Tetrathiafulvalene – a redox-switchable building block to control motion in mechanically interlocked molecules

• Hendrik V. Schröder and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2018, 14, 2163–2185, doi:10.3762/bjoc.14.190

• between the TTF unit and the wheel inducing a motion of the wheel towards the now energetically preferred green-colored binding site. Therefore, the most populated and consequently the ground-state co-conformation in the oxidized state is the wheel on the green station. Because of the reversibility of TTF

• groups of Becher and Stoddart reported on a series of similar, but non-degenerate [2]rotaxanes [74][75]. After several structural optimizations, the bistable rotaxane 14 with a high switching efficiency was reported in 2003 (Figure 12) [76]. In the unswitched state, host 3 is located at the TTF binding

• site. Chemical oxidation to the dication TTF2+ triggers a translational motion of the wheel towards the 1,5-dihydroxynaphthalene station (green) as shown by UV–vis and 2D NMR experiments. Chemical reduction with zinc powder restored the spectroscopic properties of the starting state and back-shuttling

A switchable [2]rotaxane with two active alkenyl groups

• Xiu-Li Zheng,
• Rong-Rong Tao,
• Rui-Rui Gu,
• Wen-Zhi Wang and
• Da-Hui Qu

Beilstein J. Org. Chem. 2018, 14, 2074–2081, doi:10.3762/bjoc.14.181

• ]rotaxane R1, the DB24C8 macrocycle is functionalized with an alkenyl unit on one of the benzene groups. Two distinguishable recognition sites, a dibenzylammonium (DBA) and an amide binding site, are introduced to the axle and linked with a long alkyl chain. The amide moiety could act as another combining

Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH

• Femke Beiroth,
• Tomas Koudelka,
• Thorsten Overath,
• Stefan D. Knight,
• Andreas Tholey and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2018, 14, 1890–1900, doi:10.3762/bjoc.14.163

• comprising a lectin domain FimHL hosting the α-D-mannose-specific carbohydrate binding site and a pilin domain FimHP connecting the protein to the fimbrial shaft (Figure 2). Complexation of α-D-mannopyranoside ligands involves the entire mannoside glycon moiety whereas the aglycon portion sticks out of the

• binding site, undergoing interactions with the protein surface, which add to affinity. Especially CH–π or π–π interactions of a sugar ligand with the side chains of Y48 and Y137, called the “tyrosine gate” [19][20], are known to considerably increase the affinity of a specific mannoside for FimH

• mannosides 3–5 as photolabile ligands of FimH and evaluated their potential affinity by computer-aided docking. Docking studies Mannosides 3–5 (Figure 3) were docked into the FimH carbohydrate binding site using FlexX as implemented in Sybyl 6.9 [21][22][23]. Ligand structures were minimized using the Tripos

Synthesis of 9-arylalkynyl- and 9-aryl-substituted benzo[b]quinolizinium derivatives by Palladium-mediated cross-coupling reactions

• Siva Sankar Murthy Bandaru,
• Darinka Dzubiel,
• Heiko Ihmels,
• Mohebodin Karbasiyoun,
• Mohamed M. A. Mahmoud and
• Carola Schulzke

Beilstein J. Org. Chem. 2018, 14, 1871–1884, doi:10.3762/bjoc.14.161

• ct DNA with the methoxy-substituted derivative 2b led to an increase of the low emission intensity by a factor of 3 (Figure 8B). Although this effect is rather small, it indicates the suppression of a deactivation pathway in the excited state upon the accommodation of 2b in a constrained binding site

• of ct DNA, presumably due to the restriction of the conformational flexibility inside the binding site [65]. Conclusion In summary, different synthetic approaches toward the Pd-mediated coupling reactions of benzo[b]quinolizinium derivatives were assessed that enable the functionalization and further

Defining the hydrophobic interactions that drive competence stimulating peptide (CSP)-ComD binding in Streptococcus pneumoniae

• Bimal Koirala,
• Robert A. Hillman,
• Erin K. Tiwold,
• Michael A. Bertucci and
• Yftah Tal-Gan

Beilstein J. Org. Chem. 2018, 14, 1769–1777, doi:10.3762/bjoc.14.151

• binding site, either by not occupying the entire binding pockets or by having some unfavorable steric clashes (Figure 2). To do so, one can either use computational models, when structural information of the protein/receptor is available [30], or utilize conservative point mutations within the ligand

• CSP for the receptor binding site was evaluated using the same assay conditions as described above, except that in this case native CSP (for this purpose, CSP2) was added to every well in a set concentration (250 nM). This concentration was chosen to afford full activation of the QS circuit, as

The phenyl vinyl ether–methanol complex: a model system for quantum chemistry benchmarking

