Using generative AI to transform peptide hits into small molecule leads

• Joshua Mills and
• Yu Heng Lau

Beilstein J. Org. Chem. 2026, 22, 672–679, doi:10.3762/bjoc.22.51

• databases (ZINC [48], CASF [49], GEOM [50]), input fragments were represented as three-dimensional point clouds, while the appropriately-sized linker was iteratively generated and refined by sampling atom types and positions using Gaussian noise as the starting point. The model could also be trained on a

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

• targeting an E3 ubiquitin ligase and the other binding to a protein of interest (POI), covalently joined by a flexible linker [12]. Upon cellular entry, the PROTAC molecule facilitates the formation of a ternary complex by simultaneously recruiting the POI and the E3 ligase (Figure 1). This proximity

• the conformation of the ternary complex through the strategic modification of the POI ligand, the linker, and the E3 ligase ligand. Several studies have successfully utilized this strategy to enhance disease treatment outcomes via the PROTAC technology [22][28][29]. The rapid progression of the PROTAC

• validation not only confirms the unique advantages of PROTACs in addressing previously undruggable targets but also highlights the critical importance of understanding how linker composition, E3 ligase choice, and protein–protein interactions govern the exquisite selectivity required for clinical success [24

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

• conjugating a CAM4066-derived warhead to CRBN or VHL ligands, four VHL-recruiting PROTACs, were prepared using PEG and alkyl linkers, alongside two CRBN-recruiting analogues featuring constrained linkers. A ligand–linker analogue in which a linker is projected from the solvent-exposed region of CK2α retained

• binding affinity comparable to CAM4066, confirming that linker installation is tolerated and preserves key interactions in the αD and ATP sites. Keywords: CAM4066; casein kinase 2 (CK2); PROTACs; targeted protein degradation; Introduction Protein kinases form a large family of more than 500 enzymes that

• conjugated CAM4066-derived ligands to both CRBN or VHL E3-ligase recruiters. We created VHL-recruiting PROTACs for CK2 using PEG and alkyl linkers, while the CRBN-recruiting analogues featured more constrained linkers. A ligand–linker analogue bearing a linker projected from the solvent-exposed region 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

• Discussion FGFR2-targeted degrader design PROTAC molecules are composed of three key elements: a specific ligand targeting the protein of interest (POI), a recruiter for an E3 ubiquitin ligase, and a linker that covalently connects these two functional moieties into a single molecular entity [29]. Herein, we

• were designed by conjugating the aliphatic amine in erdafitinib to two sites on CRBN (Figure 2b and Scheme 1), and the length and type of the linker were modified to achieve the selective degradation of FGFR2. Compound 5 was prepared according to the previously reported procedure [32][33], and then

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

• (vide infra). Again, molecular docking of peptide and tweezer moiety 2a on survivin led to stable arrangements on survivin, suggesting simultaneous occupation of the H3 binding site and potential complexation at Lys-121 (Figures S10 and S11 in Supporting Information File 1). The triazole linker may act

• binds in the canonical H3-peptide binding site with very well defined density. The tweezer moiety and the linker also have very well defined densities, but, contrary to our expectation, the tweezer does not bind to Lys-121, but instead packs against a proline of the second survivin monomer in the

• only buried in the crystal, but also in the biological target, the CPC complex, two obvious design options remain: either introducing a shorter linker to address lysines closer to the peptide binding site and benefit from increased affinity due linker rigidity, or using a longer linker that could reach

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

• active site [17]. Hence, we decided to functionalize this position with an alkyl linker consisting of 9 carbon atoms to mitigate any steric clashes between the HDAC inhibitor and the nanogold particle, which could be detrimental to the probe binding affinity (Figure 1). Further to this, we previously

• functionalized this position with linkers for the development of HDAC1–3 proteolysis targeting chimeras (PROTACs) [14][18]. Alkyl-linker lengths of approximately 12 atoms and greater were the most effective degraders [18]. We chose the commercially available amine functionalized nanogold particles (Au–NH2

• routes (Scheme 1) [14][15][18]. Intermediates 5–7 were prepared in a manner analogous to Smalley et al. [14]. The first step in the linker synthesis for Au–(CI-994) involved a monoprotection of nonanedioic acid with a benzyl group to give 5 which proceeded in moderate yield due to the formation of 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

• (Supporting Information File 1, S11–S13 and S16–S18). In the ¹H NMR spectrum of compound 7, the tert-butyl protons appeared as a singlet at 1.27 ppm. The protons of the propylene linker chain resonated in the aliphatic region at 2.22, 4.08, and 4.37 ppm. The aromatic protons of the tert-butyl-substituted

