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

• . CDK4/6 has high homology and has been shown to play a crucial role in the development of breast cancer [26]. In recent years, it has been proved that expression of CDK6, but not of the highly related CDK4, is required for the proliferation and survival of Ph+ acute lymphoblastic leukemia cells

• simultaneously degrade CDK4 (the degradation rate exceeds 50% at 0.1 μM in Jurkat cells) and CDK6 (the degradation rate exceeds 95% at 0.1 μM in Jurkat cells), and it shows a certain degree of selectivity towards CDK6. In the same year, Gray, Winter et al. developed another PROTAC named BSJ-03-123 (2), which can

• compound 4 in HPNE and MiaPaCa2 cells, respectively. It was found that compound 4 could selectively degrade CDK6 without affecting other members of the CDK family (CDK2, 4, 5, 7, and 9). Based on the above studies, it seems an effective development strategy to use a longer linker to connect the POI ligand

Towards the targeted protein degradation of CK2: design and synthesis of CAM4066-based PROTACs

• Sophie Day-Riley,
• Sona Krajcovicova,
• Aryaman Raj Sokhal,
• Jan L. Venne,
• Paul Brear,
• Marko Hyvönen,
• Benjamin C. Whitehurst,
• Jason S. Carroll and
• David R. Spring

Beilstein J. Org. Chem. 2026, 22, 611–619, doi:10.3762/bjoc.22.47

• for their ability to induce degradation of CK2α and CK2α′ in cell-based assays. Western blot profiling across six colorectal cancer cell lines revealed heterogeneous expression of both CK2 isoforms. HCT116 cells exhibited robust expression of CK2α and CK2α′, with CK2α predominating, and were therefore

• 29 were tested under identical conditions but likewise failed to induce degradation of CK2α or CK2α′ in HCT116 or MDA-MB-231 cells (see Supporting Information File 1, section 2.4). Upon biological evaluation, ITC analysis of 24, selected as a representative PROTAC, revealed no detectable productive

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

• negligible activity (Table 2). To evaluate the possible mechanism of antibiotic action on bacterial cells, we have studied the antibacterial activity of the isoxazole derivatives on the reporter strains E. coli ΔtolC pDualrep2 (AmpR) and E. coli lptDmut pDualrep2.1 (KanR) as described previously [32][33

• monooxidated 3-nitrosulfonylisoxazole 4b exhibited high activity against both reporter strains. Furthermore, these samples demonstrated strong induction of the RFP reporter protein, indicating that their antibacterial action is associated with induction of the SOS response in bacterial cells (Figure 2). 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

• design and synthesize a series of PROTAC molecules with different linkers. Screening was performed in KATO III cells with high FGFR2 expression, leading to the identification of LC-JD-6 as a potent degrader. Experimental results demonstrated that LC-JD-6 effectively induced FGFR2 protein degradation with

• a half-maximal degrading concentration (DC50) of 121.4 nM, and this effect exhibited time- and concentration-dependence. Assessed at the cellular level, LC-JD-6 has a half-maximal inhibitory concentration in the KATO III (IC50) of 96.0 nM and showed low inhibitory activity in normal cells

• rearrangements or fusions involving FGFR2 can create novel chimeric proteins with enhanced or aberrant signaling capabilities, further driving cells towards a malignant phenotype [13][15]. Notably, FGFR2 amplification and fusions are frequently detected in patients with advanced gastric cancer and

Molecular tweezer–peptide conjugates disrupt the protein–protein interaction between survivin and histone H3 essential in mitosis

• Catherine Gsell,
• Philipp Rebmann,
• Karina Opara,
• Christine Beuck,
• Peter Bayer,
• David Bier,
• Ingrid R. Vetter and
• Thomas Schrader

Beilstein J. Org. Chem. 2026, 22, 557–567, doi:10.3762/bjoc.22.41

• crystallization experiments, competitive fluorescence titrations, and cell division assays. Conclusion This report introduces a new supramolecular attempt to interfere with the critical interaction between kinetochore and CPC during mitosis in cells. The concept builds on the discovery that a specific protein

• prevent its binding to histone H3, thus creating an interesting tool to specifically interfere with this interaction in the cell. If these constructs are not sufficiently cell-permeable, they may be introduced via electroporation into mammalian cells, a protocol that is well established in the Musacchio

Experimental and DFT studies on the regioselective methanolysis of 5-azido-9-oxabicyclo[6.1.0]nonan-4-yl 4-nitrobenzoate isomers