• Dominic Bernhard,
• Fabian Dietrich,
• Mariyam Fatima,
• Cristóbal Pérez,
• Hannes C. Gottschalk,
• Axel Wuttke,
• Ricardo A. Mata,
• Martin A. Suhm,
• Melanie Schnell and
• Markus Gerhards

Beilstein J. Org. Chem. 2018, 14, 1642–1654, doi:10.3762/bjoc.14.140

• dispersion interactions [48]. The aim of the presented study is the unambiguous experimental identification of the preferred binding site of a first methanol solvent molecule to the multivalent hydrogen bond scaffold of phenyl vinyl ether, followed by a classification of theoretical methods in terms of

• contribution from the ether oxygen to the phenyl ring. The latter leads to a slightly decreased electron density at the binding site for the methanol molecule and therefore weakens the hydrogen bond. These findings are in line with observations in previous studies on diphenyl ether–alcohol complexes [20][21

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

• research group. Docking and modelling of cryptophycin derivatives There is no X-ray analysis of cryptophycin–tubulin complexes available to provide information on the binding site. Based on biochemical evidence, binding close to the vinca-alkaloid binding site of β-tubulin, the so called “peptide-site

• oriented towards the GDP binding site that might influence GTP hydrolysis. Compound 22 with the triethylene glycol-based substituent prevents correct binding, the binding energy was decreased and mainly nonspecific interactions outside the binding pocket were observed (Figure 3). This was not the case for

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• . However, these energetic costs are balanced and outweighed by favorable contributions from the hydrophobic transfer of drugs from solution to DNA-binding site [28][29]. Groove binding usually does not influence huge structural/conformational changes in the DNA duplex; this mode of binding may be

• telomere foci clearly because of their fluorescent nature. Later on, the authors successfully designed tandem tetramer Py–Im polyamides with 4 hairpins and 3 hinges targeting 24 bp of the human telomere sequences [88]. Thus, the authors set the new record for the longest binding site of synthetic, non

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

• receptor binding studies, we can assume that the binding site of the receptor is not essentially disturbed by the converted conformation, but it might be possible that the receptor internalization is influenced by the structure of the bound ligand. Considering all these data, we can conclude that the

Carbohydrate inhibitors of cholera toxin

• Vajinder Kumar and
• W. Bruce Turnbull

Beilstein J. Org. Chem. 2018, 14, 484–498, doi:10.3762/bjoc.14.34

• 0.5 r.m.s.) from exact rotational symmetry. Five long α-helices surround the central cylindrical pore through which the A2-subunit is threaded. Each subunit of a B-pentamer has a single binding site for the GM1 oligosaccharide on the face of the pentamer distal to the A1-subunit [12][14]. GM1 is a

• induced upon binding [21]. More recently, a second binding site has been discovered on the edge of the B-subunit sitting closer to the A-subunit face (Figure 2) [13][22][23][24][25], This secondary binding site recognises fucosylated structures including blood group oligosaccharides of the Lewis-y family

• the highest affinity site on the SLT-1 B-subunit has a Kd of only 1 mM [26], yet the toxin achieves sub-nanomolar affinity at a cell membrane. The purpose of the CTB blood group oligosaccharide binding site remains a topic for debate, but it may be responsible for the reported blood group dependence

Stimuli-responsive oligonucleotides in prodrug-based approaches for gene silencing

• Françoise Debart,
• Christelle Dupouy and
• Jean-Jacques Vasseur

Beilstein J. Org. Chem. 2018, 14, 436–469, doi:10.3762/bjoc.14.32

• binding site (miRNA masking) [8]. Although many ONs are under investigation for clinical use, several hurdles remain to be overcome for the exploitation of ONs as therapeutic compounds. Among the major limitations of unmodified ONs, poor stability in vivo, low delivery and lack of specificity to target

Fluorogenic PNA probes

• Tirayut Vilaivan

Beilstein J. Org. Chem. 2018, 14, 253–281, doi:10.3762/bjoc.14.17

• ratio by preventing the binding of the CCP on the DNA strand in the region remote from the PNA binding site, which is quite problematic in the detection of long DNA targets derived from PCR. On the other hand, addition of an organic solvent, such as N-methylpyrrolidinone [118], or a surfactant [119][120

Polarization spectroscopy methods in the determination of interactions of small molecules with nucleic acids – tutorial

• Tamara Šmidlehner,
• Ivo Piantanida and
• Gennaro Pescitelli

Beilstein J. Org. Chem. 2018, 14, 84–105, doi:10.3762/bjoc.14.5

• determine exact concentrations. Also, short oligonucleotides can fail in representing a biologically significant structural model, because of heterogeneous binding sites due to the “capping” effect, whereby a ligand can bind similarly to the end base pairs and to a binding site along the helix [19

