reactions employing TFISYs as key coupling partners. The discussion is organized to provide a clear methodological classification based on the multifunctional roles of TFISYs, which can act as alkenylating reagents as well as C1, C2, and C2N1 cyclic unit. A comprehensive evaluation of substrate compatibility, reaction mechanisms, structure modification, and practical applications in functional molecule synthesis is presented.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7861-7890"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational approaches for identifying quorum sensing inhibitors.","authors":"Lin Zhong, Shwetlaxmi Patil, B Lakshmi, Pratibha Singh, Satish Kumar Rajasekharan, S L Rath, Vinothkannan Ravichandran","doi":"10.1007/s11030-026-11606-2","DOIUrl":"10.1007/s11030-026-11606-2","url":null,"abstract":"<p><p>Quorum sensing (QS) is a critical cell-to-cell communication mechanism employed by microorganisms to coordinate their collective behaviors, including biofilm formation, virulence regulation, and development of antimicrobial resistance (AMR). Disruption of QS using quorum sensing inhibitors (QSIs) has emerged as a promising anti-virulence strategy for combating multidrug-resistant bacterial infections. This review focuses on new technologies in drug discovery applied to the identification and optimization of QSIs, with particular emphasis on computational and data-driven methods. The key methodologies discussed include molecular docking, molecular dynamics simulations, virtual screening, and quantitative structure-activity relationship (QSAR) modeling. Studies demonstrating the successful application of these technologies against clinically relevant pathogens, such as Pseudomonas aeruginosa and Chromobacterium violaceum, are highlighted to illustrate the structure-guided QSI discovery. In addition, this review examines the current challenges in QSI development, including target specificity, resistance avoidance, and translational limitations. Recent advances in machine learning, artificial intelligence assisted screening, and systems biology-based modeling are also discussed as transformative tools that enhance hit identification, lead optimization, and mechanistic understanding. Collectively, these emerging technologies underscore the potential of QS-targeted drug discovery to deliver innovative anti-virulence therapies and contribute to global efforts to mitigate AMR.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7773-7793"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baicalin attenuates angiotensin II-induced vascular endothelial injury via targeted activation of the Nrf2 signaling pathway: Integrated computational and in vitro evidence.","authors":"Dongli Zhang, Qian Zheng, Liyan Zhang, Haiyan Jia, Xin Zhao, Shuangjie Ren, Yanmin Wu, Yeran Zhu, Xinwen Zhang","doi":"10.1007/s11030-026-11602-6","DOIUrl":"10.1007/s11030-026-11602-6","url":null,"abstract":"<p><p>Angiotensin II (AngII)-mediated oxidative stress is a primary driver of vascular endothelial dysfunction, a critical pathogenesis in hypertension and cardiovascular diseases. While baicalin is recognized for its cardioprotective properties, the precise atomic-level mechanism governing its interaction with the Nrf2 signaling axis remains to be fully characterized. This study employs an integrated in silico and in vitro framework to elucidate the molecular determinants by which baicalin mitigates AngII-induced endothelial injury. Quantum chemical calculations using Density Functional Theory (DFT) revealed a relatively narrow HOMO-LUMO energy gap (∆E = 3.86 eV), suggesting enhanced electronic reactivity and a potential tendency toward redox-related activity. Pharmacokinetic profiling further predicted a favorable ADMET profile with negligible toxicity risks. Molecular docking and 500 ns molecular dynamics (MD) simulations identified a stable, high-affinity binding mode (∆G_bind=-34.54 kcal/mol) for baicalin within the key regulatory pocket. Notably, Free Energy Landscape (FEL) and per-residue energy decomposition analyses unveiled a synergistic binding mechanism, driven predominantly by a persistent backbone hydrogen bond at Val608 and hydrophobic clustering involving Val369 and Cys368. Experimental validation in AngII-stimulated HUVECs corroborated these computational predictions, demonstrating that baicalin treatment effectively abrogates the pathological upregulation of Keap1, thereby facilitating Nrf2 stabilization and the subsequent restoration of downstream cytoprotective enzymes (HO-1 and NQO-1). Taken together, these findings provide a structural elucidation of the mechanism by which baicalin activates the Nrf2 signaling pathway through direct binding to Keap1 and the subsequent inhibition of Nrf2 ubiquitination and degradation. Consequently, this study establishes a theoretical and experimental foundation for its therapeutic application in vascular protection.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"8499-8513"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148154785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent developments of α-nitroketones/α‑nitro-α,β-unsaturated ketones as nucleophilic/electrophilic acyl transfer reagents in the catalytic asymmetric reaction.","authors":"Soumen Mistri, Keshab Mondal","doi":"10.1007/s11030-026-11590-7","DOIUrl":"10.1007/s11030-026-11590-7","url":null,"abstract":"<p><p>The utilization of α-nitro ketones and α-nitro-α,β-unsaturated ketones as both nucleophilic and electrophilic acyl transfer agents has attracted significant attention in asymmetric synthesis due to their unique electronic characteristics and high reactivity. The presence of the strongly electron-withdrawing nitro group at the α-position significantly enhances the acidity of adjacent protons and activates the carbonyl group of α-nitro ketones toward nucleophilic attack. A comparable activation effect is observed in α-nitro-α,β-unsaturated ketones where the conjugated olefinic moiety becomes more susceptible to nucleophilic addition. This dual reactivity enables a wide range of asymmetric acyl transfer processes under mild and enantioselective conditions. In asymmetric catalysis, these nitro-substituted ketones serve as versatile intermediates capable of generating chiral acylated products with excellent enantiocontrol and also demonstrate their efficiency in enantioselective carbon-carbon and carbon-hetero bond-forming reactions to access highly functionalized chiral building blocks. The development of these reagents provides an environmentally benign alternative to traditional acyl reagents by minimizing corrosive by-products and improving atom economy. Moreover, the nitro group can be readily transformed into various functional motifs, broadening the synthetic utility of these compounds. This review highlights recent developments in the use of α-nitroketones and α-nitro-α,β-unsaturated ketones as bifunctional acyl transfer reagents, focusing on mechanistic insights, catalyst design, and their applications in the construction of optically active building blocks relevant to pharmaceutical and natural product chemistry.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":"7735-7771"},"PeriodicalIF":4.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148051499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}