Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

• various potential drug targets present within pqs QS. These range from enzymes within the biosynthesis cascade of the signal molecules PqsABCDE to the receptor of these autoinducers PqsR (MvfR). This review shortly introduces P. aeruginosa and its pathogenicity traits regulated by the pqs system and

• strains. Hence, these antibiotic-inactivating enzymes provide resistance against penicillins and cephalosporins [14]. In addition to these intrinsic capabilities, P. aeruginosa is able to acquire resistances toward antibiotics it has come in contact with. These acquired resistances can be the result of

• Gram-negatives consists of a transcription regulator, the signal molecules and one or several enzymes involved in the synthesis of the latter. The regulator usually controls the transcription of the biosynthetic enzymes and also functions as a receptor for the signal molecules themselves. As these are

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• infections [61]. While not typically classed as toxins, bacterial proteolytic enzymes, such as collagenases or elastases, often account for host cell damage and immune evasion. Janda and co-workers developed thiol-based small molecules targeting the active site zinc ion in P. aeruginosa elastase LasB showing

• (PQS) and its biosynthetic precursors in P. aeruginosa some of which are also found in Burkholderia [71], two species that often co-infect patients for example in cystic fibrosis airways infections. By blocking QS processes, the release of virulence factors such as host degrading enzymes or chemicals

• signal molecules and mimic their structures. The PQS system of P. aeruginosa is particularly attractive and can be considered as a pathogen specific target. The biosynthesis of the PQS signal 23 involves a set of biosynthetic enzymes PqsABCDEH and its autocatalytic receptor PqsR (MvfR). Biaryl methanols

Learning from B₁₂ enzymes: biomimetic and bioinspired catalysts for eco-friendly organic synthesis

• Keishiro Tahara,
• Ling Pan,
• Toshikazu Ono and
• Yoshio Hisaeda

Beilstein J. Org. Chem. 2018, 14, 2553–2567, doi:10.3762/bjoc.14.232

• 10.3762/bjoc.14.232 Abstract Cobalamins (B12) play various important roles in vivo. Most B12-dependent enzymes are divided into three main subfamilies: adenosylcobalamin-dependent isomerases, methylcobalamin-dependent methyltransferases, and dehalogenases. Mimicking these B12 enzyme functions under non

• methylcobalamin and adenosylcobalamin (coenzyme B12) that serve as organometallic cofactors in B12-dependent enzymes. The photolysis (thermolysis) of alkylcob(III)alamins leads to the formation of the corresponding alkyl radical and cob(II)alamin with homolytic Co(III)–C bond cleavage (Figure 1b). This high

• constant of 14 [11]. It is slightly basic, with a pKa lower than 1 for the Co–H complex [12]. The “supernucleophilic” cob(I)alamin is found in many enzymes such as methionine synthetases, adenosyltransferases, and reductive dehalogenases. In addition, the reactivity of cob(I)alamin has been investigated

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

• Eszter Lajkó,
• Sarah Spring,
• Rózsa Hegedüs,
• Beáta Biri-Kovács,
• Sven Ingebrandt,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 2495–2509, doi:10.3762/bjoc.14.226

• receptor-mediated endocytosis of the receptor–conjugate complex and (iv) the desensitization of GnRH-R [4][18]. The 3Trp-4Ser bond is a most susceptible site to be cleaved by proteolytic enzymes (e.g., chymotrypsin, angiotensin-converting enzyme). The substitution of Ser4 by its N-methyl analog (N-Me-Ser

• -containing conjugates with the non-acylated Lys-containing one ([4Lys]-GnRH-III(Dau=Aoa)). However, the substitution with 4Lys was formerly shown to lead increased cytostatic activity on different cancer cell lines (e.g., MCF-7, HT-29), this conjugate was less stable against different digestive enzymes and

• (i) expression of cell adhesion molecules (e.g., α3 integrin [25], non-integrin laminin receptor [56]) and (ii) regulate the actin polymerization by interacting with small GTPases (e.g., Rac1, CdC24 [54]) or (iii) interfere with the expression/activity of matrix-degrading enzymes (e.g., MMP-2 [25

The enzymes of microbial nicotine metabolism

• Paul F. Fitzpatrick

Beilstein J. Org. Chem. 2018, 14, 2295–2307, doi:10.3762/bjoc.14.204

• steps in the pyrrolidine pathway. This review summarizes the present status of our understanding of these pathways, focusing on what is known about the individual enzymes involved. Keywords: biodegradation; enzyme mechanism; flavoprotein; metabolic pathway; nicotine; Introduction The toxic alkaloid (S

