Syntheses and chemical properties of β-nicotinamide riboside and its analogues and derivatives

• Mikhail V. Makarov and
• Marie E. Migaud

Beilstein J. Org. Chem. 2019, 15, 401–430, doi:10.3762/bjoc.15.36

• phosphodiesterase (prepared from Crotalus adamanteus venom) and subsequent transformation of NMN to NR+ under catalysis with a prostatic monoesterase. Kasasarov and Moat [44] used a crude enzyme preparation from Proteus vulgaris OX-19 to prepare NR+ from NAD+, with the process being conducted at 37 °C. This set of

Study on the regioselectivity of the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide

• Pedro N. Batalha,
• Luana da S. M. Forezi,
• Maria Clara R. Freitas,
• Nathalia M. de C. Tolentino,
• Ednilsom Orestes,
• José Walkimar de M. Carneiro,
• Fernanda da C. S. Boechat and
• Maria Cecília B. V. de Souza

Beilstein J. Org. Chem. 2019, 15, 388–400, doi:10.3762/bjoc.15.35

• work we described the synthesis and antiviral activity of some 4-oxoquinoline acyclonucleosides 3a and 3b [15] and studies on their anticancer activity are also underway. It is also worth mentioning that derivative 4 presented an excellent inhibitory profile for the enzyme hystone deacetylase (HDAC

Thiol-free chemoenzymatic synthesis of β-ketosulfides

• Adrián A. Heredia,
• Martín G. López-Vidal,
• Marcela Kurina-Sanz,
• Fabricio R. Bisogno and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2019, 15, 378–387, doi:10.3762/bjoc.15.34

• formed, an enzyme-catalysed hydrolysis and protonation of the resulting enolate would render the title β-ketosulfide products. This strategy avoids the use of acidic or basic conditions for the hydrolysis of the ester moiety that, normally, result unsuitable for methylene active-containing products as β

• both, substrate solubility and enzyme activity. Hence, two different buffer solutions (KPi 50 mM pH 7.5 and Tris·HCl 50 mM pH 7.5) containing 5% v/v of an (miscible or inmiscible) organic cosolvent, were tested towards a set of commercially available lipases. In this line, a remarkable hydrolytic

• , substrates containing diversely substituted aryl moieties at the α-position of the enol ester, underwent smooth conversion (typically 94–99% except for p-nitrophenyl derivative 1f, for which more enzyme was needed to reach 96%, Table 2, entry 6), regardless the electronic nature of the substituents (see

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• cells synthesis of L-glutamine is interfered as a result of reduced activity of GS [2]. γ-Glutamyl transpeptidase (GGT) which catalyses transfer of the γ-glutamyl group from glutathione is another enzyme relevant in cancer. High activities of GGT are observed during neoplastic transformation [3

Computational characterization of enzyme-bound thiamin diphosphate reveals a surprisingly stable tricyclic state: implications for catalysis

• Ferran Planas,
• Michael J. McLeish and
• Fahmi Himo

Beilstein J. Org. Chem. 2019, 15, 145–159, doi:10.3762/bjoc.15.15

• applications. All ThDP-catalyzed reactions require the reaction of the ThDP ylide (the activated state of the cofactor) with the substrate. Given that the cofactor can adopt up to seven states on an enzyme, identifying the factors affecting the stability of the pre-reactant states is important for the overall

• , serves as the prototypical ThDP-dependent enzyme. A model of the active site was constructed on the basis of available crystal structures, and the cofactor states were characterized in the presence of three different ligands (crystallographic water, benzoylformate as substrate, and (R)-mandelate as

• . Keywords: binding site; DFT; enzyme mechanism; quantum chemical calculations; ThDP-dependent; Introduction Enzymes that depend on thiamin diphosphate (ThDP, Scheme 1) can be found in a wide range of metabolic pathways. Although they are known to catalyze the formation of C–N, C–O and C–S bonds, ThDP

Unexpected loss of stereoselectivity in glycosylation reactions during the synthesis of chondroitin sulfate oligosaccharides

