Advantages of PROTACs in achieving selective degradation of homologous protein families

• Luxi Yang,
• Xinfei Mao,
• Jingyi Zhang,
• Jing Shu,
• Wenhai Huang,
• Xiaowu Dong,
• Yinqiao Chen and
• Mingfei Wu

Beilstein J. Org. Chem. 2026, 22, 628–661, doi:10.3762/bjoc.22.49

• pharmacology; inhibitors that lack specificity may interfere with off-target biological functions, resulting in diminished therapeutic efficacy and unacceptable toxicity [24]. Consequently, maximizing compound selectivity is a primary objective in drug discovery [25][26]. In the context of PROTAC design, it is

• -target toxicity and reduce the therapeutic effect [53]. Since PROTACs have been proven to demonstrate significant advantages over small-molecule inhibitors in selectivity, more and more research has focused on how to design PROTACs that can target the degradation of the CDK family with high specificity

• , PROTACs can achieve isoform-specific degradation. This approach not only minimizes off-target toxicity but also enables the targeting of CDK6 in contexts where CDK4 is functionally redundant, such as in Ph+ ALL. Currently, small-molecule inhibitors for the CDK family approved by the FDA all target CDK4/6

Regioselective approach to 5-arylsulfonylisoxazoles and their antimicrobial activity

• Artem S. Sazonov,
• Dmitry A. Vasilenko,
• Denis V. Porfiriev,
• Yuri K. Grishin,
• Rimma A. Gazzaeva,
• Alisa P. Chernyshova,
• Maxim A. Kryakvin,
• Anna A. Baranova,
• Vera A. Alferova and
• Elena B. Averina

Beilstein J. Org. Chem. 2026, 22, 592–602, doi:10.3762/bjoc.22.45

• promising compounds with a wide spectrum of biological activity [1][2][3][4][5]. The attractiveness of isoxazole derivatives for medicinal chemistry is determined by high-affinity binding to many targets, low toxicity of isoxazole-containing compounds and the use of the isoxazole ring as a bioisoster of the

Design and synthesis of an erdafitinib-based selective FGFR2 degrader

• Yumeng Jin,
• Shidong Wang,
• Sihan Pan,
• Shuqi Huang,
• Weichen Zhou,
• Xiaohao Huang,
• Lei Zheng and
• Lingfeng Chen

Beilstein J. Org. Chem. 2026, 22, 583–591, doi:10.3762/bjoc.22.44

• signaling pathway [35][36]. These advances have driven the development of several selective FGFR2 inhibitors, including erdafitinib, infiglatinib, and FGF401 [37][38][39]. However, issues such as acquired drug resistance and on-target toxicity emerging in clinical applications have limited the long-term

Synthesis and uranyl(VI) extraction performance of a calix[4]pyrrole–tetrahydroxamic acid receptor

• Sara Karnib,
• Rana Baydoun,
• Wissam Zaidan,
• Nancy AlHaddad,
• Omar El Samad,
• Bilal Nsouli,
• Francine Cazier-Dennin and
• Pierre-Edouard Danjou

Beilstein J. Org. Chem. 2026, 22, 486–494, doi:10.3762/bjoc.22.36

• , contributing to the increased accumulation of uranium in ecosystems [29][30][31]. Owing to its radioactivity, chemical toxicity, and long half-life, environmental uranium contamination poses serious ecological and public health risks [32]. In this context, hydroxamic acid functionalities have been successfully

Synthesis and anti-cancer activity of naphthalimide–organylselanyl conjugates

• Rajkumar Ravi and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2026, 22, 416–435, doi:10.3762/bjoc.22.29

• parent compounds amonafide (4) and mitonafide (5), which have progressed to clinical trials but exhibited unpredictable toxicity [30]. Consequently, recent research has focused on minimising these adverse effects while enhancing antiproliferative potency through diverse synthetic modifications [31]. One

Design, synthesis and biological evaluation of 2,5-diaryloxazolo[4,5-d]pyrimidin-7-ylamines as selective cytotoxic agents against HeLa cells

• Maryna V. Kachaeva,
• Agnieszka B. Olejniczak,
• Marta Denel-Bobrowska,
• Victor V. Zhirnov,
• Yevheniia S. Velihina,
• Stepan G. Pilyo and
• Volodymyr S. Brovarets

Beilstein J. Org. Chem. 2026, 22, 390–398, doi:10.3762/bjoc.22.27

• combination of the [1,3]oxazolo[4,5-d]pyrimidin-7-amine fragment (structures A and B) with cytisine, glucamine, and aminoethylamine represents a promising strategy for the rational design of multifunctional hybrids with improved biological activity, water solubility, lower toxicity and target engagement

