Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells

• Rainer Kufka,
• Robert Rennert,
• Goran N. Kaluđerović,
• Lutz Weber,
• Wolfgang Richter and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2019, 15, 96–105, doi:10.3762/bjoc.15.11

• been identified as fast and efficiently internalizing GPCR in those cells upon agonist binding [29][30]. The NPY Y1 receptor subtype for these reasons is a very promising molecular target to be addressed by selective peptide–drug conjugates (PDCs), notably for cancer treatment or diagnosis. However

Non-native autoinducer analogs capable of modulating the SdiA quorum sensing receptor in Salmonella enterica serovar Typhimurium

• Matthew J. Styles and
• Helen E. Blackwell

Beilstein J. Org. Chem. 2018, 14, 2651–2664, doi:10.3762/bjoc.14.243

• receptor activation (or inactivation). Most LuxR-type proteins are highly unstable in vitro in the absence of an agonist ligand, and this instability is typically heightened in the presence of an antagonist [38]. As such, the observed stability of EHEC SdiA in vitro, both in the absence and presence of

• Figure 2. For agonism at 100 μM, 119 compounds (79% of the library), and at 1 μM, 71 compounds (47% of the library), activated SdiA by at least 50% (above the negative control). This level of promiscuity in terms of agonist ligands is high for a LuxR-type receptor. For comparison, RhlR and QscR were

• heightened stringency of testing against an agonist (here, L-OOHL) at its EC90 value. For reference, 24% and 12% of a comparable in-house library were found to inhibit QscR [57] (at 5 μM) and RhlR [56] (100 μM) by greater than 65%, respectively. Lowering our cut-off, we found 23 compounds that could inhibit

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

• -position of the quinolone core through action of the P. aeruginosa enzyme PqsH (Figure 14), turning the inverse agonist 33 into a strong agonist 34 (EC50 = 2.8 nM). This phenomenon was overcome by blocking the metabolic susceptible 3-position with various functional groups resulting in 35 which showed good

• , the chlorine is able to occupy a vacant sub pocket. A hydrogen bond is found between the backbone oxygen of L207 and the 3-NH2 hydrogen atoms. Interestingly, adding the chlorine substituent in 7-position of PQS leads to a 135 times more potent agonist, indicating the importance of the vacant sub

• production at a concentration of 10 µM. Various analogues were synthesized resulting in compound 42 (M64), where similar as in the quinolones described by Lu et al., introduction of the electron-withdrawing nitro function led to very potent inverse agonist (Figure 18) [72]. M64 (42) proved a very potent

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

• depending on the cellular milieu or function, the GnRH analogs could elicit different – even opposite – actions [6][40]. For example, Aguilar-Rojas and his co-workers reported a similar combination of actions (invasion inhibitory and adhesion increasing effects) of a GnRH agonist in a breast cancer cell

Recyclable hypervalent-iodine-mediated solid-phase peptide synthesis and cyclic peptide synthesis

• Dan Liu,
• Ya-Li Guo,
• Jin Qu and
• Chi Zhang

Beilstein J. Org. Chem. 2018, 14, 1112–1119, doi:10.3762/bjoc.14.97

• reversed-phase HPLC (RP-HPLC). For the target peptides, we aimed at peptides with specific biological activities. Leu-enkephalin, which is isolated from pig brains, acts as an endogenous mediator at central morphine receptor sites and thus possesses potent opiate agonist activity [34][35][36]. Leu

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

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

• studies have been prepared as previously described [29][51][52][55]. Radioiodinated GnRH-I agonist triptorelin was prepared by chloramines-T method and purified by RP-HPLC [29][51][52][56]. This radioligand has been well-characterized and shows high-affinity binding to human and rat pituitaries as well as

Diastereoselective auxiliary- and catalyst-controlled intramolecular aza-Michael reaction for the elaboration of enantioenriched 3-substituted isoindolinones. Application to the synthesis of a new pazinaclone analogue

• Romain Sallio,
• Stéphane Lebrun,
• Frédéric Capet,
• Francine Agbossou-Niedercorn,
• Christophe Michon and
• Eric Deniau

Beilstein J. Org. Chem. 2018, 14, 593–602, doi:10.3762/bjoc.14.46

• agonist at GABAA (γ-aminobutyric acid type A) benzodiazepine receptors [17]. In order to circumvent any hydrolysis of the ketal group during the preparation of the starting benzamide (see Supporting Information File 1), the synthesis of intermediate 24 was performed according another pathway depicted in

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

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

• vaccine adjuvants [59][60][61]. X-ray structural analyses of the MD-2∙TLR4 complexes with bound variably acylated lipid A uncovered markedly different modes of interaction of agonist and antagonist TLR4 ligands. Commonly, the binding of hexaacylated bisphosphorylated lipid A (such as lipid A from E. coli

