Host–guest complexes of conformationally flexible C-hexyl-2-bromoresorcinarene and aromatic N-oxides: solid-state, solution and computational studies

• Rakesh Puttreddy,
• Ngong Kodiah Beyeh,
• S. Maryamdokht Taimoory,
• Daniel Meister,
• John F. Trant and
• Kari Rissanen

Beilstein J. Org. Chem. 2018, 14, 1723–1733, doi:10.3762/bjoc.14.146

• , aiding in the binding of polar guests such as N-oxides. Keywords: aromatic N-oxides; C–H···π Interactions; ditopic receptors; endo/exo complexation; host–guest chemistry; resorcinarenes; Introduction Resorcinarenes are macrocyclic compounds with a bowl-shaped cavity stabilised by circular

• intramolecular O···H–O hydrogen bonds (HBs) [1][2]. The combination of their confined cavity and conformational flexibility has driven the interest in these synthetic receptors [3], a subclass of calixarenes [4], for a wide range of applications in fields such as catalysis [5][6][7][8][9], sensors [10][11

Drug targeting to decrease cardiotoxicity – determination of the cytotoxic effect of GnRH-based conjugates containing doxorubicin, daunorubicin and methotrexate on human cardiomyocytes and endothelial cells

• Livia Polgár,
• Eszter Lajkó,
• Pál Soós,
• Orsolya Láng,
• Marilena Manea,
• Béla Merkely,
• Gábor Mező and
• László Kőhidai

Beilstein J. Org. Chem. 2018, 14, 1583–1594, doi:10.3762/bjoc.14.136

• potentially increases the tumor selectivity of drugs and decreases their cardiotoxicity. Increased expression of gonadotropin-releasing hormone (GnRH) receptors on the surface of tumor cells has been reported. Thus, the attachment of the aforementioned chemotherapeutic drugs to GnRH-based peptides may result

• the first step in the hypothalamus-pituitary-gonadal axis, which plays an important role in reproduction [1]. It has been reported that gonadotropin-releasing hormone receptors (GnRH-Rs) are highly expressed on the surface of tumor cells, especially in gynaecological malignant tumors (breast, ovarian

• . Small peptides that recognize target receptors on tumor cells might be suitable targeting moieties for this purpose. Hormone peptides, in particular, GnRH and somatostatin derivatives that possess antiproliferative effect on their own, are among the best candidates as homing peptides [10]. A.V. Schally

A conformationally adaptive macrocycle: conformational complexity and host–guest chemistry of zorb[4]arene

• Liu-Pan Yang,
• Song-Bo Lu,
• Arto Valkonen,
• Fangfang Pan,
• Kari Rissanen and
• Wei Jiang

Beilstein J. Org. Chem. 2018, 14, 1570–1577, doi:10.3762/bjoc.14.134

• , Wuhan, 430079, China 10.3762/bjoc.14.134 Abstract Large amplitude conformational change is one of the features of biomolecular recognition and is also the basis for allosteric effects and signal transduction in functional biological systems. However, synthetic receptors with controllable conformational

• binding behavior of ZB4 and lays the basis for the construction of stimuli-responsive materials with ZB4 as a major component. Keywords: conformations; host–guest chemistry; macrocycles; supramolecular chemistry; zorb[4]arene; Introduction Macrocyclic receptors are the principal workhorses used in

• [15][16] and signal transduction [17] observed with bioreceptors. However, similar conformationally adaptive synthetic macrocyclic receptors are relatively rare in the literature [18][19][20][21][22][23]. During the last five years, we have developed two classes of macrocyclic receptors with

Design and biological characterization of novel cell-penetrating peptides preferentially targeting cell nuclei and subnuclear regions

• Anja Gronewold,
• Mareike Horn and
• Ines Neundorf

Beilstein J. Org. Chem. 2018, 14, 1378–1388, doi:10.3762/bjoc.14.116

• molecules is regulated, separates the nucleus from the cytosol. Macromolecules, like proteins, gain access to the nucleus by recognition of their nuclear localization sequences (NLS) by NLS-receptors, and following energy-dependent uptake processes. Several such natural occurring protein-derived NLS have