• İlknur Polat,
• Selçuk Eşsiz and
• Emine Salamci

Beilstein J. Org. Chem. 2026, 22, 547–556, doi:10.3762/bjoc.22.40

• to design pharmacological tools in the future. Experimental General information Melting points are uncorrected. Infrared spectra were obtained from solution in 0.1 mm cells or KBr pellets on an FT-IR Mattson 1000 instrument. The 1H and 13C NMR spectra were recorded on 400 (100) MHz Varian or 400 (100

Modern synthetic pathways towards eribulin and its subunits

• Sebastian Dominik Graf

Beilstein J. Org. Chem. 2026, 22, 495–526, doi:10.3762/bjoc.22.37

• within their isolation study on halichondrin B, in 1986, Hirata and Uemura showed its promising activity against murine cancer cells [6], which led to a great interest in the pharmaceutical society [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Only 6 years later, Kishi and co-workers first

Synthesis of a HDAC inhibitor–nanogold probe for cryo-EM visualization in class I HDAC co-repressor complexes

• Wiktoria A. Pytel,
• John W. R. Schwabe and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2026, 22, 480–485, doi:10.3762/bjoc.22.35

• localization within a cell, as well as in cellular cryo-electron tomography [11][12]. More recently, gold nanoparticles have been used as labeling tools in vitrified cells to locate cellular compartments in cellular cryo-EM [13]. Given the considerable utility of nanogold particles in microscopy, we aimed to

• confirm that the conjugation of CI-994 to the nanogold particle did not significantly affect HDAC inhibition. The HDAC1-LSD1-CoREST complex, incorporating a FLAG tag in CoREST, was expressed and purified from HEK293F cells as previously reported [10]. Fluorescent deacetylase assays were carried out using

Recent advances in the stereoselective synthesis of distal biaxially chiral molecules

• Fanxing Zhou,
• Chen Zhang,
• Lingyu Sun,
• Yiyun Fang,
• Siming Zheng,
• Lina Hu,
• Mengyang Shen,
• Zhen Zhao,
• Wei Xu,
• Yunqiang Sun and
• Zi-Qiang Rong

Beilstein J. Org. Chem. 2026, 22, 461–479, doi:10.3762/bjoc.22.34

• (Scheme 11) [52]. A preliminary biological evaluation revealed inhibitory activity of selected products against MV4-11 cancer cells, highlighting their potential in pharmaceutical research. At the same time, efficient synthetic routes to uracils bearing a single C–N axis were also achieved in yields

Structural reassignment of compound 968, an allosteric glutaminase inhibitor

• Lindsey A. Albertelli,
• Sainabou Jallow,
• Chun Li and
• Scott M. Ulrich

Beilstein J. Org. Chem. 2026, 22, 455–460, doi:10.3762/bjoc.22.33

• Lindsey A. Albertelli Sainabou Jallow Chun Li Scott M. Ulrich Department of Chemistry, Ithaca College, Ithaca, NY 14850, USA 10.3762/bjoc.22.33 Abstract Many cancer cells require extracellular glutamine to meet the energetic, biosynthetic, and redox demands of the proliferative state

• . Glutaminases catalyze the hydrolysis of glutamine to glutamate, which supports the biosynthesis of amino acids, lipids, and glutathione and can also be oxidatively deaminated to α-ketoglutarate and enter the citric acid cycle. The “glutamine addiction” of cancer cells has made glutaminase an attractive

• anticancer drug target. Compound 968 is a glutaminase inhibitor that is widely used to probe cancer cells’ dependence on glutaminase activity. Here, we show by NMR spectroscopy and X-ray crystallography that the reported benzo[c]phenanthridine structure of compound 968 is incorrect; its true structure is the

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

• structurally characterised by single-crystal X-ray diffraction analysis. The anticancer potential of the NAP-SePh and NAP-Se(n-Oct) was evaluated using an in vitro cell viability assay with MDA-MB-231 triple-negative breast cancer (TNBC) cells. The IC₅₀ values for compounds NAP-SePh and NAP-Se(n-Oct) were

• , a 4-nitro-substituted benzylic diselenide 3 was reported to inhibit the Akt/mTOR and ERK pathways while suppressing NF-κB–mediated inflammation and invasiveness in TNBC cells [29]. On the other hand, naphthalimides (NAP) are well known for their potent anticancer activity, as exemplified by the

• -231 breast cancer cell line. The cells were kept in a CO₂ incubator at 37 °C, 5% CO₂, and 90% relative humidity. They were cultivated in Dulbecco's Modified Eagle Medium (DMEM), supplemented with 10% fetal bovine serum (FBS). MTT-Assay protocols Cell viability was evaluated using the MTT assay. MDA-MB

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

• liquid chromatography–mass spectrometry. Their anticancer activity was assessed against human cancer cell as well as non-cancer cell lines. Three compounds, 1, 3, and 9, were the most cytotoxic to HeLa cells (IC50 = 6.13 ± 1.95, 13.99 ± 1.80 and 49.92 ± 3.98 μM, respectively). However, only compounds 1

