Efficient solid-phase synthesis and structural characterization of segetalins A–H, J and K

• Liangyu Liu,
• Wanqiu Lu,
• Quanping Guo and
• Zhaoqing Xu

Beilstein J. Org. Chem. 2025, 21, 2612–2617, doi:10.3762/bjoc.21.202

• scalable methodology overcomes limitations of prior syntheses, enabling biological evaluation. Keywords: Fmoc-solid-phase peptide synthesis (Fmoc-SPPS); head-to-tail cyclization; plant cyclopeptides; Vaccaria segetalis; Introduction Cyclopeptides have garnered significant research interest owing to their

• from the high cost of the specialized resin and large solvent volumes required for dilution, coupled with DPPA's poor efficiency in forming sterically hindered peptide bonds involving residues like Val or Ile. Dahiya and Kaur synthesized segetalin C (3) via a solution-phase fragment coupling strategy

• and solid-phase approaches are viable for peptide synthesis, Fmoc-based SPPS offers distinct advantages in operational simplicity and efficiency for laboratory-scale production [20]. We therefore devised a streamlined solid-phase strategy for synthesizing the Vaccaria segetalis cyclopeptide family

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

• acid (RNA) impacts many biological processes; however, the complexities of its many roles are not completely understood. Therefore, designing tools for molecular recognition is of paramount importance. Peptide nucleic acids (PNA) show promise as a tool for selective recognition of double helical

• bonding; modified nucleobases; peptide nucleic acids; PNA–RNA triplexes; RNA recognition; Introduction RNA is a key contributor in countless biological processes. Though coding RNA has a well-known role in the central dogma of biology, most RNA is non-coding (ncRNA) and plays a multitude of roles

• oligonucleotides (TFOs) [8]. TFOs are utilized in both RNA and DNA recognition [9][10][11][12] and a particular type of TFO, peptide nucleic acid (PNA), has emerged as a promising probe for recognizing ncRNA [13][14][15][16]. The Nielsen lab first designed PNA with the N-(2-aminoethyl)glycine backbone for the

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

• -bonded to a chiral peptide station. This rotaxane works as a chiroptical switch by light-induced macrocycle movement along the axle [65]. The need to understand the photochemistry of fumaramides to aid their usage in various applications led to the design of rotaxanes containing different axles. Both

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

• as the activating agent under standard peptide coupling conditions. Cleavage of the Boc-protecting group with TFA afforded the target 6-oxoindolo[1,2-c]quinazoline-12-carboxamides 7a–c (Scheme 2). 3-Aminomethylindole derivatives represent a well-established class of compounds with diverse biological

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

• HSA in aqueous medium shows a characteristic oxidation wave that begins to rise around +0.5 V and significantly increases up to +1.2 V vs Ag/AgCl (Figure 3). This wave is attributed to oxidation processes at peptide bonds or specific side chains (such as cysteine, methionine, tyrosine, serine

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

• the peptide chain [94]. Arylhydrazones Arylhydrazones are a class of extremely versatile photoswitches, with good fatigue resistance and thermal half-lives that span from a few hours to years (Figure 17). The common feature of arylhydrazones is the presence of a H-bond acceptor in the rotor, which

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

• developed a SAC4A grafted self-assembled peptide hydrogel for hypoxia-responsive controlled drug release in anti-inflammatory treatment of ischemic stroke (Figure 17) [125]. Following PBS induction, the peptide hydrogel was tailored to exhibit a rheological modulus and shear-thinning behavior similar to

• -DM) or fingolimod (FTY720) in vitro. Upon local administration, the hypoxia-responsive self-assembling peptide hydrogel resulted in improved motor function and reduced inflammation in vivo. Recently, Geng and colleagues created additional binding sites by modifying the upper rim of CA4 with glucose

• responses have a broad application prospect in controlling drug release. For example, supramolecular peptide assemblies that naturally respond to pH or ion strength can be designed to include light-responsive elements or feature-specific enzyme substrates, thus utilizing two separate stimulus-response

N-Salicyl-amino acid derivatives with antiparasitic activity from Pseudomonas sp. UIAU-6B