• selenium center. The second important feature is the torsional motion in the propylene linker attached to the imide nitrogen of the naphthalimide core. The calculated O–C–C–C torsional angle from the gas-phase structure of 7 is −61.5°. The observed torsional angle from the solid-state structure of 7 is

• compounds indicates considerable torsional motion permissible across the propylene linker. This motion is relevant in the solution phase. While a direct correlation could not be made between the solid-state structure and the gas-phase (or solution-phase) geometry, the calculation reveals that a considerable

Design and synthesis of an axially chiral platinum(II) complex and its CPL properties in PMMA matrix

• Daiki Tauchi,
• Sota Ogura,
• Misa Sakura,
• Kazunori Tsubaki and
• Masashi Hasegawa

Beilstein J. Org. Chem. 2026, 22, 143–150, doi:10.3762/bjoc.22.7

• state [28]. Conclusion In conclusion, we synthesized a novel pincer-type platinum(II) complex by incorporating an axially chiral binaphthyl ligand through an acetylene linker. Spectroscopic and theoretical analyses revealed that the axial chirality of the binaphthyl moiety imposes a chiral arrangement

Synthesis of new tetra- and pentacyclic, methylenedioxy- and ethylenedioxy-substituted derivatives of the dibenzo[c,f][1,2]thiazepine ring system

• Gábor Berecz,
• András Dancsó,
• Mária Tóthné Lauritz,
• Loránd Kiss,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2645–2656, doi:10.3762/bjoc.21.205

• ring systems containing a two or three-carbon linker between the nitrogen atom of the thiazepine ring and the nitrogen (3), oxygen (4), or sulfur (5) atom linked to the C(11) atom [2][3]. In continuation of our efforts to study new ring systems, we decided to synthesize new tetra- and pentacyclic

Isoorotamide-based peptide nucleic acid nucleobases with extended linkers aimed at distal base recognition of adenosine in double helical RNA

• Grant D. Walby,
• Brandon R. Tessier,
• Tristan L. Mabee,
• Jennah M. Hoke,
• Hallie M. Bleam,
• Angelina Giglio-Tos,
• Emily E. Harding,
• Vladislavs Baskevics,
• Martins Katkevics,
• Eriks Rozners and
• James A. MacKay

Beilstein J. Org. Chem. 2025, 21, 2513–2523, doi:10.3762/bjoc.21.193

• regions of RNA. We herein report the synthesis and binding studies of new isoorotamide-based PNA monomers that target uridine–adenosine base pairs via a distal base recognition strategy. Monomers were designed with an arylisoorotamide core attached to a linker aimed at bypassing the uridine in a U–A pair

• distal binding monomers (Db) demonstrated slightly higher affinity for A–U base pairs while one demonstrated slightly higher affinity for the G–C base pair. These results provide insight into the nature of PNA monomer design particularly around linker design and rigidity. Keywords: Hoogsteen hydrogen

• Hoogsteen face of the RNA duplex allowing for recognition of U–A base pairs through a distal base recognition approach (Figure 3c). We proposed that by developing a linker of appropriate length that could reach across the uridine base, we could recognize the distal adenosine base and in turn essentially

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

• modulated the co-conformation of the rotaxane. However, the folded geometry of the axle restricts long-range movement of the macrocycle. Therefore, the authors later reported a photoswitchable rotaxane with an unfolded molecular thread, achieved by modifying the stopper groups and adjusting the linker chain

Research towards selective inhibition of the CLK3 kinase

• Vinay Kumar Singh,
• Frédéric Justaud,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Blandine Baratte,
• Thomas Robert,
• Stéphane Bach,
• Chada Raji Reddy,
• Nicolas Levoin and
• René L. Grée

Beilstein J. Org. Chem. 2025, 21, 2250–2259, doi:10.3762/bjoc.21.172

• previously described DB18 [23][24], a moderate inhibitor (IC50 = 1.28 μM) docked into CLK3 (Figure 2A), and we proposed to introduce, through an appropriate linker, an acid group close to this lysine 241 (Figure 2B). Preliminary studies indicated that a simple aromatic group could be very appropriate as a

• linker between the core of the inhibitor and the acidic function. The acid could be placed in meta or para positions taking into account the flexible backbone of lysine 241 (Figure 3). Further, in case the binding of these new targets would require a little more flexibility around the basic skeleton, we