• activity. They combine purine-like recognition features with the synthetic flexibility of heterocycles, offering a platform for selective targeting of tumor-related enzymes and receptors. Tumor cells overexpress kinases, DNA/RNA polymerases, and metabolic enzymes that bind purine nucleotides. Cancer cell

• lines such as HepG2 (liver), HeLa (cervix), A549 (lung), and glioblastoma models rely on enhanced nucleotide metabolism to sustain rapid DNA/RNA synthesis. Oxazolopyrimidines can inhibit these overactive enzymes in cancer cells, while normal cells (with lower demand) are less affected. This explains why

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

• : <10 and TPSA – topological polar surface area: <140 Å2. The obtained results are presented in Supporting Information File 1, Table S4. Since antitumor drugs usually damage healthy cells along with tumor cells, while developing new substances, it is extremely important to pay attention to their ADMET

• 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

• potential in the brain with regard to bioavailability in the CNS. Antiproliferative activity study. Cancer cells are favorable in vitro models that are widely used in cancer research and drug discovery. In this study, the MTS assay was applied to evaluate the antiproliferative activity of the synthesized

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

• provided in Supporting Information File 1, pages S3 and S52–S53. Cytotoxicity of compounds 9–14 was assessed in vitro using an MTT assay [48] on a panel of human cell lines, including non-cancerous HEK293T and VA13, as well as cancerous MCF7 and A549 cells (see Supporting Information File 1, page S52

• 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

Symmetrical D–π–A–π–D indanone dyes: a new design for nonlinear optics and cyanide detection

• Ergin Keleş,
• Alberto Barsella,
• Nurgül Seferoğlu,
• Zeynel Seferoğlu and
• Burcu Aydıner

Beilstein J. Org. Chem. 2026, 22, 131–142, doi:10.3762/bjoc.22.6

• attention due to their widespread use in materials chemistry. This type of dye is of particular interest in the fields of organic electronics, photonics, and optoelectronics etc., used in areas such as dye-sensitized solar cells (DSSC), organic light-emitting diodes (OLED), nonlinear optics (NLO), and

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

• where organic synthesis plays a central role, including pharmaceuticals, agrochemicals, materials chemistry, organic semiconductors, and organic thin-film solar cells. These areas are intimately linked to human life; thus, advances in organic synthesis are essential for improving human well-being

Competitive cyclization of ethyl trifluoroacetoacetate and methyl ketones with 1,3-diamino-2-propanol into hydrogenated oxazolo- and pyrimido-condensed pyridones

• Svetlana O. Kushch,
• Marina V. Goryaeva,
• Yanina V. Burgart,
• Marina A. Ezhikova,
• Mikhail I. Kodess,
• Pavel A. Slepukhin,
• Alexandrina S. Volobueva,
• Vladimir V. Zarubaev and
• Victor I. Saloutin

Beilstein J. Org. Chem. 2025, 21, 2716–2729, doi:10.3762/bjoc.21.209

• compound ribavirin (Table 5, entry 2). In addition, this entire series of compounds is distinguished by the absence of cytotoxicity towards MDCK cells. Conclusion To sum up, we have, for the first time, demonstrated the possibility of 1,3-diaminopropan-2-ol being involved in cyclization as an ambident N,N

• yields of products 4b,c and 5b,c. Conversion and preparative yields of products 4d. The difference in chemical shifts Δea = δeq – δax of diastereotopic protons at C(9) for compounds 4a–d. Antiviral activity of heterocycles 4 and 5 against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells

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

Chemoenzymatic synthesis of the cardenolide rhodexin A and its aglycone sarmentogenin

• Fuzhen Song,
• Mengmeng Zheng,
• Dongkai Wang,
• Xudong Qu and
• Qianghui Zhou

Beilstein J. Org. Chem. 2025, 21, 2637–2644, doi:10.3762/bjoc.21.204

• isolated from the leaves and roots of the Japanese evergreen plant Rohdea japonica in 1951, and was also discovered in several other plants later [18]. Rhodexin A is the only natural CG that exhibits both cardiotonic activity and strong inhibitory activity on human leukemia K562 cells with an IC50 = 19 nM

Recent advances in total synthesis of illisimonin A

• Juan Huang and
• Ming Yang

Beilstein J. Org. Chem. 2025, 21, 2571–2583, doi:10.3762/bjoc.21.199

• embellished by additional bridging via a γ-lactone and a γ-lactol ring, resulting in a caged pentacyclic scaffold with a 5/5/5/5/5 ring arrangement. The compound demonstrates neuroprotective activity by mitigating oxygen-glucose deprivation-induced cell injury in SH-SY5Y cells. Since its isolation in 2017