The first Pd-catalyzed Buchwald–Hartwig aminations at C-2 or C-4 in the estrone series

• Ildikó Bacsa,
• Dávid Szemerédi,
• János Wölfling,
• Gyula Schneider,
• Lilla Fekete and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 998–1003, doi:10.3762/bjoc.14.85

• estrogen receptors (ERα and ERβ) [28]. Certain derivatives of 2- or 4-aminoestrone or their 3-methyl ether possess diverse biological activities, including enzyme inhibitory or antiproliferative properties [1][2][3][29][30]. The 17β-HSD1 enzyme is responsible for the reduction of estrone into 17β-estradiol

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

• diminishing expressed nucleoside receptors responsible for the cell uptake of gemcitabine [6]. Additionally, chemotherapy with anticancer agents is often hampered by their poor aqueous solubility, low oral bioavailability and metabolic instability. These drawbacks are linked to the unfavorable ADME

• exploited for developing targeted cytotoxic agents: Dysregulation of translation initiation factors and regulators [14]. Mutations in epigenetic regulatory genes [15]. Overexpression of surface receptors like HER2R [16], folate receptor [17], GnRH receptor [18][19] and amino acid transporters [20

• , present on the cell surface of the targeted tissues and not within their cytosol or nucleus (i.e., steroid receptors [33]). The selected receptor should be uniquely expressed or overexpressed on cancer cells (usually 3-fold or higher in comparison with normal cells). Additionally, it should be expressed

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

• receptors are highly expressed on cancer cells/tissues. NGR (Asn-Gly-Arg) motif-containing peptides identified by phage display are suitable candidates for selective drug delivery. NGR peptides bind to CD13-receptors on tumor cells and tumor related angiogenic blood vessels [1][2]. CD13 is a transmembrane

• ratio of 3:1 after hydrolysis [5][6][7][8][9][10][11]. IsoDGR peptides are bound to RGD-integrin receptors with high affinity [12][13][14]. Due to their function in tumor proliferation, metastasis and angiogenesis, integrin receptors are also promising targets for cancer therapy. Thus, NGR-peptide

• in vitro antitumor activity of the conjugates. We believe that the measurement of binding affinity on isolated receptors, that was not task of this experiment, could not explain properly the efficacies and selectivity. The receptor profile of both cell types are very complex. HT-1080 contain

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

• Debrecen, 4032 Debrecen, Hungary 10.3762/bjoc.14.64 Abstract Gonadotropin releasing hormone-III (GnRH-III), a native isoform of the human GnRH isolated from sea lamprey, specifically binds to GnRH receptors on cancer cells enabling its application as targeting moieties for anticancer drugs. Recently, we

• liver lysosomal homogenate have been performed. All derivatives showed high binding affinities to GnRH receptors and displayed in vitro cytostatic effects on HT-29 and MCF-7 cancer cells with IC50 values in a low micromolar range. Moreover, we found that the release of the active drug metabolite and the

• chemotherapeutics. A promising treatment option to overcome these drawbacks can be targeted tumor therapy. This approach is based on the fact that receptors for many regulatory ligands such as peptide hormones are overexpressed on the surface of various cancer cells including gonadotropin-releasing hormone

Synthesis of a sucrose-based macrocycle with unsymmetrical monosaccharides "arms"

• Karolina Tiara,
• Mykhaylo A. Potopnyk and
• Sławomir Jarosz

Beilstein J. Org. Chem. 2018, 14, 634–641, doi:10.3762/bjoc.14.50

• ; Introduction Chiral macrocyclic compounds play an important role in supramolecular and biological systems [1][2]. Many of them serve as convenient receptors for cations [3], anions [4], ion pairs [5], neutral molecules [6] etc. Binaphthols [7][8][9], amino acids [10], chiral diamines [11][12], carbohydrates

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

• sedative-hypnotic activities used for the treatment of anxiety by acting as partial agonists at GABAA (γ-aminobutyric acid type A) benzodiazepine receptors [17]. All these studies have highlighted a strong correlation between the compound pharmacological activities and the absolute configurations of their