• also mentioned in chapter 2.1., achiral ligands upon binding to DNA or RNA can eventually acquire an induced CD (ICD) spectrum, especially when their transition moments are uniformly oriented with respect to the DNA/RNA binding site, which could give useful information about modes of interaction and

• ) competition experiments between two ligands aiming for the same binding site would require a specific design; and so on. 3.1. Practical information Cuvettes: quartz, preferably high-quality manufactured with precisely parallel walls (e.g., fluorimetric cuvettes) and minimal residual strain. Cylindrical cells

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

Beilstein J. Org. Chem. 2018, 14, 25–53, doi:10.3762/bjoc.14.3

• ). Application of natural or synthetic TLR4 antagonists represents one of the most effective approaches for down-regulation of the TLR4-mediated signaling. So far, several lipid A variants which can block the LPS-binding site on human (h)MD-2 have been identified: tetraacylated lipid IVa [47] and a non

• for tracking ligand–receptor interactions was exploited. However, the hydrophobic character and the large size of most fluorescent labels which could potentially compete with lipid A for the LPS binding site at the TLR4 complex, posed an additional challenge. The only optional hydroxyl group which

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• amino acid residues of the binding site, thus making P1’-HfLeuFA a better substrate than the non-fluorinated Leu peptide. Several such interactions are possible, as described in our previous work [39][40][64]. The S2’ subsite of α-chymotrypsin exhibits a hydrophobic character and thus prefers to

• , respectively, which means that the cleavage site was shifted towards the C-terminus by one residue. This cleavage pattern was also detected for α-chymotrypsin before, and indicates that HfLeu is well accepted by pepsin in its S1 binding site. Furthermore, we identified a second cleavage site for P2-HfLeuFA at

• , but also valine, leucine, isoleucine [56][73]. Its binding site extends over eight subsites (S5 to S1, and S1’ to S3’) [74]. The fact that in this study larger and more hydrophobic amino acids [44][45] were introduced may explain why degradation of most of the variants during the first 120 min of

What contributes to an effective mannose recognition domain?

• Christoph P. Sager,
• Deniz Eriş,
• Martin Smieško,
• Rachel Hevey and
• Beat Ernst

Beilstein J. Org. Chem. 2017, 13, 2584–2595, doi:10.3762/bjoc.13.255

• mammalian mannose-binding sites are in general flat and solvent exposed, the half-lives of carbohydrate–lectin complexes are rather short since water molecules can easily access and displace the ligand from the binding site. In contrast, the bacterial lectin FimH benefits from a deep mannose-binding site

• binding site pre-organization, are more difficult to assess and accordingly have been highlighted in this review. Mannose-binding CLECs are involved in various pathways of the human innate immune response, including the blood dendritic cell antigen 2 (BDCA-2, also known as CD303) [18], langerin (CD207

• the binding site hosts a second calcium ion (G and H), advantageous interactions between O–C2 and O–C3 can also occur. Additional contributions from H-bonds formed in the buried binding pockets further improve affinity. In contrast, the calcium-free, buried binding site of the bacterial lectin FimH (I

Conformational impact of structural modifications in 2-fluorocyclohexanone

• Francisco A. Martins,
• Josué M. Silla and
• Matheus P. Freitas

Beilstein J. Org. Chem. 2017, 13, 1781–1787, doi:10.3762/bjoc.13.172

• transition state) or in the ligand assessment to an enzyme binding site. Thus, the replacement of the endocyclic oxygen in 3-fluorodihydro-2H-pyran-4(3H)-one, as well as of the carbonyl oxygen, with other groups, can shift the conformational equilibrium of the resulting molecule towards the equatorial or the

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

• independent study by Demangel and co-workers, who confirmed by global proteome analysis via stable-isotope labeling with amino acids in cell culture (SILAC) [101] in T cells that mycolactone A/B is a broad-spectrum Sec61 inhibitor [102]. The mycolactone binding site on Sec61 appears to be located near a

Glycoscience@Synchrotron: Synchrotron radiation applied to structural glycoscience

• Serge Pérez and
• Daniele de Sanctis

Beilstein J. Org. Chem. 2017, 13, 1145–1167, doi:10.3762/bjoc.13.114

• of high-resolution three-dimensional structures of carbohydrate–antibody complexes [45] provides a way to classify the different types of bindings. Antibodies that recognize a terminal carbohydrate motif present a cavity-like binding feature, while a groove-like binding site is found in antibodies