• Joy E. Rajakulendran,
• Emmanuel Tope Oluwabusola,
• Michela Cerone,
• Terry K. Smith,
• Olusoji O. Adebisi,
• Adefolalu Adedotun,
• Gagan Preet,
• Sylvia Soldatou,
• Hai Deng,
• Rainer Ebel and
• Marcel Jaspars

Beilstein J. Org. Chem. 2025, 21, 1388–1396, doi:10.3762/bjoc.21.103

• tentative biosynthesis follows that of pseudomonine, a non-ribosomally synthesized isoxazolidone produced by P. fluorescens. The previous studies on the biosynthesis revealed seven genes, three non-ribosomal peptide synthases (Pms D, E, G) and four precursor biosynthetic enzymes (Pms A, B, C, F) [23][24][25

A versatile route towards 6-arylpipecolic acids

• Erich Gebel,
• Cornelia Göcke,
• Carolin Gruner and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 1104–1115, doi:10.3762/bjoc.21.88

• . It contains a six-membered ring and is, like its five-membered correlate, known for its secondary structure inducing properties, which are particularly useful in the design of peptide conformations. We present a new and improved way to generate enantiomerically pure pipecolic acid derivatives with

• important role as building blocks for peptide synthesis [1][2][3][4][5], as organocatalysts [6][7][8][9][10] and as enzyme inhibitors [4][11][12][13]. The incorporation of such amino acids into peptides can, for example, influence peptide conformation, the binding affinity to receptors [14], as well as

• pharmacokinetics [15][16], stability against degradation [17] and general stability [10][18] of the peptide [19]. One of those amino acids is pipecolic acid [20][21], a homolog of proline with a six-membered piperidine ring. Pipecolic acid has similar features as proline in regard to its rigid nature and turn

Studies on the syntheses of β-carboline alkaloids brevicarine and brevicolline

• Benedek Batizi,
• Patrik Pollák,
• András Dancsó,
• Péter Keglevich,
• Gyula Simig,
• Balázs Volk and
• Mátyás Milen

Beilstein J. Org. Chem. 2025, 21, 955–963, doi:10.3762/bjoc.21.79

• silico for non-peptide malignant brain tumor (MBT) antagonist activity, showing hits on three MBT-containing proteins [35]. Although Carex brevicollis DC has been observed to have a teratogenic effect on animals [1][36], which could be linked with the presence of the two mentioned β-carboline alkaloids

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

Asymmetric synthesis of fluorinated derivatives of aromatic and γ-branched amino acids via a chiral Ni(II) complex

• Maurizio Iannuzzi,
• Thomas Hohmann,
• Michael Dyrks,
• Kilian Haoues,
• Katarzyna Salamon-Krokosz and
• Beate Koksch

Beilstein J. Org. Chem. 2025, 21, 659–669, doi:10.3762/bjoc.21.52

• amino acids. We synthesized two fluorinated analogs of phenylalanine, which are still unexplored in the context of peptide and protein chemistry. Furthermore, both diastereomers of trifluoroleucine were synthesized, demonstrating that the described strategy can also be applied to synthesize enantio‑ and

• -natural amino acids are pivotal in protein engineering and drug development. Over 30% of approved small‑molecule drugs today contain non‑canonical amino acid building blocks [1][2]. In peptide and protein engineering, non‑natural amino acids significantly increase the respective range of tools used to

• modify a series of peptide and protein-related properties such as stability, specificity, and folding. In this regard, fluorinated amino acids are particularly important. Incorporation of fluorinated groups into the sequence of peptides and proteins can, for instance, regulate the respective

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

• such methods are generally reported with a heterogeneous DAR, the group developed a site-specific approach leading to a homogeneous DAR 2, thanks to a photoreactive Fc-binding peptide derivative (pFcBP) containing a photoleucine (pLeu) [46]. By analyzing the X-ray crystal structure of IgG, the

• acts as a microtubule destabilizer. To ensure the stability and homogeneity of the final product, the design of the FcBP included a norbornene motif at the N-terminal end of the peptide sequence. The norbornene motif selectively reacts with a tetrazine located on the spacer-payload. This study

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

• peptide carbonyl group. Both moieties result from the glyoxylate compound (Scheme 43). There are many examples in which the ester moiety opens the possibility of a further intramolecular cyclization with a nucleophile (for example, a protected amine in an Ugi/deprotection/cyclization sequence [98][99][100