• using the enzymes involved to synthesize specialty chemicals [1][2]. To date, the best-characterized bacterial pathways are those of Arthrobacter nicotinovorans and several pseudomonads. These are, respectively, known as the pyridine and pyrrolidine pathways due to the initial reactions in each. More

• biochemical level. In the more than a decade since that review was published, a great deal has been learned about other pathways for nicotine metabolism and the enzymes involved. The goal of the present report is to summarize our present understanding of the different pathways by which microbes metabolize

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

• Maroš Bella,
• Sergej Šesták,
• Ján Moncoľ,
• Miroslav Koóš and
• Monika Poláková

Beilstein J. Org. Chem. 2018, 14, 2156–2162, doi:10.3762/bjoc.14.189

• ability to inhibit only selected α-mannosidases, i.e., to exhibit high inhibition activity and selectivity against the enzymes within the GH38 family or even within the whole GH family. These enzymes were represented by model GH38 α-mannosidases from Drosophila melanogaster Golgi α-mannosidase II (GMIIb

• pyrrolidines 2–5 demonstrated inhibitory activity against the target enzyme (GMIIb) with IC50 values in the range of 0.30 mM to 2.95 mM (Table 1). On the other hand, none of them was effective against LManII at 2 mM concentration. Therefore in this panel of tested enzymes the pyrrolidines 2–5 are selective

• -mannosidases GMIIb, LManII and JBMan from GH38 family enzymes. Supporting Information Supporting Information File 247: Experimental procedures and analytical data. Supporting Information File 248: Copies of 1H and 13C NMR spectra of all prepared compounds. Acknowledgements The financial support received from

Chiral bisoxazoline ligands designed to stabilize bimetallic complexes

• Deepankar Das,
• Rudrajit Mal,
• Nisha Mittal,
• Zhengbo Zhu,
• Thomas J. Emge and
• Daniel Seidel

Beilstein J. Org. Chem. 2018, 14, 2002–2011, doi:10.3762/bjoc.14.175

• monooxygenase [10], ribonucleotide reductase [11], catechol oxidase [12], and arginase [13], are prominent examples of such bimetallic enzymes. A range of bi- and multi-metallic complexes have been utilized in asymmetric catalysis (Figure 1) [6]. For instance, Shibasaki and co-workers introduced a number of

Synthesis of new p-tert-butylcalix[4]arene-based polyammonium triazolyl amphiphiles and their binding with nucleoside phosphates

• Vladimir A. Burilov,
• Guzaliya A. Fatikhova,
• Mariya N. Dokuchaeva,
• Ramil I. Nugmanov,
• Diana A. Mironova,
• Pavel V. Dorovatovskii,
• Victor N. Khrustalev,
• Svetlana E. Solovieva and
• Igor S. Antipin

Beilstein J. Org. Chem. 2018, 14, 1980–1993, doi:10.3762/bjoc.14.173

• are very important as a universal energy source and as intracellular mediators in many biological processes [6]. In the cellular metabolism, adenosine 5'-triphosphate (ATP) is hydrolyzed to adenosine 5'-monophosphate (AMP) or adenosine 5'-diphosphate (ADP) by enzymes [7]. Thus, the receptors for

Synthesis and photophysical studies of a multivalent photoreactive Ru^II-calix[4]arene complex bearing RGD-containing cyclopentapeptides

• Sofia Kajouj,
• Lionel Marcelis,
• Alice Mattiuzzi,
• Adrien Grassin,
• Damien Dufour,
• Pierre Van Antwerpen,
• Didier Boturyn,
• Eric Defrancq,
• Mathieu Surin,
• Julien De Winter,
• Pascal Gerbaux,
• Ivan Jabin and
• Cécile Moucheron

Beilstein J. Org. Chem. 2018, 14, 1758–1768, doi:10.3762/bjoc.14.150

• activity of enzymes such as RNA polymerase or endonuclease is inhibited in vitro at the level of the photoadduct [23][24]. In order to target a specific DNA sequence, photoreactive RuII complexes have been anchored to specific antisense oligonucleotides to inhibit the expression of the complementary

β-Hydroxy sulfides and their syntheses

• Mokgethwa B. Marakalala,
• Edwin M. Mmutlane and
• Henok H. Kinfe

Beilstein J. Org. Chem. 2018, 14, 1668–1692, doi:10.3762/bjoc.14.143

• host–guest complexes by non-covalent bonding [64]. This mode of catalysis is similar to the way enzymes mediate biochemical reactions [64]. The use of water as a solvent and the non-toxicity of the cyclodextrin catalyst make the method attractive. This method, like the previously reported protocols, is

