Enantioselective supramolecular devices in the gas phase. Resorcin[4]arene as a model system

• Caterina Fraschetti,
• Matthias C. Letzel,
• Antonello Filippi,
• Maurizio Speranza and
• Jochen Mattay

Beilstein J. Org. Chem. 2012, 8, 539–550, doi:10.3762/bjoc.8.62

• life's supramolecular systems in which the guest molecule (e.g., amino acids, neurotransmitters, drugs) is selectively captured into the host macromolecular structure (molecular recognition) and transformed catalytically at a specific “active site” (enzyme catalysis) [1][2][3]. Furthermore, the

• biorecognition may require the partial or complete desolvation of the guest molecule and of the polar groups of the active site by greatly enhancing its reactivity [4]. An important step towards the elucidation of enzyme mechanisms requires a comprehensive study of the structure, dynamics, and reactivity of

Synthesis and biological evaluation of nojirimycin- and pyrrolidine-based trehalase inhibitors

• Davide Bini,
• Francesca Cardona,
• Matilde Forcella,
• Camilla Parmeggiani,
• Paolo Parenti,
• Francesco Nicotra and
• Laura Cipolla

Beilstein J. Org. Chem. 2012, 8, 514–521, doi:10.3762/bjoc.8.58

• action and chemical topography of the active site of the enzyme under consideration. We proposed the synthesis of a small set of iminosugar derivatives, which in some cases resulted in selective inhibitors of trehalases of different origin, despite the fact that their activity was in the micromolar range

Thermodynamic and kinetic stabilization of divanadate in the monovanadate/divanadate equilibrium using a Zn-cyclene derivative: Towards a simple ATP synthase model

• Hanno Sell,
• Anika Gehl,
• Frank D. Sönnichsen and
• Rainer Herges

Beilstein J. Org. Chem. 2012, 8, 81–89, doi:10.3762/bjoc.8.8

• presence of metal cations such as Zn2+, Mg2+ and Mn2+ in the active site [9]. It is generally assumed that the coordination of the metal cations to the phosphate oxygen atoms reduces the Coulomb repulsion in the transition states or in the intermediates, thus, lowering the activation barrier [10]. In

Novel fatty acid methyl esters from the actinomycete Micromonospora aurantiaca

• Jeroen S. Dickschat,
• Hilke Bruns and
• Ramona Riclea

Beilstein J. Org. Chem. 2011, 7, 1697–1712, doi:10.3762/bjoc.7.200

• atoms, with the final chain length being solely dependent on the size of the acting FAS’s active site (although FA biosynthesis is catalysed by several discrete enzymes in bacteria, the term FAS, strictly speaking short for fatty acid synthase and thereby implying the action of only one single enzyme

Dependency of the regio- and stereoselectivity of intramolecular, ring-closing glycosylations upon the ring size

• Patrick Claude,
• Christian Lehmann and
• Thomas Ziegler

Beilstein J. Org. Chem. 2011, 7, 1609–1619, doi:10.3762/bjoc.7.189

• donors and acceptors (prearranged glycosides) resembles to some extent enzyme-catalyzed glycosylation reactions where the glycosyl donor and glycosyl acceptor are first bound in the active site of an enzyme and thus, the glycosidic bond forms intramolecularly. Three different concepts for the

Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent

• Michael Zengerle,
• Florian Brandhuber,
• Christian Schneider,
• Franz Worek,
• Georg Reiter and
• Stefan Kubik

Beilstein J. Org. Chem. 2011, 7, 1543–1554, doi:10.3762/bjoc.7.182

• the phosphonylation of this nucleophilic group, similar to the phosphonylation of the serine residue in the active site of AChE during OP-mediated inhibition of this enzyme. If the compound thus formed is hydrolytically unstable, it will be cleaved in the aqueous medium, releasing the original

Chimeric self-sufficient P450cam-RhFRed biocatalysts with broad substrate scope

• Aélig Robin,
• Valentin Köhler,
• Alison Jones,
• Afruja Ali,
• Paul P. Kelly,
• Elaine O'Reilly,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2011, 7, 1494–1498, doi:10.3762/bjoc.7.173

• , presumably because it opens up the active site. S. Flitsch, L.-L Wong and coworkers for example showed that P450cam (Y96A) was able to hydroxylate diphenylmethane to 4-hydroxydiphenylmethane, an activity that was not observed with the wild-type enzyme [15]. For the present study, incorporation of the Y96A

Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays

• Ian Cumpstey,
• Jens Frigell,
• Elias Pershagen,
• Tashfeen Akhtar,
• Elena Moreno-Clavijo,
• Inmaculada Robina,
• Dominic S. Alonzi and
• Terry D. Butters