• HeLa cells (SI = 8.37), suggesting potential selective toxicity. Its activity against other cancer lines was less pronounced (SI < 2). Moreover, compounds 7 and 9 showed high selectivity (SI > 10), and 1 demonstrated only moderate one (SI < 10) to the HeLa cell line. Compound 9 also showed noteworthy

• selectivity for HeLa cells (SI = 14.15), with a high CC50 value for non-cancer NCTC clone 929 cells (706.50 µM), suggesting low general toxicity. Compound 3 displayed low selectivity towards HeLa cells (SI = 1.54). All compounds showed very low SI values for other cancer lines (SI ≤ 0.6), indicating limited

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• properties: absorption, distribution, metabolism, excretion, and toxicity. In this paper, these were evaluated in silico using an online resource accessible via https://preadmet.webservice.bmdrc.org/. The following ADME descriptors were selected: blood-brain barrier permeability (BBB), human intestinal

• absorption (HIA), in vitro permeability to Caco-2 cells (Caco2), in vitro binding to plasma proteins (PPB), solubility, and inhibition of CYP2D6. The following were selected as descriptors of toxicity: carcinogenicity for rats and mice, mutagenicity according to the Ames test, and cardiotoxicity by

A mild and atom-efficient four-component cascade strategy for the construction of biologically relevant 4-hydroxyquinolin-2(1H)-one derivatives

• Dmitrii A. Grishin,
• Kseniia I. Sharkovskaia,
• Ilya G. Kolmakov,
• Daria A. Ipatova,
• Rostislav A. Petrov,
• Nikolai D. Dagaev,
• Dmitry A. Skvortsov,
• Maria G. Khrenova,
• Valeriy V. Andreychev,
• Sergei A. Evteev,
• Yan A. Ivanenkov,
• Roman L. Antipin,
• Olga А. Dontsova and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2026, 22, 244–256, doi:10.3762/bjoc.22.18

• ). Most compounds showed no significant cytotoxicity at concentrations up to 100 μmol/L. However, compounds 10a, 10b, and 10c demonstrated considerable toxicity toward both the rapidly proliferating HEK293T and the slowly proliferating VA13 cell lines. This cytotoxicity pattern contrasts with that of the

• well-known topoisomerase II inhibitor doxorubicin (see Supporting Information File 1, page S52), whose toxicity correlates with the cell proliferation rate. Compounds 13b and 13c exhibited non-specific toxicity across all tested cell lines. Antibacterial activities of compounds 9–14 were evaluated in

• demonstrate pronounced antibacterial activity, their low toxicity toward human cells and distinctive molecular scaffold render them promising candidates for further development as biologically active agents. Conclusion In conclusion, we have developed a novel organocatalyzed four-component cascade reaction

Advances in Zr-mediated radical transformations and applications to total synthesis

• Hiroshige Ogawa and
• Hugh Nakamura

Beilstein J. Org. Chem. 2026, 22, 71–87, doi:10.3762/bjoc.22.3

• afford reactions that are cheaper, safer, and less toxic. In this context, we focus on mild radical reactions mediated by zirconium (Zr), which has recently attracted attention because of its low toxicity and ease of handling. We discuss the utility of Zr in such radical processes and consider prospects

• properties [1]. Among its notable physical attributes is its high corrosion resistance: metallic zirconium is exceptionally stable toward acids and bases at ambient temperature and is less susceptible to corrosion than titanium. Its low toxicity and excellent biocompatibility have historically supported the

• widely employed in the field of organic synthesis. This widespread use is underpinned by zirconium’s abundance in the Earth’s crust and its low toxicity, among other advantageous properties. Traditionally, its applications have predominantly involved two-electron processes via hydrozirconation. In recent

One-pot synthesis of ethylmaltol from maltol

• Immanuel Plangger,
• Marcel Jenny,
• Gregor Plangger and
• Thomas Magauer

Beilstein J. Org. Chem. 2025, 21, 2755–2760, doi:10.3762/bjoc.21.212

• , perfumes, ice cream, cakes, confections, e-liquids, cigarettes, and oral medications. In the European Union, ethylmaltol (1) has the food additive code E 637 and due to its lack of toxicity is approved to be dosed quantum satis, which means as much as necessary with typical concentrations ranging between 1

Recent advancements in the synthesis of Veratrum alkaloids

• Morwenna Mögel,
• David Berger and
• Philipp Heretsch

Beilstein J. Org. Chem. 2025, 21, 2657–2693, doi:10.3762/bjoc.21.206

• trans-fusion of the A,B-rings and the configuration of the methyl group at C25, among other features [13]. Like the related subclasses, cevanine-type alkaloids exhibit toxicity in humans by acting on the sodium channels of nerve cells. Increased stimulation, associated with the vagal nerve results in a

