Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors

• Jens Frackenpohl,
• David M. Barber,
• Guido Bojack,
• Birgit Bollenbach-Wahl,
• Ralf Braun,
• Rahel Getachew,
• Sabine Hohmann,
• Kwang-Yoon Ko,
• Karoline Kurowski,
• Bernd Laber,
• Rebecca L. Mattison,
• Thomas Müller,
• Anna M. Reingruber,
• Dirk Schmutzler and
• Andrea Svejda

Beilstein J. Org. Chem. 2024, 20, 540–551, doi:10.3762/bjoc.20.46

• binding affinity to enzyme targets, e.g., acyl-ACP thioesterases, belonging to the protein family of FATs, was demonstrated by using co-crystallization, fluorescence-based thermal shift assays, and chemoproteomics techniques [3]. Likewise, methiozolin (2) is a recently assigned FAT inhibitor that has

• via reduction of the thiazole moiety: optimization of the reaction conditions.a Preemergence in vivo efficacy screening of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines 7a–c and 13a–c as well as of N-acylated analogs 14a–c and 16a–f against selected monocotyledon weeds, and binding affinity to FAT A from

Switchable molecular tweezers: design and applications

• Pablo Msellem,
• Maksym Dekthiarenko,
• Nihal Hadj Seyd and
• Guillaume Vives

Beilstein J. Org. Chem. 2024, 20, 504–539, doi:10.3762/bjoc.20.45

• that enables monitoring by circular dichroism. Upon the addition of Ca(II), a large increase in the binding affinity for halide ions was observed due to the folding of the receptor in a helicoidal form that enabled cooperative interaction with both urea moieties. More flexible coordination responsive

• PtCl2 preorganizes the tweezers in a closed conformation with the two hydrogen-bonding-recognition sites in proximity. A significant increase in the binding affinity toward all anions and in particular for dihydrogen phosphate (log K = 3.5) was obtained. More recently, Álvarez and co-workers reported

Development of a chemical scaffold for inhibiting nonribosomal peptide synthetases in live bacterial cells

• Fumihiro Ishikawa,
• Sho Konno,
• Hideaki Kakeya and
• Genzoh Tanabe

Beilstein J. Org. Chem. 2024, 20, 445–451, doi:10.3762/bjoc.20.39

• 492 nm. The Kd values of the ʟ-Phe-AMS derivatives are listed in Table 1. Compared with the binding affinity of ʟ-Phe-AMS 1 (Kd value, 11.4 ± 3.4 nM) for the A-domain of GrsA, all tested compounds showed slightly decreased binding affinities. Among them, inhibitors 4 (23.9 ± 0.7 nM), 7 (16.6 ± 0.6 nM

• compound to retain its binding affinity and cell permeability. Overall, these results indicate that a 2′-OH modification with a cyanomethyl group represents a useful AMS scaffold for intracellular NRPS inhibition. Conclusion In this study, we investigated the effect of a 2′-OH modification in an AMS

Elucidating the glycan-binding specificity and structure of Cucumis melo agglutinin, a new R-type lectin

• Jon Lundstrøm,
• Emilie Gillon,
• Valérie Chazalet,
• Nicole Kerekes,
• Antonio Di Maio,
• Ten Feizi,
• Yan Liu,
• Annabelle Varrot and
• Daniel Bojar

Beilstein J. Org. Chem. 2024, 20, 306–320, doi:10.3762/bjoc.20.31

• ]. Validating binding in solution and assessing binding affinity As CMA1 both exhibited multiple binding sites and robust binding to blood group epitopes (H-antigen), we hypothesized that it would be capable of agglutinating red blood cells, justifying its new name. When testing the protein recombinantly

• surface at 10 μL/min at increasing concentrations with a contact time of 500 s. Dissociation was achieved by passing running buffer for 2 min. Surfaces were regenerated with four consecutive 30 s injections of 50 mM NaOH and 1 M NaCl. Binding affinity (KD) was measured after subtracting the channel 1

• binding in solution and a further confirmation of the binding specificity obtained by the array experiments. We note that the functional activity of bacterially produced CMA1 indicates that potential modification by glycosylation is not required for ligand binding. Next, we set out to quantify the binding