• Teresa Mena-Barragán,
• José L. de Paz and
• Pedro M. Nieto

Beilstein J. Org. Chem. 2019, 15, 137–144, doi:10.3762/bjoc.15.14

• anomeric center of the glycosyl acceptor. We hypothesized that the isopropyl moiety would not affect the CS–enzyme interaction. Trichloroacetimidate 12 was obtained by oxidative removal of the 4-methoxyphenyl group with CAN at 0 ºC and further treatment with trichloroacetonitrile and catalytic amounts of

Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA

• Sibylle Frei,
• Adam K. Katolik and
• Christian J. Leumann

Beilstein J. Org. Chem. 2019, 15, 79–88, doi:10.3762/bjoc.15.9

• of the enzyme. Furthermore, the phosphate-binding pocket requires a large distortion of the backbone angle α in order that the phosphate group of the AON can be positioned in it [50][51]. The 6’F-bc4,3-DNA containing strand also complied with this requirement according to the MD simulations [37

• opposite the modified part and 2’-O-methyl RNA flanks. The same construct was previously applied for the evaluation of 2’F-tc-ANA [35] and a similar one for CeNA [52]. For the assay E. coli RNase H was used due to its commercial availability and its similarity to the human enzyme [22]. The cleavage pattern

• of the RNase H is presented in Figure 5. In the DNA/RNA positive control, the RNA strand was completely cleaved as expected (lane 1). In the negative controls C1 (no antisense strand) and C2 (no enzyme) no degradation of RNA could be observed (lanes 9 and 10). Acceptable substrates for the RNase H

Asymmetric synthesis of a high added value chiral amine using immobilized ω-transaminases

• Antonella Petri,
• Valeria Colonna and
• Oreste Piccolo

Beilstein J. Org. Chem. 2019, 15, 60–66, doi:10.3762/bjoc.15.6

• excess starting from a commercial substrate. The reaction was carried out by using different commercially available immobilized enzymes, evaluating the catalytic activity and the enantioselectivity under different experimental conditions. Re-use of the most efficient enzyme was performed both in batch

• are easily regenerated in situ without the need for another enzyme. In principle, enantiomerically pure chiral amines can be prepared following two approaches: through kinetic resolution starting from racemic amines or by asymmetric synthesis starting from suitable substrates, e.g., the corresponding

• used in excess and/or this excess can cause inhibition of the enzyme. The use of isopropylamine (IPA) as amino donor allowed optimizing the use of TAs in organic synthesis thanks to its ability to shift the transamination reactions towards complete conversion together with easy removal of the low

New standards for collecting and fitting steady state kinetic data

• Kenneth A. Johnson

Beilstein J. Org. Chem. 2019, 15, 16–29, doi:10.3762/bjoc.15.2

• additional information, while the ratio of kcat/Km provides a measure of enzyme specificity and is proportional to enzyme efficiency and proficiency. Moreover, kcat/Km provides a lower limit on the second order rate constant for substrate binding. For these reasons it is better to redefine the Michaelis

• fitting to derive kcat and kcat/Km is illustrated by considering the role of conformational changes in enzyme specificity where kcat and kcat/Km can reflect different steps in the pathway. This highlights the pitfalls in attempting to interpret Km, which is best understood as the ratio of kcat divided by

• kcat/Km. Keywords: computer simulation; data fitting; enzyme catalysis; induced-fit; Michaelis constant; specificity constant; Review When Henri, Michaelis and Menten derived the equation for steady state enzyme turnover, they chose to define the rate in terms of Vmax and the substrate dissociation

Thermophilic phosphoribosyltransferases Thermus thermophilus HB27 in nucleotide synthesis

• Ilja V. Fateev,
• Ekaterina V. Sinitsina,
• Aiguzel U. Bikanasova,
• Maria A. Kostromina,
• Elena S. Tuzova,
• Larisa V. Esipova,
• Tatiana I. Muravyova,
• Alexei L. Kayushin,
• Irina D. Konstantinova and
• Roman S. Esipov