Acyl-group specificity of AHL synthases involved in quorum-sensing in Roseobacter group bacteria

• Lisa Ziesche,
• Jan Rinkel,
• Jeroen S. Dickschat and
• Stefan Schulz

Beilstein J. Org. Chem. 2018, 14, 1309–1316, doi:10.3762/bjoc.14.112

• microbiome. Often, specific mixtures of AHLs differing in chain length and oxidation status are produced by bacteria, but how the biosynthetic enzymes, LuxI homologs, are selecting the correct acyl precursors is largely unknown. We have analyzed the AHL production in Dinoroseobacter shibae and three

• Phaeobacter inhibens strains, revealing strain-specific mixtures. Although large differences were present between the species, the fatty acid profiles, the pool for the acyl precursors for AHL biosynthesis, were very similar. To test the acyl-chain selectivity, the three enzymes LuxI1 and LuxI2 from D. shibae

• DFL-12 as well as PgaI2 from P. inhibens DSM 17395 were heterologously expressed in E. coli and the enzymes isolated for in vitro incubation experiments. The enzymes readily accepted shortened acyl coenzyme A analogs, N-pantothenoylcysteamine thioesters of fatty acids (PCEs). Fifteen PCEs were

Novel unit B cryptophycin analogues as payloads for targeted therapy

• Eduard Figueras,
• Adina Borbély,
• Mohamed Ismail,
• Marcel Frese and
• Norbert Sewald

Beilstein J. Org. Chem. 2018, 14, 1281–1286, doi:10.3762/bjoc.14.109

• activity of specific enzymes. The connection between the payload and the linker is of crucial importance since its stability can dramatically change the release and thus, the activity of the compound. For this reason, the included functional groups were designed with the consideration to provide

Iodine(III)-mediated halogenations of acyclic monoterpenoids

• Laure Peilleron,
• Tatyana D. Grayfer,
• Joëlle Dubois,
• Robert H. Dodd and
• Kevin Cariou

Beilstein J. Org. Chem. 2018, 14, 1103–1111, doi:10.3762/bjoc.14.96

• trisubstituted double bond occurred with excellent selectivity and moderate to good yields. Keywords: halogenation; hypervalent iodine; monoterpenes; Introduction In nature, mostly in marine environments, halogenated compounds are produced by means of various enzymes that rely on widely available halides as

Mechanochemistry of nucleosides, nucleotides and related materials

• Olga Eguaogie,
• Joseph S. Vyle,
• Patrick F. Conlon,
• Manuela A. Gîlea and
• Yipei Liang

Beilstein J. Org. Chem. 2018, 14, 955–970, doi:10.3762/bjoc.14.81

• ]. Dubinskaya reviewed early investigations into the grinding and stretching of polypeptides and proteins which showed rapid loss of enzyme activity at 80 K [101]. In contrast, more recent reports, in which both native and immobilised enzymes were ground at higher temperatures, demonstrated efficient

On the design principles of peptide–drug conjugates for targeted drug delivery to the malignant tumor site

• Eirinaios I. Vrettos,
• Gábor Mező and
• Andreas G. Tzakos

Beilstein J. Org. Chem. 2018, 14, 930–954, doi:10.3762/bjoc.14.80

• ]. Overwhelming production of stimulus agents and enzymes [21]. For instance, many types of cancer show enhanced levels of reactive oxygen species (ROS) which are reactive molecules and play a crucial role in cell proliferation [22]. The slightly acidic pH of the tumor microenvironment [23] (Warburg effect

• usually inserted into the cell via endocytosis and then they are transported to intracellular compartments with higher concentration of enzymes and lower values of pH, where they disassociate from the receptor and afterward from the anticancer agent. The most representative examples of peptides utilized

• different enzymes and/or the tumor microenvironment might trigger the improper release of the drug from the PDC, i.e., to end up with the drug-carrying part of the linker. Another class of linkers is the stimuli-responsive/degradable linkers, designed to achieve an efficient release of the drug from the

Development of novel cyclic NGR peptide–daunomycin conjugates with dual targeting property

• Andrea Angelo Pierluigi Tripodi,
• Szilárd Tóth,
• Kata Nóra Enyedi,
• Gitta Schlosser,
• Gergely Szakács and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 911–918, doi:10.3762/bjoc.14.78

• synthesized by SPPS on a Rink-Amide MBHA Resin, using Fmoc/t-Bu strategy. The anticancer drug daunomycin was conjugated to the Aoa-GFLGK spacer via oxime linkage [17]. This spacer is degraded by lysosomal enzymes ensuring the release of the Dau=Aoa-Gly-OH as the smallest bioactive metabolite in lysosomes [19