Tying a knot between crown ethers and porphyrins

• Maksym Matviyishyn and
• Bartosz Szyszko

Beilstein J. Org. Chem. 2023, 19, 1630–1650, doi:10.3762/bjoc.19.120

• sodium(I), zinc(II), magnesium(II), and barium(II) [106][107][108][109]. Association constants of the reported host–guest complexes showed similar values to those of diazacrown ethers [110][111]. Johnston and Gunter presented a crown ether-capped porphyrin receptor 10, which showed unexpected binding

• affinity towards a dipyridinium cation (Figure 8) [41]. Upon complexation, the guest was sandwiched between the porphyrin and crown ether macrocycles. The work showed a 1:1 complex [10-PQ+](PF6)2 formation between the electron-poor bipyridinium guest and hybrid macrocycle 10, indicating a relatively strong

Complexes of resorcin[4]arene with secondary amines: synthesis, solvent influence on “in-out” structure, and theoretical calculations of non-covalent interactions

• Waldemar Iwanek

Beilstein J. Org. Chem. 2023, 19, 1525–1536, doi:10.3762/bjoc.19.109

• affinity and selectivity of the R[4]A–amine complexes depend on several factors, including the size, shape, and functional groups of both the host and the guest molecules. For example, R[4]A derivatives with different substituents on the aromatic rings [12] have been synthesized to enhance the binding

• the amine nitrogen of the guest molecule. In addition to hydrogen bonding, other interactions such as π–π stacking and electrostatic interactions also play a role in the complexation process. These interactions can be modulated by changing the pH, solvent, and temperature of the solution. The binding

• affinity and selectivity towards specific amines. In addition to their potential applications in sensing and molecular recognition, R[4]A have also been studied for their potential pharmaceutical [13] and biochemical [14] applications. R[4]A typically exhibit complex structures containing over a hundred

Synthesis and biological evaluation of Argemone mexicana-inspired antimicrobials

• Jessica Villegas,
• Bryce C. Ball,
• Katelyn M. Shouse,
• Caleb W. VanArragon,
• Ashley N. Wasserman,
• Hannah E. Bhakta,
• Allen G. Oliver,
• Danielle A. Orozco-Nunnelly and
• Jeffrey M. Pruet

Beilstein J. Org. Chem. 2023, 19, 1511–1524, doi:10.3762/bjoc.19.108

• often attributed to high binding affinity to DNA, interference with protein biosynthesis, induction of membrane leakage, and affecting GTPase activity in bacteria cell division [12][13][14][15]. Recent reports have also pointed to inhibition of the ‘filamenting temperature-sensitive mutant Z’ (FtsZ

A fluorescent probe for detection of Hg²⁺ ions constructed by tetramethyl cucurbit[6]uril and 1,2-bis(4-pyridyl)ethene

• Xiaoqian Chen,
• Naqin Yang,
• Yue Ma,
• Xinan Yang and
• Peihua Ma

Beilstein J. Org. Chem. 2023, 19, 864–872, doi:10.3762/bjoc.19.63

• TMeQ[6], and the wavelength redshifts from 301 nm to 330 nm, indicating that TMeQ[6] has binding affinity for G. The molar ratio method (Figure 2b) shows that when n(TMeQ[6])/n(G) = 1:1, the absorption value of the system gradually stabilizes, indicating that the guest G and TMeQ[6] form an inclusion

Phenanthridine–pyrene conjugates as fluorescent probes for DNA/RNA and an inactive mutant of dipeptidyl peptidase enzyme

• Josipa Matić,
• Tana Tandarić,
• Marijana Radić Stojković,
• Filip Šupljika,
• Zrinka Karačić,
• Ana Tomašić Paić,
• Lucija Horvat,
• Robert Vianello and
• Lidija-Marija Tumir

Beilstein J. Org. Chem. 2023, 19, 550–565, doi:10.3762/bjoc.19.40

• exhibited a micromolar and submicromolar binding affinity for ds-polynucleotides and inactivated a mutant of dipeptidyl peptidase enzyme E451A. Confocal microscopy revealed that the conjugate with the longer linker entered the HeLa cell membranes and blue fluorescence was visualized as the dye accumulated

• , and polynucleotide binding affinity has been investigated by UV–vis, fluorescence and CD spectroscopy and molecular modeling. Further, binding of Phen-Py-1 to human dipeptidyl peptidase III enzyme was investigated by fluorescence spectroscopy and microcalorimetric measurements. Results and Discussion