• addition to labeled E. coli type lipid A 25, the labeled tetraacylated lipid IVa was also prepared. Importantly, the bioactivity of labeled compounds was fully preserved (the labeled E. coli type lipid A 25 performed as strong TLR4 agonist and the labeled tetraacylated lipid IVa acted, as expected, as TLR4

Microfluidic radiosynthesis of [¹⁸F]FEMPT, a high affinity PET radiotracer for imaging serotonin receptors

• Thomas Lee Collier,
• Steven H. Liang,
• J. John Mann,
• Neil Vasdev and
• J. S. Dileep Kumar

Beilstein J. Org. Chem. 2017, 13, 2922–2927, doi:10.3762/bjoc.13.285

• the reduction in reaction times and consumption of reagents that often result in increased radiochemical yields and rapid optimization of reaction parameters for 18F-labeling. In this paper, we report on the two-step microfluidic radiosynthesis of the high affinity partial agonist of the serotonin 1A

• receptor, [18F]FEMPT (pKi = 9. 79; Ki = 0.16 nM) by microfluidic radiochemistry. [18F]FEMPT was obtained in ≈7% isolated radiochemical yield and in >98% radiochemical and chemical purity. The molar activity of the final product was determined to be >148 GBq/µmol (>4 Ci/µmol). Keywords: agonist; fluorine

• -18; 5-HT1A; microfluidics; PET; Introduction The development of serotonin 1A receptor (5-HT1AR) agonist radiotracers for applications in molecular imaging with positron emission tomography (PET) has been avidly sought over the past two decades, albeit with limited success. The current status of

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

• 8000 host genes identified the angiotensin type II receptor (AT2R) as the molecular target of mycolactone, which was confirmed by genetic knockout in vitro and in vivo and by chemical inhibition. In a competition binding assay mycolactone was able to displace the potent radiolabeled agonist [125I

G-Protein coupled receptors: answers from simulations

• Timothy Clark

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

• , no agonist ligand is bound. The G-protein is bound to the intracellular side of the receptor. In this state, the GPCR exhibits its basal activity, which can range from completely inactive to significantly active. Figure 3b shows the fully activated complex, which requires both an agonist ligand and

• experimental findings [29] suggest that both an agonist ligand and a bound G-protein are necessary in order to activate GPCRs. It is therefore significant that the first molecular dynamics (MD) simulations of a ternary GPCR complex were reported only four years ago [30]. Such simulations are now commonplace

• bound. The α-subunit of the G-protein is shown in green, β in yellow and γ in magenta. In this state, the GPCR exhibits basal activity. This figure assumes pre-association of the G-protein to the receptor. (b) Fully activated GPCR. Both an agonist ligand and the G-protein are required for full

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• and noradrenaline. A new method for the synthesis of the indane 2-imidazole derivative 37 acting as a strong adrenergic receptor agonist has been proposed by Roberts et al. [30]. In this synthesis, the diacid 34 was converted to 1-indanone 36 via the AlCl3 promoted Friedel–Crafts acylation of the acid

Continuous-flow synthesis of highly functionalized imidazo-oxadiazoles facilitated by microfluidic extraction

• Ananda Herath and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2017, 13, 239–246, doi:10.3762/bjoc.13.26

• (S1P1 agonists) [27]. Gram-scale synthesis of mGlu5 NAM by continuous flow in combination with microfluidic extraction. Gram-scale synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazole S1P1 agonist scaffold by continuous flow combined with microfluidic extraction. Optimization of the flow synthesis

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

Continuous-flow synthesis of primary amines: Metal-free reduction of aliphatic and aromatic nitro derivatives with trichlorosilane

• Riccardo Porta,
• Alessandra Puglisi,
• Giacomo Colombo,
• Sergio Rossi and
• Maurizio Benaglia

Beilstein J. Org. Chem. 2016, 12, 2614–2619, doi:10.3762/bjoc.12.257

• [29]. The corresponding amide 6 is a direct precursor of the GABA receptor agonist Baclofen (Scheme 5). Nitro compound 5 was continuously reduced in a 5 mL reactor and, after work-up under neutral conditions, chiral lactam 6 was isolated in 48% yield. Finally we explored the possibility of performing

The direct oxidative diene cyclization and related reactions in natural product synthesis

• Juliane Adrian,
• Leona J. Gross and
• Christian B. W. Stark

Beilstein J. Org. Chem. 2016, 12, 2104–2123, doi:10.3762/bjoc.12.200

• by Sakai et al. together with the already known and closely related dysiherbaine [42]. Neodysiherbaine A (14) is a neurologically active compound that acts as a glutamate receptor agonist and shows epileptogenic properties. Contiguous to the isolation, the first synthesis has been carried out by the

