α-Ketoglutaric acid in Ugi reactions and Ugi/aza-Wittig tandem reactions

• Vladyslav O. Honcharov,
• Yana I. Sakhno,
• Olena H. Shvets,
• Vyacheslav E. Saraev,
• Svitlana V. Shishkina,
• Tetyana V. Shcherbakova and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2025, 21, 2021–2029, doi:10.3762/bjoc.21.157

• as low toxicity of these substances [42]. Biological activity screening also suggests that quinoxalinone-based compounds can inhibit aldose reductase [43], α-amylase and α-glucosidase [44], as well as key enzymes involved in the processes of saturated fatty acid conversion [45] and glycogenolysis [46

Synthesis, biological and electrochemical evaluation of glycidyl esters of phosphorus acids as potential anticancer drugs

• Almaz A. Zagidullin,
• Emil R. Bulatov,
• Mikhail N. Khrizanforov,
• Damir R. Davletshin,
• Elvina M. Gilyazova,
• Ivan A. Strelkov and
• Vasily A. Miluykov

Beilstein J. Org. Chem. 2025, 21, 1909–1916, doi:10.3762/bjoc.21.148

• differences in IC50 values reflected the degree of alkylating potency and the selective toxicity toward cancer cells. Conclusion In this study, we synthesized and comprehensively characterized a series of glycidyl esters of phosphorus acids 1–3, evaluating their structural features, cytotoxic potential, and

• cancer cell lines (PC-3 and MCF7), with diglycidyl methylphosphate (2) demonstrating the highest potency toward MCF7 cells. While all compounds exhibited some level of toxicity toward non-cancerous HSF cells, their IC50 values in fibroblasts were generally higher than those observed in tumor cells

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• , stimulus responsiveness, specific recognition and binding, and multi-target synergistic action [14][15][16]. These characteristics enable precise control of drug release and targeted drug delivery, thereby improving drug stability and bioavailability, and reducing drug toxicity and side effects

• cyclodextrins in terms of controllable functionalization [61]. In clinical applications, particularly for anticancer drug conjugation, CAs demonstrate remarkable cancer cell selectivity, minimized off-target effects, enhanced delivery efficiency, and reduced systemic toxicity. Additionally, their synthetic

• further utilized this feature to achieve reversible transformation of amphiphilic guest molecules between micellar and vesicular states and have successfully applied it to the controlled release of dye molecules. Notably, the system can also effectively neutralize the toxicity of paraquat through host

Facile synthesis of hydantoin/1,2,4-oxadiazoline spiro-compounds via 1,3-dipolar cycloaddition of nitrile oxides to 5-iminohydantoins

• Juliana V. Petrova,
• Varvara T. Tkachenko,
• Victor A. Tafeenko,
• Anna S. Pestretsova,
• Vadim S. Pokrovsky,
• Maxim E. Kukushkin and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2025, 21, 1552–1560, doi:10.3762/bjoc.21.118

• therapeutic efficacy (lower IC50 values) [18] but greater toxicity to healthy cells in comparison with spiro compounds [19]. Such hybrid-designed molecules may contain a third heterocycle as a linker, spiro-joined with one of the pharmacophore moieties. In this case, another pharmacophore fragment is included

Azide–alkyne cycloaddition (click) reaction in biomass-derived solvent Cyrene^TM under one-pot conditions

• Zoltán Medgyesi and
• László T. Mika

Beilstein J. Org. Chem. 2025, 21, 1544–1551, doi:10.3762/bjoc.21.117

• viscosity. Accordingly, the CuAAC reactions are usually performed in fossil-based common organic reaction media having high vapor pressure, toxicity, flammability, etc., which could result in several serious environmental concerns. According to the FDA guideline [14], common polar aprotic organic solvents

• position, the Circa Group announced the production of CyreneTM of 1 ton/year in 2020, signifying the large-scale production of this new biobased molecule [24]. CyreneTM is a non-toxic substance with an LD50,oral > 2000 mg/kg (OECD No. 423, acute toxicity method). E(L)C50 > 100 mg/L (daphnia and algae), and

Ambident reactivity of enolizable 5-mercapto-1H-tetrazoles in trapping reactions with in situ-generated thiocarbonyl S-methanides derived from sterically crowded cycloaliphatic thioketones

• Grzegorz Mlostoń,
• Małgorzata Celeda,
• Marcin Palusiak,
• Heinz Heimgartner,
• Marta Denel-Bobrowska and
• Agnieszka B. Olejniczak

Beilstein J. Org. Chem. 2025, 21, 1508–1519, doi:10.3762/bjoc.21.113

• by MTT assay and expressed as CC50 parameter (50% cytotoxic concentration) [32]. All results are gathered in Table 2. In general, the tested compounds did not demonstrate high levels of toxicity towards the investigated non-cancer cell lines. Among them, Vero cells showed the highest sensitivity