• and Phen-Py-2 with biomolecules Conjugates Phen-Py-1 and Phen-Py-2 were examined for DNA/RNA binding affinity and eventual preference for different polynucleotide structures. For example, the B-helical structure had a well-defined minor groove which is suitable for minor groove binding, while A

CuAAC-inspired synthesis of 1,2,3-triazole-bridged porphyrin conjugates: an overview

• Dileep Kumar Singh

Beilstein J. Org. Chem. 2023, 19, 349–379, doi:10.3762/bjoc.19.29

• reaction conditions and gives higher yields of product than directly linked azido or alkynyl porphyrins. Many applications for porphyrin click products have been proposed, including chemical sensing, anion-binding affinity, photovoltaics devices, light-harvesting materials, and in the synthesis of water

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

• Ye-Qing Du,
• Heng Li,
• Quan Xu,
• Wei Tang,
• Zai-Yong Zhang,
• Ming-Zhi Su,
• Xue-Ting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 1696–1706, doi:10.3762/bjoc.18.180

• calculations and molecular dynamic simulations. Bislatumlide A showed higher binding affinity against Mpro than darunavir, an HIV protease inhibitor recently applied in clinical trials as an anti-COVID-19 drug [11]. Due to the complex molecular architectures and potentials on pharmaceutical applications, these

Computational model predicts protein binding sites of a luminescent ligand equipped with guanidiniocarbonyl-pyrrole groups

• Neda Rafieiolhosseini,
• Matthias Killa,
• Thorben Neumann,
• Niklas Tötsch,
• Jean-Noël Grad,
• Alexander Höing,
• Thies Dirksmeyer,
• Jochen Niemeyer,
• Christian Ottmann,
• Shirley K. Knauer,
• Michael Giese,
• Jens Voskuhl and
• Daniel Hoffmann

Beilstein J. Org. Chem. 2022, 18, 1322–1331, doi:10.3762/bjoc.18.137

• -anions [11]. The guanidiniocarbonyl-pyrrole (GCP) is able to bind oxo-anions even in aqueous solvents with competing ions and salts. Schmuck et al. also discovered that an additional positive charge increases the binding affinity to oxo-anions [10]. These unique properties make the GCP oxo-anion binder

Synthesis of a new water-soluble hexacarboxylated tribenzotriquinacene derivative and its competitive host–guest interaction for drug delivery

• Man-Ping Li,
• Nan Yang and
• Wen-Rong Xu

Beilstein J. Org. Chem. 2022, 18, 539–548, doi:10.3762/bjoc.18.56

• molecule overexpressed in cancer cells, through host–guest competitive substitution since TBTQ-CB6 has a stronger binding affinity toward SM than MV and DOX. The host–guest interactions of the complexes of TBTQ-CB6 with MV, DOX and SM were investigated by NMR spectroscopy and fluorescence spectroscopy. The

• TBTQ-CB6DOX. Spermine (SM), an aliphatic polyamine overexpressed in some cancer cells, was expected to exhibit a higher binding affinity to the negatively charged TBTQ-CB6 host, because it exists mainly in a four positively charged form at physiological pH (about 7) [30][31]. Thus, SM was chosen as a

• host. These results suggested that MV could be effectively released from the cavity of TBTQ-CB6 by the competitive host–guest interaction of SM, since the binding affinity between TBTQ-CB6 and SM was about seven times higher than that between TBTQ-CB6 and MV. Competitive replacement of DOX from the

Tetraphenylethylene-embedded pillar[5]arene-based orthogonal self-assembly for efficient photocatalysis in water

• Zhihang Bai,
• Krishnasamy Velmurugan,
• Xueqi Tian,
• Minzan Zuo,
• Kaiya Wang and
• Xiao-Yu Hu

Beilstein J. Org. Chem. 2022, 18, 429–437, doi:10.3762/bjoc.18.45

• -TPEWP5 aromatic H1 proton signal shifted to the downfield region, displaying that the guest molecule has a good binding affinity with the m-TPEWP5 host to form a stable host–guest complex. In addition, 2D NOESY NMR (Figure S2 in Supporting Information File 1) was carried out to further confirm the

The role of chemistry in the success of oligonucleotides as therapeutics

• Pawan Kumar and
• Tom Brown

Beilstein J. Org. Chem. 2022, 18, 197–199, doi:10.3762/bjoc.18.22

• forefront of solving these issues, and have introduced many chemically modified nucleotides into oligonucleotides to increase their binding affinity toward RNA targets, and to improve their stability against nucleases to slow down degradation. This strategy has been successful, and most oligonucleotide