Binding of tryptophan and tryptophan-containing peptides in water by a glucose naphtho crown ether

• Gianpaolo Gallo and
• Bartosz Lewandowski

Beilstein J. Org. Chem. 2025, 21, 541–546, doi:10.3762/bjoc.21.42

• towards ʟ-Trp over its ᴅ-enantiomer (entries 1 and 6, Table 1). Since tryptophan fulfills many of its biological functions as a component of peptides and proteins [2][3][4][5], we also probed, if 1 can recognize tryptophan residues within peptide sequences. For this purpose, we prepared six model

• tripeptides 2–7 consisting of one tryptophan and two alanine residues. We varied the position of the tryptophan in the peptide sequence, N-terminus in 2, middle of the chain in 3, and C-terminus in 4 to check if this affects their binding by 1. To probe the importance of the N-terminal amino group in the

• , Table 2). The binding affinity of 1 towards peptide 4 is around 1.5 times higher than for the free amino acid (entry 3, Table 2). The acetylated analogues of peptides 2 and 3 – compounds 5 and 6, are bound by 1 notably weaker, with 1.8× and 1.3× lower affinities respectively (entries 4 and 5, Table 2

Synthesis of N-acetyl diazocine derivatives via cross-coupling reaction

• Thomas Brandt,
• Pascal Lentes,
• Jeremy Rudtke,
• Michael Hösgen,
• Christian Näther and
• Rainer Herges

Beilstein J. Org. Chem. 2025, 21, 490–499, doi:10.3762/bjoc.21.36

• accumulation in the environment after excretion [1][6][7]. These superior properties of diazocines have been exploited in several applications such as the control of protein folding by implementation as cross-linkers between protein side chains [8] or in peptide backbones [9], as photoswitchable

Antibiofilm and cytotoxic metabolites from the entomopathogenic fungus Samsoniella aurantia

• Rita Toshe,
• Syeda J. Khalid,
• Blondelle Matio Kemkuignou,
• Esteban Charria-Girón,
• Paul Eckhardt,
• Birthe Sandargo,
• Kunlapat Nuchthien,
• J. Jennifer Luangsa-ard,
• Till Opatz,
• Hedda Schrey,
• Sherif S. Ebada and
• Marc Stadler

Beilstein J. Org. Chem. 2025, 21, 327–339, doi:10.3762/bjoc.21.23

• previously reported study investigating the biosynthesis of tenellin from Beauveria bassiana CBS110.25 [13], it was established that tenellin and a vast array of related metabolites could be synthesized through a cascade involving hybrid highly reducing polyketide synthase–non-ribosomal peptide synthetase

Streamlined modular synthesis of saframycin substructure via copper-catalyzed three-component assembly and gold-promoted 6-endo cyclization

• Asahi Kanno,
• Ryo Tanifuji,
• Satoshi Yoshida,
• Sota Sato,
• Saori Maki-Yonekura,
• Kiyofumi Takaba,
• Jungmin Kang,
• Kensuke Tono,
• Koji Yonekura and
• Hiroki Oguri

Beilstein J. Org. Chem. 2025, 21, 226–233, doi:10.3762/bjoc.21.14

• of saframycin A (1) is assembled from two molecules of ʟ-tyrosine derivative 5 and peptidyl aldehyde 6 by non-ribosomal peptide synthetases (NRPS, Scheme 1a) [15][16][17][18][19][20][21]. The pivotal NRPS module, SfmC, catalyzes iterative regio- and stereoselective Pictet–Spengler (PS)-type

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

• condensation of carboxylic acids with anilines, often promoted by activating agents such as thionyl chloride or peptide coupling agents [86][87][88][89]. However, these protocols rely on environmentally harmful reagents and produce unwanted byproduct wastes. Recently, the research group of Son showcased a

Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• dehydration, release of the chiral acid, and aromatization through tautomerization of intermediate Int-50 generate the desired product 195. Kwon et al. compared the effectivity of traditional biaryl phosphoric acid C30 with peptide phosphoric acid C46 in the cyclodehydration of trifluorophenylaminoacetals

• present. On the other hand, peptide phosphoric acid C46 appears to work through an alternative mode of enantioinduction, where conformational adaptation presumably limits repulsive interactions. CPA C40 was utilized in the construction of the imidazole ring of axially chiral products 200 (Scheme 59) [89