Beilstein J. Org. Chem. 2011, 7, 1115–1123, doi:10.3762/bjoc.7.128

• activity [50], and the possibility that the inhibitor is actually binding not to the enzyme active site, but to this lectin domain instead, is not ruled out at present. Conclusion Unsaturated carbohydrate derived electrophiles react readily with carbohydrate nitrogen nucleophiles to form amine-linked

Metathesis access to monocyclic iminocyclitol-based therapeutic agents

• Ileana Dragutan,
• Valerian Dragutan,
• Carmen Mitan,
• Hermanus C.M. Vosloo,
• Lionel Delaude and
• Albert Demonceau

Beilstein J. Org. Chem. 2011, 7, 699–716, doi:10.3762/bjoc.7.81

• binding with the active site of enzymes. The unusual spatial distribution of the hydroxy groups in these compounds should generate new inhibitory profiles. According to in vitro assays, seven-membered ring iminocyclitols are noted inhibitors of α-mannosidase, an enzyme that plays important roles in

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• structure, mutation studies have shown that the AT2 antagonists such as losartan bind to an active site located within the membrane-bound part of the receptor, which is different to that of the peptide agonist. Further studies led to the discovery of valsartan, where the imidazole ring of losartan is

• binding to a hydrophilic pocket close to the active site of COX-2. Celecoxib (235, Celebrex, Figure 7) belongs to the group of selective COX-2 inhibitors acting on the prostaglandin G/H synthase 2 as well as 3-phosphoinositide-dependent protein kinase 1 and is marketed by Pfizer. Interestingly, celecoxib

• studies this fused heterocycle was found to be more metabolically stable compared to earlier leads that contained a simple piperazine ring. Furthermore, the triazolopiperazine is not only involved in a tight H-bond network within the active site of DPP-IV, but also in π-stacking with the aromatic ring of

Michael-type addition of azoles of broad-scale acidity to methyl acrylate

• Sławomir Boncel,
• Kinga Saletra,
• Barbara Hefczyc and
• Krzysztof Z. Walczak

Beilstein J. Org. Chem. 2011, 7, 173–178, doi:10.3762/bjoc.7.24

• . Other reaction conditions including enzymatic catalysis (Bacillus subtilis) [13], zinc-active-site acylases from Escherichia coli and Aspergillus oryzae [23] as well as ultrasonic irradiation in the presence of montmorillonite [14] have also been reported. In addition, there has been several recent

Stereoselectivity of supported alkene metathesis catalysts: a goal and a tool to characterize active sites

• Christophe Copéret

Beilstein J. Org. Chem. 2011, 7, 13–21, doi:10.3762/bjoc.7.3

• of time/conversion and to plot the (E/Z) ratio of products as a function of the (E/Z) ratio of the reactants; the latter approach leads to, in most cases, a straight line, any deviation indicating the approach to thermodynamic equilibrium or a change of the active site structure (a full kinetic

• active sites. This once again demonstrates the power of this method to probe active site structures. Conclusion Overall, obtaining selectivities at low conversions (E/Z)0 can help to probe the structure of surface species at a molecular level, and should probably be used more often as a probe to

Achiral bis-imine in combination with CoCl₂: A remarkable effect on enantioselectivity of lipase-mediated acetylation of racemic secondary alcohol

• K. Arunkumar,
• M. Appi Reddy,
• T. Sravan Kumar,
• B. Vijaya Kumar,
• K. B. Chandrasekhar,
• P. Rajender Kumar and
• Manojit Pal

Beilstein J. Org. Chem. 2010, 6, 1174–1179, doi:10.3762/bjoc.6.134

• ., serine, histidine, and aspartate) at the active site of CAL-B increases the nucleophilicity of the serine residue. This then interacts with the carbonyl group of the vinyl acetate to form the “acyl-enzyme intermediate” T-1 (Scheme 4) which finally transfers the acyl group to the substrate alcohol 4 via T

Catalysis: transition-state molecular recognition?

• Ian H. Williams

Beilstein J. Org. Chem. 2010, 6, 1026–1034, doi:10.3762/bjoc.6.117

• in one respect, because, although the structure of SRenz is (by definition) geometrically the same for the substrate in both the enzyme active site and in aqueous solution, the structures of ST in the two different environments are not the same. A fair point of criticism for the concept of TS binding

• each case the structures are the same. Owing to the structural distortions of both the reactant and transition states in going from aqueous solution into the enzyme active site, the quantity ΔGTbind − ΔGRbind is an apparent catalytic power which differs from the intrinsic catalytic power ΔGTint

• displacement mechanism involving a covalent glycosyl-enzyme intermediate. Formation and hydrolysis of this covalent intermediate occur via oxacarbenium ion-like TSs, with the assistance of two key active site glutamic acid residues [20]. Glu78 is deprotonated in the noncovalent enzyme-substrate reactant