• neuroprotective effects against oxygen-glucose deprivation-induced cell injury in SH-SY5Y cells, suggesting its potential as a lead compound for the treatment of neurodegenerative diseases. The possible biosynthetic pathway of illisimonin A was also proposed by Yu and co-workers, as illustrated in Scheme 1. 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

• chains at the lower rim. The resulting amphiphilic calix[4]arene derivative 3 spontaneously self-assembled into nanoscale aggregates in aqueous medium, as demonstrated by dynamic light scattering analysis. The cytotoxicity of compound 3 towards cancer cells was assessed using human renal carcinoma cells

• (786-O cells) and compared with that in non-malignant fibroblast cells (SW1 cells). Compound 3 showed a significantly greater antiproliferative effect on cancer cells (IC50 37.4 µM) than on normal fibroblasts (517 µM). The importance of the isothiouronium moieties in the observed cytoxic effect was

• to the nanosize, the calixarene-based nanoconstructs could preferentially accumulate in cancer tissues by exploiting the enhanced tumor permeability and retention (EPR) effect [24] or selectively penetrate cancer cells through specific ligand–receptor interactions on the surface of target cells [25

Effect of a photoswitchable rotaxane on membrane permeabilization across lipid compositions

• Udyogi N. K. Conthagamage,
• Lilia Lopez,
• Zuliah A. Abdulsalam and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2498–2512, doi:10.3762/bjoc.21.192

• ; membrane fluidity; membrane permeability; photoswitchable rotaxane; Introduction Lipid membranes play a vital role in biology by acting as protective barriers for cells and organelles while regulating the passage of substances. Additionally, their structure and dynamics influence the activity of membrane

• proteins that are responsible for essential cellular functions [1]. As a result, the function and properties of lipid membranes are significantly influenced by their lipid composition, which varies across various domains of life, including mammalian, prokaryotic, and plant cells, and even between

• bacteria or malignant cells like cancer) [5][6], or to influence membrane protein function and thereby control cellular behavior [7][8]. One promising approach is the development of light-activated molecules that can modulate membrane properties upon irradiation, enabling remote activation with high

Assembly strategy for thieno[3,2-b]thiophenes via a disulfide intermediate derived from 3-nitrothiophene-2,5-dicarboxylate

• Roman A. Irgashev

Beilstein J. Org. Chem. 2025, 21, 2489–2497, doi:10.3762/bjoc.21.191

• materials for various types of organic solar cells [8][9][10][11][12][13]. TT-extended phthalocyanines and related dyes have also been applied in gas-sensing devices, benefiting from their π-stacked alignment and electron-rich character [14]. On the other hand, the biological potential of TT molecules has

Transformation of the cyclohexane ring to the cyclopentane fragment of biologically active compounds

• Natalya Akhmetdinova,
• Ilgiz Biktagirov and
• Liliya Kh. Faizullina

Beilstein J. Org. Chem. 2025, 21, 2416–2446, doi:10.3762/bjoc.21.185

• [96] used the semipinacol rearrangement as a key step in converting indole 219 to spirooxindole 221. The spirooxindole alkaloids, (−)-citrinadin A and (+)-citrinidin B, exhibit notable activity against murine leukemia L1210 (217, IC50 6.2 μg/mL; 229, 10 μg/mL) and human epidermoid KB cells (218, IC50

Rotaxanes with integrated photoswitches: design principles, functional behavior, and emerging applications

• Jullyane Emi Matsushima,
• Khushbu,
• Zuliah Abdulsalam,
• Udyogi Navodya Kulathilaka Conthagamage and
• Víctor García-López

Beilstein J. Org. Chem. 2025, 21, 2345–2366, doi:10.3762/bjoc.21.179

• generate singlet oxygen (¹O2), which can be controlled through dithienylethene photoisomerization. Therefore, the authors investigated these nanoparticles for bioimaging and apoptosis of HeLa cells. When the dithienylethene is in the open form, the nanoparticles have relatively high cytotoxicity due to the

• photoswitchable rotaxanes into lipid membranes has revealed exciting opportunities for future biooriented applications. These applications include light-controlled systems for drug release, ion transport, rotaxane-based therapeutics, and molecular tools capable of modulating biological processes in living cells

• . Figure 7 was adapted with permission from [16], Copyright 2023 American Chemical Society. This content is not subject to CC BY 4.0. Dithienylethene-based [1]rotaxane shuttling motion triggered by pH changes (top). Dithienylethene photoswitch modulates singlet oxygen generation to kill HeLa cells (bottom