Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

• Sivaraman Balasubramaniam,
• Sajith Vijayan,
• Liam V. Goldman,
• Xavier A. May,
• Kyra Dodson,
• Sweta Adhikari,
• Fatima Rivas,
• Davita L. Watkins and
• Shana V. Stoddard

Beilstein J. Org. Chem. 2020, 16, 628–637, doi:10.3762/bjoc.16.59

• involve acetylation/deacetylation of histone proteins by histone deacetylases (HDACs) [1]. HDACs belong to an important family of enzymes consisting of 18 isozymes. They control protein acetylation, which is a change that occurs after translation. In addition, they regulate gene transcription, cell

• differentiation, cell cycle progression and apoptosis by targeting both histone and non-histone proteins. The balance between acetylation and deacetylation is pivotal for typical cell function. Abnormal or increased HDAC expression has been reported in several human tumors and cancer cell lines [2]. As such, the

Opening up connectivity between documents, structures and bioactivity

• Christopher Southan

Beilstein J. Org. Chem. 2020, 16, 596–606, doi:10.3762/bjoc.16.54

• . Although their expert-curated numbers are lower (i.e., ≈2 million compounds against ≈3700 human proteins), these open sources have the great advantage of being merged within PubChem. Parallel efforts have focused on the extraction of document-to-compound (D-C-only) connectivity. In the absence of molecular

• -R indicates C to be a potent inhibitor of P). Compounds: a full range of cheminformatic analysis including 2D or 3D clustering, property prediction and chemical ontology assignments. Proteins: a full range of bioinformatic analysis including gene ontology (GO) assignments, pathway annotation

•  4 are noteworthy and persist despite the ChEMBL/BindingDB selective mirroring. As for PMID coverage it would be useful to know which types of selectivity were responsible for this divergence in connectivity. For BindingDB some unique proteins are likely to be patent-only but exploring further causes

Convenient synthesis of the pentasaccharide repeating unit corresponding to the cell wall O-antigen of Escherichia albertii O4

• Tapasi Manna,
• Arin Gucchait and
• Anup Kumar Misra

Beilstein J. Org. Chem. 2020, 16, 106–110, doi:10.3762/bjoc.16.12

• cell wall polysaccharides with suitable proteins, which include vaccines against Haemophilia influenza type b (Hib) [12][13], meningitis [14], pneumococcal infections [15][16] and enteric diseases such as cholera [17], diarrhea [18] and urinary tract infections [19]. Despite the possibility of

Light-controllable dithienylethene-modified cyclic peptides: photoswitching the in vivo toxicity in zebrafish embryos

• Sergii Afonin,
• Oleg Babii,
• Aline Reuter,
• Volker Middel,
• Masanari Takamiya,
• Uwe Strähle,
• Igor V. Komarov and
• Anne S. Ulrich

Beilstein J. Org. Chem. 2020, 16, 39–49, doi:10.3762/bjoc.16.6

• differences of erythrocytes compared to other somatic cells. Although easily measured, hemolytic activity gives only a rough estimate of toxicity for peptide therapeutics. Erythrocytes are terminally differentiated non-adherent organelle-free cells, densely packed with oxygen-carrying proteins; their

Synthesis and characterization of bis(4-amino-2-bromo-6-methoxy)azobenzene derivatives

• David Martínez-López,
• Amirhossein Babalhavaeji,
• Diego Sampedro and
• G. Andrew Woolley

Beilstein J. Org. Chem. 2019, 15, 3000–3008, doi:10.3762/bjoc.15.296

• . While many classes of photoswitches are known [1][2], few of these are easily adaptable to controlling targets, such as proteins [3], while simultaneously exhibiting robust photochemistry in the red or near-infrared (NIR) regions of the spectrum [4][5][6][7]. Azonium ions – protonated forms of

Pigmentosins from Gibellula sp. as antibiofilm agents and a new glycosylated asperfuran from Cordyceps javanica

• Soleiman E. Helaly,
• Wilawan Kuephadungphan,
• Patima Phainuphong,
• Mahmoud A. A. Ibrahim,
• Kanoksri Tasanathai,
• Suchada Mongkolsamrit,
• Janet Jennifer Luangsa-ard,
• Souwalak Phongpaichit,
• Vatcharin Rukachaisirikul and
• Marc Stadler