Visible-light-driven NHC and organophotoredox dual catalysis for the synthesis of carbonyl compounds

• Vasudevan Dhayalan

Beilstein J. Org. Chem. 2025, 21, 2584–2603, doi:10.3762/bjoc.21.200

• process, such as being environmentally friendly, offering operational simplicity, lower cost, and easy availability, reducing waste and toxicity, as well as providing excellent chemo-, regio-, and enantioselectivity through fine-tuned hydrogen bonding or covalent activation modes. Furthermore, the

Synthesis and characterization of a isothiouronium-calix[4]arene derivative: self-assembly and anticancer activity

• Giuseppe Granata,
• Loredana Ferreri,
• Claudia Giovanna Leotta,
• Giovanni Mario Pitari and
• Grazia Maria Letizia Consoli

Beilstein J. Org. Chem. 2025, 21, 2535–2541, doi:10.3762/bjoc.21.195

• , and low toxicity make calixarene derivatives valuable drug candidates against cancer. The aim of the present study was the synthesis and characterization of a calix[4]arene derivative in which known anticancer isothiouronium groups were clustered on a calix[4]arene scaffold bearing long C12 alkyl

• sciences [13][14][15][16][17]. Their synthetic versatility, ease of functionalization, conformational rigidity or flexibility, steric bulk, and low cost make them highly attractive in the development of novel, non-conventional anticancer agents with a great potential for overcoming the toxicity of cancer

• leukemia cells and low toxicity toward non-cancerous cells [43]. Therefore, the aim of this study was to evaluate whether introducing isothiouronium moieties at the upper rim of a calix[4]arene scaffold, bearing long C12 alkyl chains at the lower rim, could yield a novel derivative (compound 3) with

Pentacyclic aromatic heterocycles from Pd-catalyzed annulation of 1,5-diaryl-1,2,3-triazoles

• Kaylen D. Lathrum,
• Emily M. Hanneken,
• Katelyn R. Grzelak and
• James T. Fletcher

Beilstein J. Org. Chem. 2025, 21, 2524–2534, doi:10.3762/bjoc.21.194

• counterparts 13–18. Because fused ring heterocycles are common components of bioactive molecules, a preliminary evaluation of toxicity for this newly defined class of compounds was completed. Antimicrobial potency against Gram-positive bacteria Bacillus subtilis and Staphylococcus epidermidis, Gram-negative

• orientation, the distribution of nitrogen atom centers within the ring system appears essential for eliciting bioactivity. Orientation of isoquinoline and N3-triazole subunit nitrogen atoms is identical between 17 and 35 as well as between 18 and 36. In contrast, 34 showed toxicity towards Gram-positive

The high potential of methyl laurate as a recyclable competitor to conventional toxic solvents in [3 + 2] cycloaddition reactions

• Ayhan Yıldırım and
• Mustafa Göker

Beilstein J. Org. Chem. 2025, 21, 2389–2415, doi:10.3762/bjoc.21.184

• , toxicity, pesticide similarity, and biodegradability of methyl laurate in comparison with a series of conventional organic solvents, water, some fatty acids and their derivatives. The findings of this investigation revealed that methyl laurate exhibited better green solvent properties when evaluated

• troublesome [21][22]. It is evident that this class of solvents may be accompanied by a number of drawbacks. For instance, they are frequently expensive, exhibit negligible or non-existent biodegradability, and there is a lack of data concerning their potential toxicity. Conversely, while water is regarded as

• ADMETLab 3.0 platform [87] are illustrated in Figure 2a. Conversely, the oral toxicity values of methyl laurate, in conjunction with toluene and chloroform – two conventional solvents that are commonly employed in [3 + 2] cycloaddition reactions were calculated with ProTox 3.0 (a webserver for the

Enantioselective radical chemistry: a bright future ahead

• Anna C. Renner,
• Sagar S. Thorat,
• Hariharaputhiran Subramanian and
• Mukund P. Sibi

Beilstein J. Org. Chem. 2025, 21, 2283–2296, doi:10.3762/bjoc.21.174

• abundance, low cost, less toxicity, and existence of multiple oxidation states (I, II, and III) make copper an essential transition metal for catalytic purposes [60][61]. The fact that copper, like other transition metals, has multiple oxidation states makes it an excellent redox catalyst. Owing to the

• individually or synergistically with other catalytic systems. Enzymatic catalysis can pose challenges including enzyme engineering, reaction scale-up, etc. but is optimal in terms of the toxicity profile of the reaction conditions. Biomolecules such as enzymes are attractive candidates for efficient and

• chemical oxidant or reductant [80][85], thereby reducing toxicity and waste. With these advantages, organic electrochemistry holds significant promise for improving efficiency and sustainability while enabling the development of new transformations. Meggers and co-workers developed an electrochemical

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