• insensitive to the investigated compounds (CC50 > 1000 µM for HepG2, A549 and CC50 > 300 µM for T98G), whereas HeLa cells demonstrated increased sensitivity. The most active compounds 9a, 9h and 10i, revealed their toxicity with CC50 < 10 µM (6.35 ± 1.75 µM; 2.11 ± 0.53 µM and 9.26 ± 3.14 µM, respectively

• ). In the same cell line, the remaining compounds demonstrated cytotoxic activity in the range of 35.68‒74.12 µM (10o, 10h, 10q, 9j, and 9i), while the least active compound 10l showed a level of toxicity an order of magnitude lower (CC50 = 215.31 ± 27.51 µM). The results obtained in this study

Heterologous biosynthesis of cotylenol and concise synthesis of fusicoccane diterpenoids

• Ye Yuan,
• Zhenhua Guan,
• Xue-Jie Zhang,
• Nanyu Yao,
• Wenling Yuan,
• Yonghui Zhang,
• Ying Ye and
• Zheng Xiang

Beilstein J. Org. Chem. 2025, 21, 1489–1495, doi:10.3762/bjoc.21.111

• activity than cotylenin A in cell growth inhibition assays and less toxicity in single-agent treatments [27][28]. Recently, Jiang and Renata described a chemoenzymatic approach that combines the skeletal construction by chemical methods and enzymatic C–H oxidations [29]. The synthesis employs a catalytic

• cotylenin A by Nakada and co-workers [21]. However, installing the C9 hydroxy group requires the use of stoichiometric MoOPH [39], which raises toxicity and safety issues. Therefore, we sought an enzymatic method to selectively oxidize 5 at the C9 position. Dairi and co-workers reported that Orf7 oxidizes

Microwave-enhanced additive-free C–H amination of benzoxazoles catalysed by supported copper

• Andrei Paraschiv,
• Valentina Maruzzo,
• Filippo Pettazzi,
• Stefano Magliocco,
• Paolo Inaudi,
• Daria Brambilla,
• Gloria Berlier,
• Giancarlo Cravotto and
• Katia Martina

Beilstein J. Org. Chem. 2025, 21, 1462–1476, doi:10.3762/bjoc.21.108

• environmental abundance, low cost and low overall toxicity. A wide range of aminating reagents have been utilised, including nitrogen electrophiles and amines in the presence of external or internal oxidants [27], in many types of copper-catalysed synthetic protocols. The direct copper-catalysed C–H amination

Investigations of amination reactions on an antimalarial 1,2,4-triazolo[4,3-a]pyrazine scaffold

• Henry S. T. Smith,
• Ben Giuliani,
• Kanchana Wijesekera,
• Kah Yean Lum,
• Sandra Duffy,
• Aaron Lock,
• Jonathan M. White,
• Vicky M. Avery and
• Rohan A. Davis

Beilstein J. Org. Chem. 2025, 21, 1126–1134, doi:10.3762/bjoc.21.90

• Plasmodium falciparum 3D7 strain. The tertiary alkylamine products 10–14 displayed antimalarial activity with IC50 values ranging from 9.90 to 23.30 µM against P. falciparum 3D7, with compounds 10–12 demonstrating no toxicity at 80 µM against the human embryonic kidney cell line HEK293. Keywords: amine

Gold extraction at the molecular level using α- and β-cyclodextrins

• Susana Santos Braga

Beilstein J. Org. Chem. 2025, 21, 1116–1125, doi:10.3762/bjoc.21.89

• most effective solvents for gold [20]. Because of the high toxicity and strong environmental impact of cyanides, eco-friendlier alternatives are currently under research. Some are based on replacing cyanide with less harmful chemicals, such as thiocyanate, thiourea, or thiosulfate. Another alternative

Recent advances in synthetic approaches for bioactive cinnamic acid derivatives

• Betty A. Kustiana,
• Galuh Widiyarti and
• Teni Ernawati

Beilstein J. Org. Chem. 2025, 21, 1031–1086, doi:10.3762/bjoc.21.85

• cinnamic acid (7) in a deep eutectic solvent of choline chloride/urea (ChCl/urea) to give amides 12 and 13 in moderate yields via triacylated triazine 14 as the active ester (Scheme 5A) [36]. The TCT reagent and ChCl/urea solvent are known for their non-toxicity and low cost, promoting their wide

Biobased carbon dots as photoreductants – an investigation by using triarylsulfonium salts

• Valentina Benazzi,
• Arianna Bini,
• Ilaria Bertuol,
• Mariangela Novello,
• Federica Baldi,
• Matteo Hoch,
• Alvise Perosa and
• Stefano Protti