Synthesis of a novel analogue of DPP-4 inhibitor Alogliptin: Introduction of a spirocyclic moiety on the piperidine ring

• Arumugam Kodimuthali,
• Padala Lakshmi Prasunamba and
• Manojit Pal

Beilstein J. Org. Chem. 2010, 6, No. 71, doi:10.3762/bjoc.6.71

• inhibit DPP-4 enzyme in vitro at three concentrations, e.g., 1.0, 5.0 and 10.0 µM [24]. While significant inhibition of DPP-4 was observed at these concentrations, compound C however, was found to be less potent than Alogliptin. Based on the interaction [8] of compound B with the active site of DPP-4

Synthesis of lipophilic 1-deoxygalactonojirimycin derivatives as D-galactosidase inhibitors

• Georg Schitter,
• Elisabeth Scheucher,
• Andreas J. Steiner,
• Arnold E. Stütz,
• Martin Thonhofer,
• Chris A. Tarling,
• Stephen G. Withers,
• Jacqueline Wicki,
• Katrin Fantur,
• Eduard Paschke,
• Don J. Mahuran,
• Brigitte A. Rigat,
• Michael Tropak and
• Tanja M. Wrodnigg

Beilstein J. Org. Chem. 2010, 6, No. 21, doi:10.3762/bjoc.6.21

• to compare the different aromatic substituents. Additionally, Wong [15] as well as Suzuki [23] have shown from computational studies, that in case of N-substitution on compounds 8b and 10, the iminosugar and carbasugar units respectively, were found to interact with the active site of the

• corresponding enzymes whereas the alkyl chains were located in the distinctly hydrophobic entrance region to the active site. Thus, for comparison, a lipophilic aliphatic tert-butyl group in compound 20 was included in this study. In addition to the synthetic approaches, the influence of the lipophilic

Synthesis and binding studies of two new macrocyclic receptors for the stereoselective recognition of dipeptides

• Ana Maria Castilla,
• M. Morgan Conn and
• Pablo Ballester

Beilstein J. Org. Chem. 2010, 6, No. 5, doi:10.3762/bjoc.6.5

• constitutes an alternative approach to the classical active-site enzyme inhibition design. One of the strategies employed for binding protein surfaces relies on the use of arrays of synthetic receptors originally designed for the recognition of oligopeptides. Consequently, the selective recognition of

Synthesis and enzymatic evaluation of 2- and 4-aminothiazole- based inhibitors of neuronal nitric oxide synthase

• Graham R. Lawton,
• Haitao Ji,
• Pavel Martásek,
• Linda J. Roman and
• Richard B. Silverman

Beilstein J. Org. Chem. 2009, 5, No. 28, doi:10.3762/bjoc.5.28

• the isoforms [6]. In addition, the active site of nNOS is polar with multiple acidic groups, and so most inhibitors that bind with high potency are polar with multiple basic groups. In general, highly charged, hydrophilic molecules do not diffuse passively across the blood-brain barrier (BBB), thus

• partially charged in biological systems. Crystal structures of 2 bound to the active site of nNOS show that the aminopyridine group interacts with a glutamate residue (Glu592, rat nNOS), presumably via hydrogen bonding and electrostatic interactions [8][12]. The aminopyridine ring nitrogen must be

• site, however, protonation should occur to allow the aminothiazole to interact with the active site glutamate and maintain tight binding. The methyl group at the 4 position on the aminopyridine ring contributes to binding through an interaction with a hydrophobic pocket in the nNOS active site. The R

Asymmetric reactions in continuous flow

• Xiao Yin Mak,
• Paola Laurino and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2009, 5, No. 19, doi:10.3762/bjoc.5.19

• equilibration during the longer residence times. Incidentally, this silica supported catalyst system was active up to at least three weeks compared to the homogeneous catalyst that was stable up to 20 h only. This property is perhaps a consequence of favourable active site isolation [50]. Several other examples

Synthesis and glycosidase inhibitory activity of new hexa- substituted C8-glycomimetics

• Olivia Andriuzzi,
• Christine Gravier-Pelletier,
• Gildas Bertho,
• Thierry Prangé and
• Yves Le Merrer

Beilstein J. Org. Chem. 2005, 1, No. 12, doi:10.1186/1860-5397-1-12

• Diastabol®, Basen® and Glucor® or Precose®). Results In that context, new C8-carbasugars and related aminocyclitols have been targeted in order to study the effect of the enhanced flexibility and of the new spatial distribution displayed by these structures on their adaptability in the active site of the

• ] in order to study the effect of the enhanced flexibility and of the new spatial distribution displayed by these structures on their adaptability in the active site of the enzyme. As part of a program directed to the synthesis of potential glycosidases inhibitors, [31][32] we focused on the access to