Beilstein J. Org. Chem. 2019, 15, 2968–2981, doi:10.3762/bjoc.15.293

• , in particular orthopedic implant-related infections, since implants coated with proteins facilitate bacterial attachment and biofilm development [1]. In general, bacteria are known to employ different strategies to cope with the presence of antibiotics, of which a biofilm, an aggregate of

Chemical synthesis of tripeptide thioesters for the biotechnological incorporation into the myxobacterial secondary metabolite argyrin via mutasynthesis

• David C. B. Siebert,
• Roman Sommer,
• Domen Pogorevc,
• Michael Hoffmann,
• Silke C. Wenzel,
• Rolf Müller and
• Alexander Titz

Beilstein J. Org. Chem. 2019, 15, 2922–2929, doi:10.3762/bjoc.15.286

• peptide biosynthesis has previously been successfully performed using cell lysate, e.g., in case of gramicidin [24], or with purified proteins, e.g., in case of myxochelin [25] and tilivalline [26]. To evaluate if in vitro formation of argyrin is indeed possible, the reaction buffer was incubated with the

• cell lysate mixture of M. xanthus DK1622 mutants expressing the Arg2-Arg5 argyrin biosynthetic proteins. To ensure that no argyrin is present in the lysate prior to the incubation, a lysate mixture of two different mutants harboring arg2 and arg3-5 genes was used, respectively. Both of the mutants are

• incapable of argyrin production on their own, however, together they express all the necessary proteins. Despite significant efforts and evaluation of various incubation conditions, in vitro reconstitution of argyrins could never be achieved. The exact reason for this is unknown, however, it is very likely

Bacterial terpene biosynthesis: challenges and opportunities for pathway engineering

• Eric J. N. Helfrich,
• Geng-Min Lin,
• Christopher A. Voigt and
• Jon Clardy

Beilstein J. Org. Chem. 2019, 15, 2889–2906, doi:10.3762/bjoc.15.283

• can be further modified by tailoring enzymes, but the core structure can be inferred from the organization of the biosynthetic genes and the modular architecture of the associated proteins [7][8]. Terpene biosynthesis has a very different logic. Five-carbon units called isoprenes are joined to create

• Information File 1, Table S2). CYPs are heme-dependent iron proteins that catalyze a wide range of reactions [83][84]. The reactions typically involve substrate radical generation by the activated iron species and subsequent hydroxylation. Terpenes are mainly composed of nonactivated hydrocarbons that are

• ent-kaurenoic acid (27 and 28, respectively, Figure 7b) [41]. Characterization of CYPs is typically achieved by in vitro or in vivo studies. E. coli is the most popular host for obtaining proteins for in vitro studies, and proper selection of a redox system is usually the obstacle to reconstitute CYP

Emission and biosynthesis of volatile terpenoids from the plasmodial slime mold Physarum polycephalum

• Xinlu Chen,
• Tobias G. Köllner,
• Wangdan Xiong,
• Guo Wei and
• Feng Chen

Beilstein J. Org. Chem. 2019, 15, 2872–2880, doi:10.3762/bjoc.15.281

• 28–73% of sequence identities. Full-length cDNAs for the four TPS genes were cloned and expressed in Escherichia coli to produce recombinant proteins, which were tested for sesquiterpene synthase and monoterpene synthase activities. While neither PpolyTPS2 nor PpolyTPS3 was active, PpolyTPS1 and

• genes were identified from the transcriptomes. They were designated as PpolyTPS1, PpolyTPS2, PpolyTPS3, and PpolyTPS4. The length of the proteins encoded by PpolyTPS1, PpolyTPS2, PpolyTPS3, and PpolyTPS4s is 334, 347, 353, and 337 amino acids, respectively. Among the four proteins, the highest sequence

• terpene profiles (Figure 1). Four TPS genes, designated PpolyTPS1–PpolyTPS4, were identified from P. polycephalum. When E. coli-expressed PpolyTPS proteins were tested for terpene synthase activities, PpolyTPS1 was demonstrated to be a sesquiterpene synthase and PpolyTPS4 a monoterpene synthase (Figure 3