Beilstein J. Org. Chem. 2025, 21, 1024–1030, doi:10.3762/bjoc.21.84

• carbon nanomaterials category in view of their stability, water affinity/dispersibility, and low toxicity [1][2][3][4]. Such nanomaterials significantly absorb in the 280–350 nm region due to a wide range of π–π* (C=C) and n–π* (C=O) transitions in both the core and on the surface of the particles. CDs

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• interactions of these derivatives with the enzyme inducible nitric oxide synthase (iNOS), compared to dexamethasone used as a reference. Furthermore, ADMET (absorption, distribution, metabolism, excretion, and toxicity) predictions were performed to assess their drug-likeness and pharmacokinetic properties

• prediction of drug-like properties, in silico evaluations of ADMET (absorption, distribution, metabolism, excretion, and toxicity) characteristics of all potential drug candidates were conducted using the pkCSM online tool [28]. The resulting data are presented in Table 3. The absorption capability of the

• organic cation transporter 2 (OCT2) was examined, with OCT2 playing a pivotal role in the renal elimination of both xenobiotics and endogenous compounds. The predicted results suggest that none of the studied compounds act as OCT2 substrates. Toxicity was assessed using the Ames test, a widely accepted

Recent advances in allylation of chiral secondary alkylcopper species

• Minjae Kim,
• Gwanggyun Kim,
• Doyoon Kim,
• Jun Hee Lee and
• Seung Hwan Cho

Beilstein J. Org. Chem. 2025, 21, 639–658, doi:10.3762/bjoc.21.51

• , including non-toxicity, bench-stability, structural diversity, straightforward preparation, and broad commercial availability. Significant contributions include Sawamura's work with alkyl–9-BBN [32][33][34][35][36][37] as a nucleophile. These developments have collectively transformed copper-catalyzed AAA

Photocatalyzed elaboration of antibody-based bioconjugates

• Marine Le Stum,
• Eugénie Romero and
• Gary A. Molander

Beilstein J. Org. Chem. 2025, 21, 616–629, doi:10.3762/bjoc.21.49

• unconjugated and “overloaded” antibodies. Unconjugated antibodies compete with antibodies containing payloads for binding, which can diminish the effectiveness of the antibody-payload materials. On the other hand, excessive loading of the antibody can lead to antibody aggregation, increased toxicity, decreased

Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• /bjoc.21.45 Abstract Formaldehyde emerges as a cornerstone in multicomponent reactions, mainly prized for its robust reactivity. Yet, alongside these beneficial traits, this highly reactive C1-building block raises concerns, primarily regarding its toxicity. One notable issue is the challenge of

• controlling the formation of undesired byproducts during its reactions. This review explores alternative C1-building blocks that serve as surrogates for formaldehyde, aiming to mitigate some of the challenges associated with its use in multicomponent reactions. By identifying these alternatives, toxicity

• surrogate and source of formaldehyde Dimethyl sulfoxide is a well-known polar-aprotic solvent with high boiling point that is used in several organic synthetic reactions because of affordable cost and relatively low toxicity. There are numerous examples that show the use of DMSO as a C1 or C2 building block

Red light excitation: illuminating photocatalysis in a new spectrum

• Lucas Fortier,
• Corentin Lefebvre and
• Norbert Hoffmann

Beilstein J. Org. Chem. 2025, 21, 296–326, doi:10.3762/bjoc.21.22

• alcohols 32. Notably, this protocol is both energy-efficient and operationally simple, with the reaction being carried out under air in ethanol, a low-toxicity solvent. Moreover, the scalability of the reaction was demonstrated with larger-scale experiments (up to 5 mmol), achieving excellent yields and

• have been extensively studied in the literature such as bridged Eosin Y 37 [44], BODIPY 38 [45], and dibenzothiazole 39 (Figure 5) [46]. Indeed, organic dyes, with their inherent advantages of low toxicity, environmental friendliness, and tunable optical properties, represent a promising alternative

• remarkable redox versatility, enabling them to participate in both oxidation and reduction reactions and few of them are naturally occurring such as Betanin and Musca-Aurin II (Figure 9). Their relatively stable excited states, combined with their low toxicity and ease of chemical modification, make them a

Dioxazolones as electrophilic amide sources in copper-catalyzed and -mediated transformations

• Seungmin Lee,
• Minsuk Kim,
• Hyewon Han and
• Jongwoo Son

Beilstein J. Org. Chem. 2025, 21, 200–216, doi:10.3762/bjoc.21.12

• widely used as N-acylamide sources in amidation processes of challenging substrates, typically employing precious transition metals. However, these catalytic systems often present several challenges associated with cost, toxicity, stability, and recyclability. Among the 3d transition metals, copper