Discovery of an inhibitor of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells

• Bernardas Morkunas,
• Balint Gal,
• Warren R. J. D. Galloway,
• James T. Hodgkinson,
• Brett M. Ibbeson,
• Yaw Sing Tan,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2016, 12, 1428–1433, doi:10.3762/bjoc.12.137

• . Interestingly, this data suggests that 4 may have slight agonist activity at low concentrations. This type of behaviour has previously been observed for AHL-based modulators of quorum sensing. Many such compounds have been identified that can both slightly activate and inhibit a quorum sensing circuit depending

• pyocyanin inhibitors in P.aeruginosa are not directly inhibiting LasR but have an alternate mode of action(s), this hypothesis should not be completely ruled out. This may be especially relevant for compounds such as 4, which are clearly structurally distinct from OdDHL, the natural LasR agonist [12]. In

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• currently being used for the treatment of growth hormone deficiency as a potent and orally active GHSR agonist [10]. YK-4-279 can potently inhibit the growth of Ewing’s sarcoma by blocking the interaction between the oncogenic protein EWS-FLI1 and RNA helicase A (RHA) [11]. Interestingly, only (S)-YK-4-279

Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen

• Hans Sterckx,
• Johan De Houwer,
• Carl Mensch,
• Wouter Herrebout,
• Kourosch Abbaspour Tehrani and
• Bert U. W. Maes

Beilstein J. Org. Chem. 2016, 12, 144–153, doi:10.3762/bjoc.12.16

• acid as a promotor [25]. The resulting ketones are very valuable as they are intermediates in the synthesis of a variety of pharmaceuticals such as the antimalarial Mefloquine (Lariam®), the antihistamine Acrivastine, the β2-adrenergic agonist Rimiterol and the anxiolytic Bromazepam [26]. Furthermore

Copper-catalyzed intermolecular oxyamination of olefins using carboxylic acids and O-benzoylhydroxylamines

• Brett N. Hemric and
• Qiu Wang

Beilstein J. Org. Chem. 2016, 12, 22–28, doi:10.3762/bjoc.12.4

• -adrenergic receptor agonist [3]; lumefantrine, an antimalarial drug [4]; ifenprodil, an N-methyl-D-aspartate (NMDA) antagonist [5]; and tebuconazole, a commercial fungicide [6]. With the importance of 1,2-oxyamino motifs as privileged pharmacophores, the development of facile and efficient access to this

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• second study, the flow synthesis of the selective δ-opioid receptor agonist 33 was discussed (Scheme 6) [57]. Again, a strategy of integrating each of the three synthetic steps with a sequenced cascade of scavenger agents to perform the aspects of work-up and purification was used. The report also

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• enantioselectivities than phosphine ligands in rhodium-catalyzed asymmetric reactions [152][153]. Scheme 16 shows the rhodium-catalyzed asymmetric 1,4-arylation that was developed by Lin and co-workers and the subsequent transformation to the GABAB receptor agonist, (R)-(−)-baclofen. Much of the work that has been

• agonist AMG 837 [199]. Shibasaki and co-workers expanded their application of soft Lewis acid/hard Brønsted base cooperative catalysis to the asymmetric vinylogous conjugate addition of α,β-unsaturated butyrolactones to α,β-unsaturated thioamides [200]. This reaction provides a method for producing

Natural phenolic metabolites with anti-angiogenic properties – a review from the chemical point of view

• Qiu Sun,
• Jörg Heilmann and
• Burkhard König

Beilstein J. Org. Chem. 2015, 11, 249–264, doi:10.3762/bjoc.11.28

• the regulation of cell functions, including cell proliferation and cell transformation. Later, genistein was also found to act as an oestrogen receptor agonist [80]. The anti-angiogenic potential of genistein was first reported by Fotsis et al. in 1993 [81]. Then, further studies showed that genistein

Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel–[1,5]-hydride shift cyclization reaction

• László Tóth,
• Yan Fu,
• Hai Yan Zhang,
• Attila Mándi,
• Katalin E. Kövér,
• Tünde-Zita Illyés,
• Attila Kiss-Szikszai,
• Balázs Balogh,
• Tibor Kurtán,
• Sándor Antus and
• Péter Mátyus

Beilstein J. Org. Chem. 2014, 10, 2594–2602, doi:10.3762/bjoc.10.272

• unit and its analogues are found in several pharmacologically active derivatives such as the selective 5-HT1A agonist SUN 8399 (1) [1], the neuroprotective piclozotan (2) [2][3], the antihistaminic rocastine (3) [4][5], and the antihelmintic 4 [6] (Figure 1). We report herein the preparation of two