Beilstein J. Org. Chem. 2018, 14, 3098–3105, doi:10.3762/bjoc.14.289

• phosphoribosyltransferase; catalysis; enzyme; hypoxanthine phosphoribosyltransferase; multi-enzyme cascade; nucleotides; thermophiles; Introduction Bacterial phosphoribosyltransferases are used in multi-enzymatic cascades that perform nucleotide synthesis de novo [1][2]. Recently, we reported on the possibility of cascade

• phosphoribosyltransferase Thermus thermophilus (TthHPRT), investigated its substrate specificity and optimal conditions for catalytic activity, and determined the kinetic parameters of the enzyme. A comparative study of the substrate specificity of TthAPRT and TthHPRT was performed to determine the usability of

• , although for the human enzyme Km is only 5 fold less. Comparing two enzymes from different strains of Thermus thermophilus, we can conclude that TthAPRT from HB8 (in contrast with HB27), synthesizes guanosine-5`-monophosphate faster. This may be due to the difference in reaction conditions. Kinetic data

Dispersion interactions

• Peter R. Schreiner

Beilstein J. Org. Chem. 2018, 14, 3076–3077, doi:10.3762/bjoc.14.286

• , enzyme catalysis, and much more. Hence, this thematic issue covers selected aspects of the role LD plays for structures and reactivity. Naturally, it addresses diverse topics for which LD is particularly apparent. Peter R. Schreiner Giessen, November 2018 Dispersion = attractive part of the van-der-Waals

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• inhibition of the catalytic activity of the enzyme [23]. All these drug discovery successes have validated PPIs as a target and, in conjunction with the elucidation and reconstruction of protein–protein interaction networks in bacteria, have paved the way towards the development of novel and promising

• antimicrobial molecules are presented below. β-Sliding clamp Sliding clamps are prokaryotic ring-shaped proteins that secure DNA polymerases to the DNA template and slide along the double helix, enabling enzyme activity at a specific region of the DNA and increasing the rapid and processive DNA synthesis [52

• viability is bacterial transcription, a process that is executed by the enzyme RNA polymerase (RNAP) and regulated by several transcription factors. Similarly to the previously described targets, bacterial transcription represents a promising antibacterial drug target for several reasons: it is essential to

Pd-Catalyzed microwave-assisted synthesis of phosphonated 13α-estrones as potential OATP2B1, 17β-HSD1 and/or STS inhibitors

• Rebeka Jójárt,
• Szabolcs Pécsy,
• György Keglevich,
• Mihály Szécsi,
• Réka Rigó,
• Csilla Özvegy-Laczka,
• Gábor Kecskeméti and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 2838–2845, doi:10.3762/bjoc.14.262

• the test compounds inhibited the STS markedly. The structure–activity relationship evaluation revealed that 2-substituted 3-hydroxy derivatives are able to inhibit the 17β-HSD1 enzyme with submicromolar IC50 values. Dual OATP2B1 and 17β-HSD1 inhibitors have been identified. Keywords: catalysis

• ; enzyme; 13α-estrone; Hirao reaction; 17β-HSD1 inhibition; OATP2B1; STS; Introduction The biosynthesis of estrogens occurs via various enzymatic routes. Cytochrome P450 aromatase catalyzes the conversion of nonaromatic steroids to estrogens [1]. Moreover, hydrolysis of estrone 3-sulfate, existing as a

• derivatives displayed higher affinity to the enzyme than that of their parent compound estrone. Based on these findings, we tested our halogenated 13α-estrone derivatives against STS, too [23]. Both the nature and the position of the introduced halogen influenced the STS inhibitory potential markedly. The

Synthesis of a tyrosinase inhibitor by consecutive ethenolysis and cross-metathesis of crude cashew nutshell liquid

• Jacqueline Pollini,
• Valentina Bragoni and
• Lukas J. Gooßen

Beilstein J. Org. Chem. 2018, 14, 2737–2744, doi:10.3762/bjoc.14.252

• synthesis of the most potent tyrosinase inhibitor among them, the ginkgolic acid (13:0), starting from crude CNSL (Scheme 1, left). Tyrosinase is an enzyme [28] which is responsible for browning of fruits and vegetables as well as skin pigmentation [29]. Furthermore, it is linked to several