• -bromo-5-chloroaniline (2b). Next, we prepared the final targets by Suzuki-type reactions using the aromatic bromides 7. As indicated before, the acid function designed to interact with the lysine 241 has been introduced both in para and meta positions of the aromatic linker. Further we have prepared two

Discovery of cytotoxic indolo[1,2-c]quinazoline derivatives through scaffold-based design

• Daniil V. Khabarov,
• Valeria A. Litvinova,
• Lyubov G. Dezhenkova,
• Dmitry N. Kaluzhny,
• Alexander S. Tikhomirov and
• Andrey E. Shchekotikhin

Beilstein J. Org. Chem. 2025, 21, 2062–2071, doi:10.3762/bjoc.21.161

• -stranded calf thymus DNA, as evidenced by ligand fluorescence quenching (Figure 2). Elongation of the linker in the carboxamide residue is accompanied by weaker DNA complexation (Table 4). The interaction of the compounds with DNA was found to be largely dependent on electrostatic forces. Reducing the

• stoichiometry of one ligand per two base pairs at maximal DNA saturation. While the DNA binding affinity increased by an order of magnitude at low ionic strength, the characteristic decrease in affinity with longer linker lengths was still maintained. A similar trend was observed in the results of MTT assay

Aryl iodane-induced cascade arylation–1,2-silyl shift–heterocyclization of propargylsilanes under copper catalysis

• Rasma Kroņkalne,
• Rūdolfs Beļaunieks,
• Armands Sebris,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2025, 21, 1984–1994, doi:10.3762/bjoc.21.154

• linker provides entry to 1,2,3,6-tetrahydropyridines. Additionally, in the absence of internal nucleophiles, this methodology yields aryl-substituted 1,3-dienes. This work introduces a palladium-free, single-step alternative to multistep heterocycle construction from propargylsilanes and highlights the

Systematic pore lipophilization to enhance the efficiency of an amine-based MOF catalyst in the solvent-free Knoevenagel reaction

• Pricilla Matseketsa,
• Margret Kumbirayi Ruwimbo Pagare and
• Tendai Gadzikwa

Beilstein J. Org. Chem. 2025, 21, 1854–1863, doi:10.3762/bjoc.21.144

• -workers. In two separate reports, they synthesized well-defined MOFs composed of three different linkers: a proline-functionalized linker acted as the catalytic unit, while two auxiliary linkers were varied to alter catalyst activity and enantioselectivity [24], or product selectivity [25]. In those works

• mixed-linker MOF with molecular formula Zn2(BDC-NH2)2(DPG), each unit cell has a 2:1 ratio of dicarboxylate to dipyridyl and, therefore, a 1:1 ratio of amine (–NH2) to hydroxy (–OH) groups. The Zn atoms in the paddlewheel metal clusters are coordinatively saturated [45], thus we anticipated that only

• determined that, when incubated with secondary or tertiary isocyanates, KSU-1 reacts exclusively at the hydroxy groups of the DPG linker before proceeding to react at the amines of BDC-NH2 (Table 1, entries 1 and 2). Thus, we had a method to generate, from a single framework, a series of amine-based MOFs

Photoswitches beyond azobenzene: a beginner’s guide

• Michela Marcon,
• Christoph Haag and
• Burkhard König

Beilstein J. Org. Chem. 2025, 21, 1808–1853, doi:10.3762/bjoc.21.143

Synthesis of chiral cyclohexane-linked bisimidazolines

• Changmeng Xi,
• Qingshan Sun and
• Jiaxi Xu

Beilstein J. Org. Chem. 2025, 21, 1786–1790, doi:10.3762/bjoc.21.140

• the substrate scope due to their complete rigidity. Cyclohexane-1,2-linked bisoxazolines (cHBOX) are a class of bisoxazoline ligands with the more flexible cyclohexane as linker [21][22]. Chiral cyclohexane-1,2-linked bisoxazolines fix transition states in catalytic asymmetric reactions, in whch the

3,3'-Linked BINOL macrocycles: optimized synthesis of crown ethers featuring one or two BINOL units

• Somayyeh Kheirjou,
• Jan Riebe,
• Maike Thiele,
• Christoph Wölper and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2025, 21, 1719–1729, doi:10.3762/bjoc.21.134

• ]. For the synthesis of macrocycles M2 with two BINOL units, we relied on the monoiodide 12, which was first reacted in a two-fold Suzuki coupling to install the first linker, followed by silyl deprotection and introduction of the second linker via nucleophilic substitution [51]. Both procedures require

• this publication, the suffix denotes the number of ethylene glycol units in a single linker, for the structures of 75/6/7/8, see Figure 3a). The reactivity of 76 had previously been established in the reaction with the unsymmetric monoiodide 12 (see Figure 1e), which proceeded in 59% yield [51