• 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

• acid type A) benzodiazepine-receptors. Various functionalized isoindolinones were prepared in good yields and diastereomeric excesses by intramolecular aza-Michael reactions using a double stereo-induction approach. The combined use of selected cinchoninium salts as phase-transfer catalysts and of

Synthesis and biological evaluation of RGD and isoDGR peptidomimetic-α-amanitin conjugates for tumor-targeting

• Lizeth Bodero,
• Paula López Rivas,
• Barbara Korsak,
• Torsten Hechler,
• Andreas Pahl,
• Christoph Müller,
• Daniela Arosio,
• Luca Pignataro,
• Cesare Gennari and
• Umberto Piarulli

Beilstein J. Org. Chem. 2018, 14, 407–415, doi:10.3762/bjoc.14.29

• receptors. Inhibition of biotinylated vitronectin binding to αvβ3 receptor. Evaluation of anti-proliferative activity of α-amanitin and α-amanitin conjugates 7–11 in U-87, MDA-MB-468 and A549. Competition experiments of conjugates 10 and 11 in the presence of a 50-fold excess of cilengitide in U-87 and MDA

Aminosugar-based immunomodulator lipid A: synthetic approaches

• Alla Zamyatina

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

• . The receptors of the innate immune system can detect particular components present in bacteria, viruses or fungi which are designated as “pathogen associated molecular patterns” (PAMPs) [1]. These receptors, termed pattern recognition receptors (PRRs), are able of sensing and responding to PAMPs. The

• activated by the intracellular Gram-negative bacteria and largely contribute to development of endotoxic shock [70][71]. Biochemical studies revealed that caspase-4/11, which mediate inflammatory cell death by pyroptosis, are LPS receptors themselves [72][73]. Due to considerable micro-heterogeneity of the

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

• supersensitivity. Significant research has been directed at the differences between agonist and antagonist binding to 5-HT1A receptors in Alzheimer's disease [10] and this interest has led to the development of a high-resolution in vivo atlas for four of the human brain's serotonin receptors and transporters [11

• -fluoroethane in the presence of K2CO3 (Scheme 1 and Supporting Information File 1). The in vitro binding assays to establish the potency and selectivity of FEMPT towards 5-HT1AR and various other biogenic amines, brain receptors, and transporters were evaluated by the National Institute of Mental Health

• Psychoactive Drug Screening Program (NIMH-PDSP). FEMPT shows 0.2 nM binding affinity (Ki) to 5-HT1AR. The next closest bindings for MPT are Sigma2 PC12, H1, 5-HT7, and 5-HT1B (Table 1) and are >50 times higher than 5-HT1AR. The Ki values for several other brain receptors and transporters were low (0.1 to 10 μM

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

• strong, short C–F bonds and perturb the acidity and basicity of adjacent functional groups. Moreover, these changes may strongly influence hydrogen bonding and electrostatic interactions that are crucial for binding to receptors or, in context of protease stability, enzymes. Thus, when introduced in the

Reagent-controlled regiodivergent intermolecular cyclization of 2-aminobenzothiazoles with β-ketoesters and β-ketoamides

• Irwan Iskandar Roslan,
• Kian-Hong Ng,
• Gaik-Khuan Chuah and
• Stephan Jaenicke

Beilstein J. Org. Chem. 2017, 13, 2739–2750, doi:10.3762/bjoc.13.270

• antimicrobial [35][36], antitumor [37][38][39], antibacterial [40], and anti-allergic agents [41]. In addition, compounds with this backbone are employed as kinase inhibitors and receptors [42][43][44] and as a tracer for PET imaging of β-amyloid plaques [45][46]. The conventional approach for the construction

• been found to be biologically active antagonists of adenosine receptors [82], inhibitors of cyclic-AMP-diphosphoesterase [83], and benzodiazepine receptor ligands [84][85]. Reported methods to access this structural motif include annulation between an aromatic amine and acid chloride [86] or via aza