The design and synthesis of an antibacterial phenothiazine–siderophore conjugate

• Abed Tarapdar,
• James K. S. Norris,
• Oliver Sampson,
• Galina Mukamolova and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2018, 14, 2646–2650, doi:10.3762/bjoc.14.242

• , the potency of such phenothiazines, including 1, needs to be significantly increased to have more activity in vivo and direct clinical application [11]. A validated target of 1 has been identified as type II NADH dehydrogenase (NDH-2), a respiratory enzyme essential for growth in M. tuberculosis and

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

• including their own biosynthetic enzyme cascade (PqsABCDE). Together with PqsH and PqsL, which are under the control of LasR from the las QS system, these enzymes manage to build up PQS and related molecules from anthranilic acid (Figure 2). This initial building block can be provided either through the

• -CoA) is then transferred to an active-site cysteine of the β-ketoacyl-ACP synthase III (FabH)-type enzyme PqsD [26][27]. Subsequently, another CoA-activated substrate comes into play. In analogy to fatty acid synthesis, malonyl-CoA is reacted with the enzyme-bound thioester to yield 2

• ]. Aforementioned enzyme PqsL is needed for the production of HQNO, as it delivers the N-oxidised substrate 2-HABA for PqsBC-mediated condensation with octanoyl-CoA analogous to HHQ biosynthesis [27]. PQS-mediated pathogenicity traits and molecular targets P. aeruginosa makes use of an arsenal of virulence factors

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

• . Numerous inhibitors have been developed against AB toxins, targeting toxin transcription, assembly, receptor binding and enzyme function [51]. A set of antibodies against diverse toxins has recently been approved for therapeutic use, which demonstrates the scientific and medical feasibility of entering the

• prolonged survival in a C. elegans infection model [62]. Hydroxamic acid-containing molecules addressing the same enzyme were developed by the Hartmann group; these compounds showed a moderate reduction of biofilm formation resulting from a lowered release of the structural biofilm component extracellular

• DNA [63]. Recently, inhibitors of the clostridial collagenase were discovered that showed high selectivity for the bacterial enzyme over related host metalloproteases [64]. It is hoped that continued research in this area will lead to a complementary class of antivirulence drugs against Clostridium

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

• Gergő Mótyán,
• László Mérai,
• Márton Attila Kiss,
• Zsuzsanna Schelz,
• Izabella Sinka,
• István Zupkó and
• Éva Frank

Beilstein J. Org. Chem. 2018, 14, 2589–2596, doi:10.3762/bjoc.14.236

• semisynthetic sex hormone analogs in consequence of their dual pharmacological importance. A number of these derivatives display an inhibitory effect on 17α-hydroxylase-C17,20-lyase (P45017α) enzyme, which, acting as an important regulator, plays an essential role in the endogenous production of androgen

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

• , we describe biomimetic and bioinspired catalytic reactions with B12 enzyme functions. The reactions are classified according to the corresponding three B12 enzyme subfamilies, with a focus on our recent development on electrochemical and photochemical catalytic systems. Other important reactions are

• using various electrophiles such as alkyl halides [13], vinyl halides [14][15][16], aryl halides [17][18] and epoxides [19][20] in homogeneous solutions (Figure 1b). 1-2. Design of biomimetic and bioinspired B12 catalytic systems Schematic representations of B12 enzymes and enzyme-involving systems are

Synthesis of 3-aminocoumarin-N-benzylpyridinium conjugates with nanomolar inhibitory activity against acetylcholinesterase

• Nisachon Khunnawutmanotham,
• Cherdchai Laongthipparos,
• Patchreenart Saparpakorn,
• Nitirat Chimnoi and
• Supanna Techasakul

Beilstein J. Org. Chem. 2018, 14, 2545–2552, doi:10.3762/bjoc.14.231

• target enzyme by a dual binding site mechanism whereby the coumarin portion binds with the peripheral anionic site while the N-benzylpyridinium residue binds with the catalytic anionic site of the enzyme. Keywords: acetylcholinesterase inhibitor; 3-aminocoumarin; N-benzylpyridinium; dual binding site

