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

An azobenzene container showing a definite folding – synthesis and structural investigation

• Abdulselam Adam,
• Saber Mehrparvar and
• Gebhard Haberhauer

Beilstein J. Org. Chem. 2019, 15, 1534–1544, doi:10.3762/bjoc.15.156

• organoammonium ions [10], and biomolecules [11][12][13][14][15][16][17]. Furthermore, modified Lissoclinum cyclopeptides were used for the construction of novel tubular and cage structures [18][19], as prototypes for mimicking multiple loops of proteins [20] and for homochiral supramolecular polymerization [21

Complexation of a guanidinium-modified calixarene with diverse dyes and investigation of the corresponding photophysical response

• Yu-Ying Wang,
• Yong Kong,
• Zhe Zheng,
• Wen-Chao Geng,
• Zi-Yi Zhao,
• Hongwei Sun and
• Dong-Sheng Guo

Beilstein J. Org. Chem. 2019, 15, 1394–1406, doi:10.3762/bjoc.15.139

• non-fluorescent in aqueous solution, but become highly fluorescent in non-polar solvents or when they are bound to proteins and membranes [42][43]. This enhancement is commonly understood in terms of the relocation of the guest into the more hydrophobic environment. The decreased rate constant of

Host–guest interactions between p-sulfonatocalix[4]arene and p-sulfonatothiacalix[4]arene and group IA, IIA and f-block metal cations: a DFT/SMD study

• Valya K. Nikolova,
• Cristina V. Kirkova,
• Silvia E. Angelova and
• Todor M. Dudev

Beilstein J. Org. Chem. 2019, 15, 1321–1330, doi:10.3762/bjoc.15.131

• molecules [27], including some amino acids [28] and proteins [29]. They are also biocompatible: compared to other types of macrocyclic molecules such as cyclodextrins and cucurbiturils (which are also water soluble), p-sulfonatocalix[n]arenes do not exhibit any toxicity, which makes them applicable in

Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction

• Maryna V. Murlykina,
• Oleksandr V. Kolomiets,
• Maryna M. Kornet,
• Yana I. Sakhno,
• Sergey M. Desenko,
• Victoriya V. Dyakonenko,
• Svetlana V. Shishkina,
• Oleksandr A. Brazhko,
• Vladimir I. Musatov,
• Alexander V. Tsygankov,
• Erik V. Van der Eycken and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2019, 15, 1281–1288, doi:10.3762/bjoc.15.126

• ]pyridine-4-carboxamides being SMYD2 inhibitors (an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB); the similar structures can be obtained using the methodology of sequential Doebner- and Ugi-type MCRs. In the present work we combined several

Phylogenomic analyses and distribution of terpene synthases among Streptomyces

• Lara Martín-Sánchez,
• Kumar Saurabh Singh,
• Mariana Avalos,
• Gilles P. van Wezel,
• Jeroen S. Dickschat and
• Paolina Garbeva

Beilstein J. Org. Chem. 2019, 15, 1181–1193, doi:10.3762/bjoc.15.115

• proteins from the 93 Streptomyces species described above were collected. After removing sequences shorter than 50 amino acids, a total of 171,033 sequences were used to construct orthologous gene families using OrthoFinder – v 2.2.6 [53] applying the default setting (BLASTp e-value cut-off = 1e−5; MCL

Molecular recognition using tetralactam macrocycles with parallel aromatic sidewalls

• Dong-Hao Li and
• Bradley D. Smith

Beilstein J. Org. Chem. 2019, 15, 1086–1095, doi:10.3762/bjoc.15.105

• of polar functional groups and non-polar surfaces which is reminiscent of the amphiphilic binding pockets within many proteins. In water, the aromatic surfaces in the tetralactam cavity drive high affinity due the hydrophobic effect and the NH groups provide secondary interactions that induce binding

• between the equatorial sugar hydroxy groups and the receptor NH residues and also in the CH···π interactions with the hydrophobic anthrylene sidewalls. This combination of noncovalent interactions closely mimics the sugar-binding behavior exhibited by lectin proteins. The Davis group has explored more

Stereo- and regioselective hydroboration of 1-exo-methylene pyranoses: discovery of aryltriazolylmethyl C-galactopyranosides as selective galectin-1 inhibitors

• Alexander Dahlqvist,
• Axel Furevi,
• Niklas Warlin,
• Hakon Leffler and
• Ulf J. Nilsson

Beilstein J. Org. Chem. 2019, 15, 1046–1060, doi:10.3762/bjoc.15.102

• /bjoc.15.102 Abstract Galectins are carbohydrate recognition proteins that bind carbohydrates containing galactose and are involved in cell signaling and cellular interactions, involving them in several diseases. We present the synthesis of (aryltriazolyl)methyl galactopyranoside galectin inhibitors

• -linked glycans on the cell surface. Surface proteins such as integrins [6][7], vascular endothelial growth factor receptor [8], and lysosome-associated membrane proteins [9] are known to be crosslinked by galectins, giving galectins a modulating role in cell adhesion, blood vessel growth and cellular