G-Protein coupled receptors: answers from simulations

• Timothy Clark

Beilstein J. Org. Chem. 2017, 13, 1071–1078, doi:10.3762/bjoc.13.106

• . Remarkably, the ligands span a wide range of efficacies; in 10 cases, they act as agonists, in 11 as antagonist and twice as partial agonists. One key to this success is that the simulations were able to identify the most stable binding site of several alternatives in each case. Multiple binding sites We

• -adrenergic receptor [31], ligands can occupy more than one binding site along the binding path. In the case of vasopressin, a cyclic peptide hormone, the simulations revealed three different sites, the conventional orthosteric one that activates the ligand, an “intermediate” and a “vestibule” site

Opportunities and challenges for the sustainable production of structurally complex diterpenoids in recombinant microbial systems

• Katarina Kemper,
• Max Hirte,
• Markus Reinbold,
• Monika Fuchs and
• Thomas Brück

Beilstein J. Org. Chem. 2017, 13, 845–854, doi:10.3762/bjoc.13.85

• sphaeroides. With an increasing number of integrated recombinant enzymes balanced (over)expression gains importance in order to sustain optimal carbon flux in the production host from cultivation medium feed to the desired product. In this respect, determining the optimal strength of the ribosomal binding

• site (RBS) may be as crucial as the correct arrangement of the genetic elements on designed operons [85][86][87]. To this end, the lycopene reporter system represents a valuable tool in determining balanced expression of terpene centered heterologous pathways in E. coli [88][89]. Furthermore, a

Polyketide stereocontrol: a study in chemical biology

• Kira J. Weissman

Beilstein J. Org. Chem. 2017, 13, 348–371, doi:10.3762/bjoc.13.39

• site-directed inactivation of the NADPH-binding site. The tandem assay strategy was also used to try to identify residues potentially participating in the epimerization reaction [88]. This is an intriguing question, as comparative sequence analysis [57][90] fails to reveal any residues which are

Posttranslational isoprenylation of tryptophan in bacteria

• Masahiro Okada,
• Tomotoshi Sugita and
• Ikuro Abe

Beilstein J. Org. Chem. 2017, 13, 338–346, doi:10.3762/bjoc.13.37

• functions as a binding site for the extension substrate, GPP or FPP. In contrast to FARM, the amino acid residues corresponding to SARM in ComQ are quite different from those in the typical FPP and GGPP synthases (Figure 4B). Since only the second aspartate is preserved in the corresponding region of ComQ

Spectral and DFT studies of anion bound organic receptors: Time dependent studies and logic gate applications

• Srikala Pangannaya,
• Neethu Padinchare Purayil,
• Shweta Dabhi,
• Venu Mankad,
• Prafulla K. Jha,
• Satyam Shinde and
• Darshak R. Trivedi

Beilstein J. Org. Chem. 2017, 13, 222–238, doi:10.3762/bjoc.13.25

• ][24][25][26]. The choice of the appropriate detection technique is highly essential as it directly dictates the efficacy of the sensor. Anion binding through colorimetric probes comprising of a binding site and a signaling unit works in a coordinative way yielding an optical output visible to the

• output, the signaling unit has been linked to a conjugated system possessing a hydroxy functionality which acts as binding site for anions. UV–vis, 1H NMR titration studies along with DFT studies of the receptors R1 and R2 would help to arrive at the binding mechanism. The presence of heteroatoms in the

• aromatic ring and possess hydrogen-bond donor functionality, namely a hydroxy group in the naphthyl part, which can act as an active binding site for anions. Additionally, both receptors R1 and R2 encompass an electron-withdrawing substituent, a CN group (R1) or a NO2 functionality (R2), in the para

Interactions between photoacidic 3-hydroxynaphtho[1,2-b]quinolizinium and cucurbit[7]uril: Influence on acidity in the ground and excited state

• Jonas Becher,
• Daria V. Berdnikova,
• Darinka Dzubiel,
• Heiko Ihmels and
• Phil M. Pithan

Beilstein J. Org. Chem. 2017, 13, 203–212, doi:10.3762/bjoc.13.23

• derivative 7 (Kb = 3 × 104 M−1) [36]. Although a comparison of binding constants from different studies has to be done carefully due to the different experimental conditions, it appears that linear acene-type quinolizinium derivatives fit better into the binding site of CB[7] with highly favorable energetic

• that can thread nicely into the binding site. Notably, the structurally resembling alkaloids berberine (8a) and palmatine (8b), that contain an angularly annelated quinolizinium unit, also bind to CB[7]. But whereas palmatine (8b) has essentially the same binding constant as 2 (Kb = 4.3 × 104 M−1, in

• increase of the pKa and pKa* values originates from the interaction of the acidic functionality with the carbonyl groups at the outer rim of the host molecule [34][55] and – as shown for cationic ligands – from the stabilization of the positive charge by the accommodation in the binding site [29