Volatiles from three genome sequenced fungi from the genus Aspergillus

• Jeroen S. Dickschat,
• Ersin Celik and
• Nelson L. Brock

Beilstein J. Org. Chem. 2018, 14, 900–910, doi:10.3762/bjoc.14.77

• cyclisation of NPP with a different stereochemical course to M is required, followed by deprotonation. Two class I TSs are encoded in the genome of A. fischeri (accession numbers XP_001265719 and XP_001262485, locus tags NFIA_033880 and NFIA_030200), and it seems likely that each of these enzymes catalyses

• diterpene was observed may point to a low gene expression under laboratory culture conditions. It is currently not possible to conclude which of the other two TSs are involved in the biosynthesis of the observed sesquiterpenes from A. kawachii. Notably, both enzymes GAA88217 and GAA91251 are closely related

• likely for 15 and 19. One of these enzymes is similar to the α-acorenol synthase from F. fujikuroi, suggesting that this enzyme is responsible for the biosynthesis of 15. The remaining STS can be assigned to 19 which is supported by the occurrence of a closely related enzyme in A. clavatus that also

A stereoselective and flexible synthesis to access both enantiomers of N-acetylgalactosamine and peracetylated N-acetylidosamine

• Bettina Riedl and
• Walther Schmid

Beilstein J. Org. Chem. 2018, 14, 856–860, doi:10.3762/bjoc.14.71

• , glycoproteins serve as ligands for specific extracellular recognition processes toward, e.g., enzymes, lectins or antibodies [2]. In O-linked glycoproteins, also known as mucins, GalNAc becomes covalently α-linked to serine or threonine during post-translational modifications [3][4][5]. This glycoconjugate

Phosphodiester models for cleavage of nucleic acids

• Satu Mikkola,
• Tuomas Lönnberg and
• Harri Lönnberg

Beilstein J. Org. Chem. 2018, 14, 803–837, doi:10.3762/bjoc.14.68

• enzymes, nucleases, is one of the underlying biological processes. The remarkable catalytic efficiency of nucleases, together with the ability of ribonucleic acids to serve sometimes as nucleases, has made the cleavage of phosphodiesters a subject of intensive mechanistic studies. In addition to studies

• the next one are cleaved by a variety of enzymes [1]. The phosphodiester bonds of DNA are hydrolyzed, depending on the enzyme, either to a 3´- or 5´-phosphate, whereas the bonds in RNA, with few exceptions (above all RNase H-catalyzed cleavages) undergo transesterification to a 2´,3´-cyclic phosphate

• at 25 °C, which means that protein enzymes, nucleases, are able to accelerate the phosphodiester cleavage by a factor of 1017 [2]. The phosphodiester linkages of RNA are much more labile, owing to the presence of neighboring hydroxy function that serves as an intramolecular nucleophile resulting in

Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides

• Kartik Temburnikar and
• Katherine L. Seley-Radtke

Beilstein J. Org. Chem. 2018, 14, 772–785, doi:10.3762/bjoc.14.65

• synthesis; modular synthesis; Introduction Nucleic acids form the genetic blueprint for all living organisms and are involved with a wide range of cellular functions [1][2][3][4][5][6][7][8][9]. Modifications to their chemical structure can have profound effects on structure and function of enzymes, cells

• glycosidic bond in 2'-deoxy ribonucleosides has a higher susceptibility to cleavage than in the corresponding ribonucleosides [38][39][40][41][43]. The rate of glycosidic (C–N) bond cleavage is enhanced by decreasing pH and enzymes, which modify the localized acid–base environment [31][35][36]. The C–N bond

• stability, ii) altered hydrogen bonding motifs, and iii) altered molecular recognition properties [25][29][37][58]. Because of these changes, C-nucleosides have been useful in the study of RNA and DNA processing enzymes, as well as drug design efforts and novel supramolecular structures [12][29][59

Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin–GnRH-III conjugates developed for targeted drug delivery

• Sabine Schuster,
• Beáta Biri-Kovács,
• Bálint Szeder,
• Viktor Farkas,
• László Buday,
• Zsuzsanna Szabó,
• Gábor Halmos and
• Gábor Mező

Beilstein J. Org. Chem. 2018, 14, 756–771, doi:10.3762/bjoc.14.64

• the ester bond resulting in a longer half-life of the conjugate during circulation. Nevertheless, the drug is released within the cancer cell by lysosomal enzymes, especially by cathepsin B, which leads to various Dau containing metabolites [26]. In case of GnRH-III–[8Lys(Dau=Aoa)] conjugates the