• were slightly increased (40% for H-M18, 53% for iPr-M18). As a general trend, we observed that the pentaethylene glycol linker seems to be too short to result in efficient macrocyclization (both in Suzuki and Williamson reactions), while the longer linkers give moderate to good yields of the desired

Structural analysis of stereoselective galactose pyruvylation toward the synthesis of bacterial capsular polysaccharides

• Tsun-Yi Chiang,
• Mei-Huei Lin,
• Chun-Wei Chang,
• Jinq-Chyi Lee and
• Cheng-Chung Wang

Beilstein J. Org. Chem. 2025, 21, 1671–1677, doi:10.3762/bjoc.21.131

• linker at the reducing end adopts a rotamer configuration, leading to the broad singlet at δ 4.22 ppm. The 13C chemical shift of the methyl groups in galactose for all (R)-4,6-O-pyruvylated residues was determined to be between δ 25.5–25.7 ppm, with corresponding δ 1.50–1.65 ppm in 1H NMR. This NMR

On the aromaticity and photophysics of 1-arylbenzo[a]imidazo[5,1,2-cd]indolizines as bicolor fluorescent molecules for barium tagging in the study of double-beta decay of ¹³⁶Xe

• Eric Iván Velazco-Cabral,
• Fernando Auria-Luna,
• Juan Molina-Canteras,
• Miguel A. Vázquez,
• Iván Rivilla and
• Fernando P. Cossío

Beilstein J. Org. Chem. 2025, 21, 1627–1638, doi:10.3762/bjoc.21.126

• interactions. Finally, a spacer (denoted as X and Y in Figure 2) and a linker (denoted as Z) to anchor the sensor to a suitable surface via a covalent interaction are required. Ideally, different configurations and conformations of the fluorophore in the free and chelated states would result in a bicolor

• -generation bicolor fluorescent indicators based on 1-aryl benzo[a]imidazo[5,1,2-cd]indolizines. X and Y represent the spacer and Z stands for the linker to the surface, respectively. The different emission wavelengths in the free and bound states are highlighted. (A) Total, peripheral and modular

Thermodynamic equilibrium between locally excited and charge transfer states in perylene–phenothiazine dyads

• Issei Fukunaga,
• Shunsuke Kobashi,
• Yuki Nagai,
• Hiroki Horita,
• Hiromitsu Maeda and
• Yoichi Kobayashi

Beilstein J. Org. Chem. 2025, 21, 1577–1586, doi:10.3762/bjoc.21.121

• -catalyzed cross-coupling reactions between bromo-substituted perylene or phenothiazine precursors and appropriate donor or linker units, followed by purification via column chromatography and gel permeation chromatography (Figures S18–S21 in Supporting Information File 1). The details of the syntheses are

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

Recent advances and future challenges in the bottom-up synthesis of azulene-embedded nanographenes

• Bartłomiej Pigulski

Beilstein J. Org. Chem. 2025, 21, 1272–1305, doi:10.3762/bjoc.21.99

• gap, aromaticity of azulene subunit and anti-Kasha’s emission from higher excited states. In such cases, the azulene unit merely acts as a linker within a more complex benzenoid framework. This review covers all types of azulene-embedded molecular scaffolds, regardless of whether they contain a

On the photoluminescence in triarylmethyl-centered mono-, di-, and multiradicals

• Daniel Straub,
• Markus Gross,
• Mona E. Arnold,
• Julia Zolg and
• Alexander J. C. Kuehne

Beilstein J. Org. Chem. 2025, 21, 964–998, doi:10.3762/bjoc.21.80

Synthesis of HBC fluorophores with an electrophilic handle for covalent attachment to Pepper RNA

• Raphael Bereiter and
• Ronald Micura

Beilstein J. Org. Chem. 2025, 21, 727–735, doi:10.3762/bjoc.21.56

• -cyanophenylacetonitrile afforded HBC 4 and HBC-like ligands 5 and 6 as bright orange solids. Finally, the bromo group was introduced under Appel conditions with carbon tetrabromide and triphenylphosphine to give the fluorophores 7, 8, and 9, with linker lengths of two, three, and five atoms. Unfortunately, this strategy

• additionally synthesized the HBC series with different linker lengths with the mesyloxy group, yielding the derivatives 16 to 18 (Scheme 5). All of these derivatives – although well soluble in the reaction buffer without the need for additional DMSO – were less reactive than N-(3-mesyloxypropyl) HBC derivative