Preparation of anthracene-based tetraperimidine hexafluorophosphate and selective recognition of chromium(III) ions

• Qing-Xiang Liu,
• Feng Yang,
• Zhi-Xiang Zhao,
• Shao-Cong Yu and
• Yue Ding

Beilstein J. Org. Chem. 2019, 15, 2847–2855, doi:10.3762/bjoc.15.278

• autoimmune and cardiovascular diseases [11]. On the other hand, the excessive incorporation of chromium(III) is toxic to humans, and can cause cancer through the oxidation of DNA and some proteins [12][13][14]. Therefore, the detection of chromium(III) has a vital practical significance for human health

Palladium-catalyzed synthesis and nucleotide pyrophosphatase inhibition of benzo[4,5]furo[3,2-b]indoles

• Hoang Huy Do,
• Saif Ullah,
• Alexander Villinger,
• Joanna Lecka,
• Jean Sévigny,
• Peter Ehlers,
• Jamshed Iqbal and
• Peter Langer

Beilstein J. Org. Chem. 2019, 15, 2830–2839, doi:10.3762/bjoc.15.276

• selected inhibitors on isozymes ENPP1 and ENPP3 modelled proteins were in accordance with in vitro experimental studies. Conclusion In conclusion, we have reported a convenient strategy for the preparation of benzo[4,5]furo[3,2-b]indoles based on Suzuki–Miyaura coupling reactions followed by Pd-catalyzed

• were engaged in core and selected region of homology models [44]. Preparation of ligands and proteins The structures of the most active compounds were drawn by utilizing the MOE builder tool [45]. After introducing hydrogen atoms and charges to the prepared structures, the MMFF94x force field was

• interactions and binding energies of the selected compounds within the binding pocket of modeled proteins were found out by using MOE (2014.0901). MOE site finder was used to locate the binding site while default setting of the triangular matcher placement method in combination with GBVI/WSA ∆G, were used to

Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission

• Lorenzo Sansalone,
• Jun Zhao,
• Matthew T. Richers and
• Graham C. R. Ellis-Davies

Beilstein J. Org. Chem. 2019, 15, 2812–2821, doi:10.3762/bjoc.15.274

• ][20] compared to 2, so a simple one-step route can be used to install the maleimides. It is this functionality that allows coupling (often called "tethering", symbolized as "t" for tetherable in Scheme 1) of the probe with mutant proteins. In our case, we developed a three-step route to install the

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

• Nicky J. Willis,
• Elliott D. Bayle,
• George Papageorgiou,
• David Steadman,
• Benjamin N. Atkinson,
• William Mahy and
• Paul V. Fish

Beilstein J. Org. Chem. 2019, 15, 2790–2797, doi:10.3762/bjoc.15.271

• , Kings Cross, London NW1 1AT, UK 10.3762/bjoc.15.271 Abstract Background: The carboxylesterase Notum has been shown to act as a key negative regulator of the Wnt signalling pathway by mediating the depalmitoleoylation of Wnt proteins. LP-922056 (1) is an orally active inhibitor of Notum. We are

• Wnt proteins is required for efficient binding to Frizzled receptors and the subsequent signal transduction. The carboxylesterase Notum has been shown to act as a key negative regulator of the Wnt signalling pathway by specifically mediating the depalmitoleoylation of Wnt proteins [3][4]. LP-922056 (1

• to just 7 steps from 16 and improves the overall yield to 40–50 %. Mouse pharmacokinetics for 1 Assessment of 1 in mouse liver microsomes (MLM) showed excellent metabolic stability (Cli 1.0 μL/min/mg protein) which predicts for low clearance in vivo. Binding to mouse plasma proteins (mPPB) was very

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• cathodes in the presence of chiral inductors, including tertiary amines, optically active proteins, and alkaloids [19][20], in 1975, Miller’s group reported the first example of the modification of electrodes via covalent binding [21]. They chemically modified air-oxidized graphite electrodes via treatment

Fluorinated maleimide-substituted porphyrins and chlorins: synthesis and characterization