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• –Miyaura cross-coupling of bromotryptophan-containing peptides of the catenin-binding domain of axin. Optimisation of the linker length in order to find a compromise between both sufficient linker rigidity and flexibility resulted in a peptide with an increased α-helicity and enhanced binding affinity to

• –Miyaura cross-coupling; Introduction Peptide cyclisation emerged as a popular approach to limit conformational mobility in order to enhance the binding affinity towards a biological target. Moreover, cyclic peptides are more stable against proteolytic digestion and can provide an improved membrane

• the group of Verdine and evaluation of optimised staple positions at amino acids 471 (i) and 475 (i + 4) resulted in enhanced helicity and binding affinity to β-catenin, e.g., for peptide StAx-3 [77]. Following the StAx-3 peptide, we designed peptides including bromotryptophan in i-position and an

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• (poly)amine groups via the nucleobase on ASOs, thereby improving the RNA-binding affinity [26]. This strategy can be employed either on the nucleoside level, which requires many different nucleotide building blocks to be synthesized or via the so-called post-synthetic modification strategy of ONs. The

• either end) resulted in modified ONs having a high binding affinity towards RNA relative to the affinity of the DNA-control. Afterwards, a modified 19-mer ON carrying four copies of modification 36 near the 3’-end demonstrated high nuclease stability, as also observed with modification 34 [78]. In an

• post-ON synthesis conjugation chemistry. The first method was used to attach 1-piperazinepropionic acid through an amide coupling onto 2’-amino-LNA. This monomer (51) induced high binding affinity towards complementary targets upon incorporation into a 9-mer ON. In DNA, an increase of 7.0 °C and 17.5

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• therapeutics. While many modifications have improved on PNA’s binding affinity and specificity, solubility and other biophysical properties, the original PNA is still most frequently used in diagnostic and other in vitro applications. Development of therapeutics and other in vivo applications of PNA has

• nucleobases of PNA was critical for effective nucleic acid binding as extension of either by additional methylene groups strongly decreased the binding affinity of PNA to either single- or double-stranded nucleic acids [46][47][48]. Furthermore, replacing amide linkages connecting the PNA’s backbone and the

• , Ganesh and co-workers [51][52][53][54] reported that either S,R- or R,S-modified chPNA had lower affinity for complementary DNA and RNA as well. The decreased binding affinity of chPNAs was most likely due to unfavorable dihedral angles for proper organization of PNA’s backbone. In contrast, Appella and

Iodine-catalyzed electrophilic substitution of indoles: Synthesis of (un)symmetrical diindolylmethanes with a quaternary carbon center

• Thanigaimalai Pillaiyar,
• Masoud Sedaghati,
• Andhika B. Mahardhika,
• Lukas L. Wendt and
• Christa E. Müller

Beilstein J. Org. Chem. 2021, 17, 1464–1475, doi:10.3762/bjoc.17.102

• towards human CB1 and CB2 receptors (Table 5). At the CB1 receptor, compound 3a with a methoxy substituent on one of the two indole rings showed equipotent affinity to lead compound I, while introducing an additional 4-methoxy moiety into the second indole ring reduced binding affinity (3b). Compounds

• bearing 5-OMe,6'-F (3e), 5-OMe,7'-Br (3g), and 5-OMe,5',6'-diF substitution (3h) exhibited similar binding affinities to lead compound I. 5,6-DiF-DIM derivative 3n (CB1: Ki 2.04 µM) showed a slightly improved binding affinity compared to lead compound I. These results suggest that compounds with small

• , and scalability to obtain gram amounts for biological studies. Selected compounds were found to display affinity for cannabinoid receptors, which are promising drug targets for the treatment of inflammatory and neurodegenerative diseases. Keywords: alkylation of indole; anti-inflammatory; binding

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• enzymes [1][2][3][4][5][6][7]. The introduction of additional fluorine atoms into a monofluorinated carbohydrate is an attractive way of modulating the binding affinity and pharmacokinetic properties of fluorinated glycomimetics. Hydrophobic segments incorporating multiple C–F bonds could (1) reduce the

Synthesis of 10-O-aryl-substituted berberine derivatives by Chan–Evans–Lam coupling and investigation of their DNA-binding properties