• increasing interest as affordable, versatile, and sustainable catalytic systems. These catalysts are extensively employed in organic synthesis owing to their cost-effectiveness, reduced toxicity, and natural abundance [20][21][22][23][24][25][26][27][28]. The use of copper salts has enabled a variety of

Recent advances in electrochemical copper catalysis for modern organic synthesis

• Yemin Kim and
• Won Jun Jang

Beilstein J. Org. Chem. 2025, 21, 155–178, doi:10.3762/bjoc.21.9

• ], however, no comprehensive review focusing on Cu-catalyzed electrochemistry has been reported to date. Copper catalysts are potential candidates for pharmaceutical applications owing to their abundance, low cost, and lower toxicity compared with noble transition metals such as palladium [39]. In terms of

Cu(OTf)₂-catalyzed multicomponent reactions

• Sara Colombo,
• Camilla Loro,
• Egle M. Beccalli,
• Gianluigi Broggini and
• Marta Papis

Beilstein J. Org. Chem. 2025, 21, 122–145, doi:10.3762/bjoc.21.7

• ; heteropolycycles; multicomponent reactions; one-pot reaction; Introduction Copper has gained a relevant role in organic synthesis as an alternative to precious metals due to its low toxicity, ease of handling, high catalytic activity, and cost-effectiveness [1][2]. In recent years, Cu(OTf)2 has significantly

• toxicity [3][4][5][6][7]. Multicomponent reactions are one of the most effective methods to assemble multiple reagents, thus facilitating access to the target molecules more quickly, due to atom/step economy, short reaction times, and eco-friendly benefits. Combining multicomponent reactions with

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• radical activation, resulting in milder and safer reaction conditions [14][15][16]. Given the toxicity of tin-based compounds, there has been significant interest in developing alternative halogen-atom-transfer reagents. Borane, alkylamine, and silane compounds have emerged as effective XAT reagents upon

Multicomponent reactions driving the discovery and optimization of agents targeting central nervous system pathologies

• Lucía Campos-Prieto,
• Aitor García-Rey,
• Eddy Sotelo and
• Ana Mallo-Abreu

Beilstein J. Org. Chem. 2024, 20, 3151–3173, doi:10.3762/bjoc.20.261

• and γ-secretase, it produces Aβ-42. This form misfolds, leading to the formation of insoluble protein aggregates known as senile plaques, causing toxicity [28][29]. Oxidative stress occurs when there is an imbalance between prooxidants and antioxidants in the body, leading to damage in various

• paralysis rate of worms (Figure 4). Specifically, they exhibited a percentage of paralysis inhibition of 67%, 47%, 57%, 42%, 45%, and 64%, respectively, which indicates their potential in inhibiting β-amyloid toxicity in AD. These compounds were selected to assess their potential as acetylcholinesterase

• (IC50 = 1.28 μM), and non-toxicity in liver HepG2 cells. Hantzsch-based strategies: As mentioned before, in response to the challenges posed by the multifactorial nature of AD, the MTDL approach has emerged as a promising strategy. This approach involves designing drugs capable of binding simultaneously

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• ]. They offer several advantages over traditional reagents, including low toxicity, high reactivity, and excellent selectivity [43] under simple reaction conditions. The distinctive reactivity of DIAS enables the smooth arylation of various carbon and heteroatom nucleophiles under gentle conditions, with

Synthesis and antimycotic activity of new derivatives of imidazo[1,2-a]pyrimidines

• Dmitriy Yu. Vandyshev,
• Daria A. Mangusheva,
• Khidmet S. Shikhaliev,
• Kirill A. Scherbakov,
• Oleg N. Burov,
• Alexander D. Zagrebaev,
• Tatiana N. Khmelevskaya,
• Alexey S. Trenin and
• Fedor I. Zubkov

Beilstein J. Org. Chem. 2024, 20, 2806–2817, doi:10.3762/bjoc.20.236

• desired pharmacological properties. Therefore, the design and synthesis of new compounds of this class with improved ADMET (absorption, distribution, metabolism, excretion, toxicity) pharmacological properties is an urgent task. Molecular docking was carried out to identify potential binding positions of

Synthesis and cytotoxicity studies of novel N-arylbenzo[h]quinazolin-2-amines

• Battini Veeraiah,
• Kishore Ramineni,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Hélène Solhi,
• Rémy Le Guevel,
• Chada Raji Reddy,
• Frédéric Justaud and
• René Grée

Beilstein J. Org. Chem. 2024, 20, 2592–2598, doi:10.3762/bjoc.20.218

• the meta-methoxy 4f and ortho-fluoro 4h show significant toxicity only on Caco-2 (IC50 4.3 and 4.6 μM, respectively). Further, the para-methyl compound 4d acts on HCT-116 only (IC50 5 μM). On the other hand, all molecules exhibited no effect on normal human fibroblasts at the highest concentration