• uptake and the antitumor activity [29]. Moreover, these GnRH-III bioconjugates displayed an enhanced stability in the presence of gastrointestinal enzymes. The most potent and efficient bioconjugate which has been evaluated in in vitro cytostatic effect measurements on human breast cancer cells (MCF7

• application to tumor cells and a reduction of toxic side effects. To ensure these benefits, stability and degradation studies are of great importance during DDS development. In vitro degradation studies in the presence of gastrointestinal enzymes and lysosomal homogenate as well as stability analyses in human

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• (enzymes), organocatalysts and metal catalysts [47]. Catalysis is defined as heterogeneous when catalysts are in an aggregated state, and are thus in a different phase than the reactants [27][48]. Heterogeneous catalysts typically consist of a solid carrier, the so called “support”, on which catalytic

• ]. Polymersomes comprise an aqueous lumen and hydrophobic membrane. Such hydrophilic and hydrophobic compartments are capable of accommodating hydrophilic (e.g., enzymes) or hydrophobic catalysts (e.g., metal catalysts) in their lumen or bilayer, respectively [28][79]. In an aqueous environment the hydrophobic

• , the system was recycled for at least 9 times without any loss in enzymatic activity. Polymersomes have proven to be very useful for the performance of multistep catalytic conversions, in particular with enzymes [81]. Voit et al. studied the use of cross-linked pH sensitive polymersomes for the

Biocatalytic synthesis of the Green Note trans-2-hexenal in a continuous-flow microreactor

• Morten M. C. H. van Schie,
• Tiago Pedroso de Almeida,
• Gabriele Laudadio,
• Florian Tieves,
• Elena Fernández-Fueyo,
• Timothy Noël,
• Isabel W. C. E. Arends and
• Frank Hollmann

Beilstein J. Org. Chem. 2018, 14, 697–703, doi:10.3762/bjoc.14.58

• areas can be achieved via heterogeneous intake, by bubbling, stirring, etc. Soluble enzymes, however, are often rather unstable under these conditions, possibly owing to the mechanical stress leading to irreversible inactivation of the biocatalyst [7][8]. Methods of bubble-free aeration have been

• enzymes) and produces only water as byproduct. These advantages, however, are counteracted by the generally low reaction rates caused by the poor O2 availability. Flow chemistry is a promising technique to provide the aqueous reaction mixture with O2 needed for the oxidation. It enables high O2 transfer

Enzyme-free genetic copying of DNA and RNA sequences

• Marilyne Sosson and
• Clemens Richert

Beilstein J. Org. Chem. 2018, 14, 603–617, doi:10.3762/bjoc.14.47

• Marilyne Sosson Clemens Richert Institute of Organic Chemistry, University of Stuttgart, 70569 Stuttgart, Germany 10.3762/bjoc.14.47 Abstract The copying of short DNA or RNA sequences in the absence of enzymes is a fascinating reaction that has been studied in the context of prebiotic chemistry

• process is catalyzed by enzymatic machineries that have polymerases at their core [1]. Polymerases catalyze not only the replication of DNA, but are also involved in repair and transcription of genes [2]. Considering that enzymes catalyze processes that lead to protein synthesis, it is reasonable to ask

• enzymes and ribozymes, relying on solely on base pairing for molecular recognition and chemical reactivity to drive the formation of phosphodiester bonds in aqueous media. This is what is usually referred to as "enzyme-free copying" (Figure 1). Studies on enzyme-free copying of genetic polymers date back

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

• Fabio Tonin and
• Isabel W. C. E. Arends

Beilstein J. Org. Chem. 2018, 14, 470–483, doi:10.3762/bjoc.14.33

• several research groups to focus their attention on the development of biotransformations with non-pathogenic, easy-to-manage microorganisms, and their enzymes. In particular, the enzymatic reactions involved are selective hydrolysis, epimerization of the hydroxy functions (by oxidation and subsequent

• biosynthesis takes place in the liver starting from cholesterol: 17 enzymes are involved in the production of these molecules. The final products are the so-called primary bile acids: CDCA and CA [23]. Subsequently, these bile acids can be modified by intestinal bacteria to form the secondary bile acids as

• deconjugation step. Chemically, the reaction is an hydrolysis of the amide derivatives, that can be carried out at high temperature in alkaline environment. This reaction requires large amounts of sodium hydroxide (30%) and high temperatures (120 °C) for extremely long times (8–12 hours). Few enzymes (acylases