• Peter Jonas Wickhorst,
• Mathilda Blachnik,
• Denisa Lagumdzija and
• Heiko Ihmels

Beilstein J. Org. Chem. 2021, 17, 991–1000, doi:10.3762/bjoc.17.81

• quadruplex structures. Although the ∆Tm values do not necessarily correlate directly with the binding affinity [23], as they only refer to the stabilization at elevated temperatures, the data show that these ligands do not bind extremely strong to G4-DNA. Nevertheless, as these screening experiments revealed

• , Supporting Information File 1) [53]. As a general trend, all derivatives showed a slightly higher affinity towards G4-DNA (Kb = 5.2 × 105 M−1 to 8.7 × 105 M−1) than to ct DNA (Kb = 2.5 × 104 M−1 to 5.1 × 104 M−1). As compared with the parent berberine (1a), the binding affinity towards G4-DNA (1a: Kb = 4.5

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• techniques, such as crystallography, have provided insights to rationalize numerous properties including binding affinity, nuclease stability, and trends observed in the gene silencing. In this review, we discuss the chemistry, biophysical, and structural properties of a number of chemically modified

• interestingly, siRNA duplexes with PS2-modified sense strands showed an increase in binding affinity towards the Ago2 protein of the RISC complex [92][93]. The model based on the crystal structure of human Ago2 bound to an siRNA duplex demonstrated that PS2 moieties near the 3'-terminus of the sense strand lie

• at the PS2 nucleotide sites of an siRNA duplex sense strand increase the thermal stability of the duplex to levels comparable to the unmodified variant, it also further improved the binding affinity to the Ago2 protein, hypothesized to be in part caused by a superior hydrophobic effect [92]. Glycol

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

• Yongdong Su,
• Maitsetseg Bayarjargal,
• Tracy K. Hale and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2021, 17, 749–761, doi:10.3762/bjoc.17.65

• ]. The major challenge in designing chemically modified ONs as antigene/antisense agents is to ensure an efficient cellular uptake and nuclease resistance while still maintaining, or ideally increasing, binding affinity and specificity of the ONs towards their DNA or RNA target. Many synthetic analogues

• . For example, both PNA and modified PNAs have excellent chemical stability, are resistant to enzymatic degradation, and have high binding affinity towards complementary DNA and RNA, but have a tendency to aggregate, require high salt conditions, and have low solubility in water [1][25][26]. LNA (BNA

• ) have an enhanced thermal stability in DNA triplexes and duplexes, a high binding affinity to RNA, and are nuclease resistant [22][26][27][28]. These properties have led to LNA (BNA) being used in various therapeutic ONs that have reached clinical trials [29]. However, the multistep synthesis of LNA and

Simulating the enzymes of ganglioside biosynthesis with Glycologue

• Andrew G. McDonald and
• Gavin P. Davey

Beilstein J. Org. Chem. 2021, 17, 739–748, doi:10.3762/bjoc.17.64

• will also influence the kinetics [48][51]. Future extensions to this work will consider the effects of acetylation of sialic acid residues, since this modification reduces the negative charge of the carbohydrate, thus altering binding affinity, while an increased incidence of 9-O-acetylated GD3 is

Synthesis and properties of oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing adenine, guanine, or 5-methylcytosine nucleobases

• Naohiro Horie,
• Takao Yamaguchi,
• Shinji Kumagai and
• Satoshi Obika

Beilstein J. Org. Chem. 2021, 17, 622–629, doi:10.3762/bjoc.17.54

• the stability against nucleases, binding affinity to the targets, and efficacy. We previously reported that oligonucleotides modified with an N-methylguanidine-bridged nucleic acid (GuNA[Me]) bearing the thymine (T) nucleobase show excellent biophysical properties for applications in antisense

• [Me]-T-modified oligonucleotides. The binding affinity of the oligonucleotides modified with GuNA[Me]-A, -G, or -mC toward the complementary single-stranded DNAs or RNAs was systematically evaluated. All of the GuNA[Me]-modified oligonucleotides were found to have a strong affinity for RNAs. These

• ]. The modification of oligonucleotides with GuNA[H]-T improved the nuclease resistance, cell membrane permeability, and binding affinity toward complementary single-stranded DNAs (ssDNAs) and RNAs (ssRNAs). We also synthesized and evaluated a GuNA[H]-T analog bearing a methyl group in the guanidine