• remains incurable; most of the existing treatments only delay the onset or further advancement of AD. Among the current hypotheses for the treatment of AD, inhibition of acetylcholinesterase enzyme (AChE), which is responsible for the degradation of the neurotransmitter acetylcholine (ACh), is the most

• that may be useful for binding with this enzyme. Herein, we report our progress on the synthesis, biological evaluation, and molecular docking of 3-aminocoumarin linked with the benzylpyridinium moiety through an amide bond. Results and Discussion Chemistry The target 3-aminocoumarin-N-benzylpyridinium

Synthesis of dihydroquinazolines from 2-aminobenzylamine: N³-aryl derivatives with electron-withdrawing groups

• Nadia Gruber,
• Jimena E. Díaz and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2018, 14, 2510–2519, doi:10.3762/bjoc.14.227

• antimicrobial [3] and antifungal properties [4]. In addition, antiparasitic activity has been studied for some members of this family as inhibitors of trypanothione reductase [5], an essential enzyme of the kinetoplastid Trypanosoma brucei. Their activity as selective T-type calcium channel blockers [6][7][8][9

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

• unmodified GnRH-III-based one (GnRH-III(Dau=Aoa)) [17]. It is worth mentioning that the free Lys in this position also increased the in vitro cytostatic effect of the conjugate; however, its cellular uptake and enzyme stability were even lower than the parent conjugate had [17]. Therefore, it was not used in

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

• . JS614; in this case the genes are chromosomal [6]. As shown in Scheme 1, the pathway begins with hydroxylation of the pyridyl ring of nicotine by the enzyme nicotine dehydrogenase to yield 6-hydroxynicotine [7]. Based on the gene sequence, this enzyme was identified as a member of the family of

• kDa subunit with an FAD binding site, and an 87.7 kDa subunit containing the molybdopterin site, respectively [9][10]. Consistent with this identification, expression of the active enzyme required molybdopterin [9], and pAO1 contains a number of genes that have been identified as coding for proteins

Investigation of the electrophilic reactivity of the biologically active marine sesquiterpenoid onchidal and model compounds

• Melissa M. Cadelis and
• Brent R. Copp

Beilstein J. Org. Chem. 2018, 14, 2229–2235, doi:10.3762/bjoc.14.197

• ), three new peaks representing mass additions of +198 mu, +216 mu, and +230 mu were detected (Figure 5 and Table 1). These adducts are likely the result of the reaction of lysine residues present in the enzyme [17]. The latter two adducts are proposed to be pyrrole adducts with incorporation of solvolytic

• , speculated to be due to formation of insoluble higher order protein adducts. ESIMS analysis of the supernatant identified only a trace of unreacted lysozyme and detection of ions arising from extensive modification of the enzyme. To simplify the analysis of these adducts, the incubation time for 11 was

• apparent with the lysine-rich enzyme hen egg white lysozyme, with onchidal (6) and model compounds 11–13 and 15–17 affording pyrrole adducts of the enzyme that were detected by (+)-ESIMS. The more reactive dialdehydes were also found to lead to protein crosslinking with formation of lysozyme dimers and

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

• target GMIIb enzyme. In contrast, no inhibition effect of the pyrrolidines against LManII was observed. The modification of the imino-L-lyxitol core is therefore a suitable motif for the design of inhibitors with desired selectivity against the target GMIIb enzyme. Keywords: azasugars; hydrolases

• , target enzyme) and lysosomal α-mannosidase (LManII, enzyme not to be inhibited), and commercial enzyme jack bean α-mannosidase (JBMan) from Canavalia ensiformis. In a series of our previous papers, it has been found that a combination of a saccharide core (D-mannose, D-mannose with modification at C-6

• ) and hydrophobic linker (benzyl, phenethyl) has an impact on the inhibition efficiency of the tested synthetic compound against the target GMIIb enzyme. Evaluation of these derivatives revealed that benzyl is a suitable hydrophobic linker. Some of them showed a weak inhibitory activity and selectivity