• Valentina A. Ol’shevskaya,
• Elena G. Kononova and
• Andrei V. Zaitsev

Beilstein J. Org. Chem. 2019, 15, 2704–2709, doi:10.3762/bjoc.15.263

• covalently conjugates thiol groups of cysteine residues in proteins or peptides by the thio-Michael addition to the double bond of the maleimide to form a corresponding succinimidyl thioether. Conjugation of the cysteine sulfhydryl group with maleimide moieties allows us to prepare the bioconjugates

• spectroscopy and mass spectrometry. These novel porphyrins and chlorins are expected to be efficient photosensitizers for cancer treatment. The presence of four maleimide groups in these compounds may provide improved binding with proteins in living systems. Synthesis of fluorinated maleimide-substituted

Emission solvatochromic, solid-state and aggregation-induced emissive α-pyrones and emission-tuneable 1H-pyridines by Michael addition–cyclocondensation sequences

• Natascha Breuer,
• Irina Gruber,
• Christoph Janiak and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 2684–2703, doi:10.3762/bjoc.15.262

• prerequisites for the application of fluorescent substances in chemistry, medicine and materials science [1]. With this respect emissive small molecules [2], fluorescent proteins [3], and quantum dots have received considerable attention and remarkable progress in their synthesis and photophysics has been

Plasma membrane imaging with a fluorescent benzothiadiazole derivative

• Pedro H. P. R. Carvalho,
• Jose R. Correa,
• Karen L. R. Paiva,
• Daniel F. S. Machado,
• Jackson D. Scholten and
• Brenno A. D. Neto

Beilstein J. Org. Chem. 2019, 15, 2644–2654, doi:10.3762/bjoc.15.257

• and by poor performances related to most of them. Therefore, many studies are still based on the use of WGA [16] (wheat germ agglutinin) or membrane proteins bearing fluorescent protein tags [11]. Water solubility is another issue that has to be considered. For the development of new fluorogenic dyes

Synthetic terpenoids in the world of fragrances: Iso E Super^® is the showcase

• Alexey Stepanyuk and
• Andreas Kirschning

Beilstein J. Org. Chem. 2019, 15, 2590–2602, doi:10.3762/bjoc.15.252

• -protein receptors consisting of seven intermembrane domains [28]. The quaternary structure including the membrane set up the active site. Approximately 370 different G-type proteins are known, that are linked with the odour perception. Because molecules can bind to an array of olfactory receptors

• generating a complex odour impression, an exact determination which proteins are linked to which smells or molecules is a very ambitious task. Hence, studies towards understanding interactions led to a Nobel Award in 2002 [29][30][31]. Even today correct modelling and protein crystallisation are immense

Probing of local polarity in poly(methyl methacrylate) with the charge transfer transition in Nile red

• Aydan Yadigarli,
• Qimeng Song,
• Sergey I. Druzhinin and
• Holger Schönherr

Beilstein J. Org. Chem. 2019, 15, 2552–2562, doi:10.3762/bjoc.15.248

• fluorescence was used to detect a lipid droplet in monkey aortic smooth muscle cells [16], for visualizing different proteins, such as lactoglobulin, casein and albumin [17]. In fluorescence lifetime imaging microscopy τf as a viable contrast parameter was employed to image lipid droplets in living HeLa cells

A toolbox of molecular photoswitches to modulate the CXCR3 chemokine receptor with light

• Xavier Gómez-Santacana,
• Sabrina M. de Munnik,
• Tamara A. M. Mocking,
• Niels J. Hauwert,
• Shanliang Sun,
• Prashanna Vijayachandran,
• Iwan J. P. de Esch,
• Henry F. Vischer,
• Maikel Wijtmans and
• Rob Leurs

Beilstein J. Org. Chem. 2019, 15, 2509–2523, doi:10.3762/bjoc.15.244

• superfamily of membrane proteins that regulate many physiological processes [12]. Despite the high relevance of GPCRs both functionally and as a drug target [12], the first synthetic GPCR photochromic small-molecule ligands appeared only five years ago [13][14][15]. Since then, photopharmacology has been

• or proteins) can be also targeted by allosteric photochromic ligands. In an initial communication [7], we recently reported a photochromic ligand class that is based on azologization of a biaryl ligand class [24] and that activates the chemokine CXCR3 receptor (CXCR3), a GPCR endogenously activated

Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors

• Christoph W. Grathwol,
• Nathalie Wössner,
• Sören Swyter,
• Adam C. Smith,
• Enrico Tapavicza,
• Robert K. Hofstetter,
• Anja Bodtke,
• Manfred Jung and
• Andreas Link

Beilstein J. Org. Chem. 2019, 15, 2170–2183, doi:10.3762/bjoc.15.214

• ‐time photomodulation of sirtuins in vitro. Keywords: azo compounds; epigenetics; photoswitch; sirtuins; stilbenes; Introduction Sirtuins are protein deacylases that cleave off not only acetyl, but also other acyl groups from the ε-amino group of lysines in histones and many other substrate proteins

• , 692; HRESIMS: calcd for [C12H9N4OF + H]+ 224.0760, found 224.0753; comp. purity (220 nm): 100%; anal. calcd for C12H9N4OF: N, 22.94; C, 59.02; H, 3.71; found: N, 22.95; C, 59.46; H, 3.92. Cloning, expression and purification of recombinant proteins: Expression and purification of Sirt1133-747, Sirt256

Bipolenins K–N: New sesquiterpenoids from the fungal plant pathogen Bipolaris sorokiniana

• Chin-Soon Phan,
• Hang Li,
• Simon Kessler,
• Peter S. Solomon,
• Andrew M. Piggott and
• Yit-Heng Chooi

Beilstein J. Org. Chem. 2019, 15, 2020–2028, doi:10.3762/bjoc.15.198

• and is a major threat to yield improvement and food security in Central Asia [13]. Recent genome sequencing of 35 Australian strains of B. sorokiniana identified a known proteinaceous necrotrophic effector, ToxA, which confers host-specific virulence proteins and is proposed to be acquired through

Complexation of chiral amines by resorcin[4]arene sulfonic acids in polar media – circular dichroism and diffusion studies of chirality transfer and solvent dependence

• Bartosz Setner and
• Agnieszka Szumna

Beilstein J. Org. Chem. 2019, 15, 1913–1924, doi:10.3762/bjoc.15.187

• amines [7][8][9]. Recently the group of Crowley showed that CSAs also co-crystalize with proteins modulating surface interactions mainly through interactions with surface-exposed lysines and arginines [10][11][12][13][14]. RSAs, in analogy to CSAs contain hydrophobic cavities and sulfonic acid groups

• protein crystallizations. Due to the interest in interactions with proteins we have selected basic amino acids as chiral bidentate amines to interact with RSAs. We have also studied interactions of RSAs with chiral tetradentate ligands (tetraaminocavitands) in order to evaluate the influence of a chelate

• , especially for those proteins that have surface exposed basic amino acids [25]. The 1:1 complexes of RSA 1 with tetradentate aminocavitand (R or S)-2 are also effectively formed in polar solvents. The complexes have capsular shape that is retained in methanol as manifested by DOSY coefficients and chirality

Installation of -SO₂F groups onto primary amides

• Jing Liu,
• Shi-Meng Wang,
• Njud S. Alharbi and
• Hua-Li Qin

Beilstein J. Org. Chem. 2019, 15, 1907–1912, doi:10.3762/bjoc.15.186

• aromatic amines with SO2F2 or the fluorosulfurylimidazolium salt have been achieved for assembly of N-sulfonyl fluorides [1][30], which have served as important active precursors for the development of noncovalent inhibitors (Scheme 1, (1)) [1][30][31]. Amides are the key connections in proteins, amides

A metal-free approach for the synthesis of amides/esters with pyridinium salts of phenacyl bromides via oxidative C–C bond cleavage

• Kesari Lakshmi Manasa,
• Yellaiah Tangella,
• Namballa Hari Krishna and
• Mallika Alvala

Beilstein J. Org. Chem. 2019, 15, 1864–1871, doi:10.3762/bjoc.15.182

• chemistry. The occurrence of an amide and/or ester bond is widely realized in organic molecules, proteins, natural products, pharmaceuticals, polymers and agrochemicals [1][2][3][4][5]. The conventional synthesis of amides involves the reaction of carboxylic acids or their derivatives such as acyl halides