Hot shape transformation: the role of PSar dehydration in stomatocyte morphogenesis

• Remi Peters,
• Levy A. Charleston,
• Karinan van Eck,
• Teun van Berlo and
• Daniela A. Wilson

Beilstein J. Org. Chem. 2025, 21, 47–54, doi:10.3762/bjoc.21.5

• for the use in drug delivery systems [12]. In this regard, synthetic polypeptides emerge as a promising candidate for constructing biodegradable and biocompatible polymersomes. Leveraging the inherent presence of peptide-degrading mechanisms within the human body and the versatile chemical

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

• functionalization (LSF) of peptide scaffolds. α,β-Unsaturated amino acids like dehydroalanine (Dha) derivatives have emerged as particularly useful structures, as the electron-deficient olefin moiety can engage in late-stage functionalization reactions, like a Giese-type reaction. Cheap and widely available

• , forming a new C(sp3)–C(sp3) bond. The reaction can be performed in a phosphate-buffered saline (PBS) solution and shows post-functionalization prospects through pathways involving classical peptide chemistry. Keywords: dehydroalanine; Giese-type reaction; hydroalkylation; photocatalysis; water

• ]. Amid the growing popularity of biomolecular drug candidates, the late-stage modification of peptide scaffolds has gained significant importance [28]. A particularly interesting class of amino acids for late-stage diversification consists of dehydroamino acids (Dha). Dha derivatives have shown

Synthesis of extended fluorinated tripeptides based on the tetrahydropyridazine scaffold

• Thierry Milcent,
• Pascal Retailleau,
• Benoit Crousse and
• Sandrine Ongeri

Beilstein J. Org. Chem. 2024, 20, 3174–3181, doi:10.3762/bjoc.20.262

• for peptide synthesis. Consequently, developing a simple and efficient methodology is still challenging. Our new strategy to synthesize these compounds is based on an aza-Barbier reaction on difluoro- or trifluoromethylated hydrazones. The thus obtained compounds will then be oxidized and cyclized in

• carbazate (NH2-NHCbz/NH2-NHBoc) were chosen as starting materials in order to obtain final building blocks suitable for peptide synthesis. While the synthesis of compound 3a was already reported [28], compounds 3b–f are not described in the literature. All the fluorinated hydrazones were obtained in good

• feature results will be further confirmed by the insertion of these cyclic β-dehydropiperazic acids in longer peptide sequences. Examples of bioactive tetrahydropyridazine derivatives. Linear and cyclic peptides incorporating the dehydropiperazic acid moiety. Piperazic acid and analogues and target

Chemical structure metagenomics of microbial natural products: surveying nonribosomal peptides and beyond

• Thomas Ma and
• John Chu

Beilstein J. Org. Chem. 2024, 20, 3050–3060, doi:10.3762/bjoc.20.253

• silico to avoid rediscovery. They are the cornerstone of chemical structure metagenomics; a few examples in this area of research are described below. NRP biosynthesis and structure prediction NRPs are biosynthesized by either type I or II nonribosomal peptide synthetase (NRPS) [50][51]. Type I NRPS is a

• megaenzyme machinery that contains multiple modules arranged in an assembly line fashion, each of which is responsible for incorporating a single BB into the growing peptide intermediate (Figure 3a). One module typically contains one adenylation (A) domain that folds and operates semi-autonomously, which

• molecules Aside from an analysis of the BB usage pattern, real NRP-like molecules can be constructed in accordance to the predicted identity and order of the BBs. Brady and co-workers used solid-phase peptide synthesis to convert the predicted NRPs from virtual into reality; they called these molecules

gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

• Monika Bilska-Markowska,
• Marcin Kaźmierczak,
• Wojciech Jankowski and
• Marcin Hoffmann

Beilstein J. Org. Chem. 2024, 20, 2946–2953, doi:10.3762/bjoc.20.247

• fluorinated Michael acceptors into peptide structures, which can act as the link between an active molecule and its cellular target [19][20]. Such endeavors hint at the potential of fluorinated acceptors in designing fluorinated peptidomimetics, an area attracting global research interest [21][22][23][24]. In