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

• ]. Crystal structures of mannose–lectin complexes The X-ray structures of six mannose-binding receptors in complex with either α-D-mannose (1) or methyl α-D-mannopyranoside (2) were analyzed (Figure 1 and Table 1, A–C and G–I). Since for DC-SIGNR (Figure 1, D) and DC-SIGN (Figure 1, E) neither complexes with

• specifically on the high-affinity state of FimH present in the isolated lectin domain of FimH, called FimHLD (Figure 1, I). Although the receptors A–F play important roles in human immune responses, they exhibit affinities only in the millimolar range (9.4–1.3 mM) for α-D-mannose (1) and methyl α-D

• -mannopyranoside (2) [40][41][42][43][44]. In contrast, the receptors G and H of bacterial origin show affinities in the micromolar range (71 and 2.8 µM, respectively) for methyl α-D-mannose (2) [31][45]. Despite the 71 µM affinity, LecB (G) preferably binds L-fucose (3 µM) and methyl α-L-fucoside (0.4 µM) [45

Phosphonic acid: preparation and applications

• Charlotte M. Sevrain,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2017, 13, 2186–2213, doi:10.3762/bjoc.13.219

• phosphonic-carboxylic acid 93 [216] or the cyclopropylphosphonic acid 94 that was assessed as inhibitor of the glutamate metabotropic receptors [217]. The synthesis of phosphonic acid via phosphonodiamide intermediates started by the use of the nucleophilic bis(dialkylamino)chlorophosphine. This possibility

Complexation of molecular clips containing fragments of diphenylglycoluril and benzocrown ethers with paraquat and its derivatives

• Leonid S. Kikot',
• Catherine Yu. Kulygina,
• Alexander Yu. Lyapunov,
• Svetlana V. Shishkina,
• Roman I. Zubatyuk,
• Tatiana Yu. Bogaschenko and
• Tatiana I. Kirichenko

Beilstein J. Org. Chem. 2017, 13, 2056–2067, doi:10.3762/bjoc.13.203

• groups of Gibson [11], Huang [12], Chiu [13], Balzani [14] and Loeb [15] have achieved great success in this field. However, flexible structures and the relatively similar nature of crown ether complexation may limit, to a certain extent, their further use. Therefore, the search for new receptors based

• on crown ethers differing in the structure of the intramolecular cavity and in the type of complexation, is still relevant. Among the large variety of synthetic receptors, so-called molecular tweezers and clips are of interest [16][17]. These are a particular case of U-shaped hosts, highly

• reorganized receptors with rigid cleft and convergent binding sites. These compounds are disposed to selective complexation with a wide range of guests. The formation of complexes in this case occurs due to fixation of the substrate molecule between the sidewalls of the molecular clips containing donor

High-speed vibration-milling-promoted synthesis of symmetrical frameworks containing two or three pyrrole units

• Marco Leonardi,
• Mercedes Villacampa and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2017, 13, 1957–1962, doi:10.3762/bjoc.13.190

• vibration milling (HSVM) [14][15]. The importance of pyrrole frameworks stems from the status of this heterocycle as a privileged structure in drug discovery due to its presence as a structural core in molecules that are able to bind various receptors [16]. Results and Discussion Our route to the target

p-tert-Butylthiacalix[4]arenes functionalized by N-(4’-nitrophenyl)acetamide and N,N-diethylacetamide fragments: synthesis and binding of anionic guests

• Alena A. Vavilova and
• Ivan I. Stoikov

Beilstein J. Org. Chem. 2017, 13, 1940–1949, doi:10.3762/bjoc.13.188

• receptors for F−, CH3CO2− and H2PO4− ions, which based on the synthesized thiacalix[4]arenes, have been obtained. It was shown that p-tert-butylthiacalix[4]arene tetrasubstituted at the lower rim by N-(4’-nitrophenyl)acetamide moieties bonded to the anions studied with association constants within the range

• in the regulation of anions is a cause of many diseases [7][8][9][10][11][12]. Thus, selective synthetic receptors can be used in medicine as medicinal and diagnostic agents. However, the design and synthesis of the systems for recognizing anions remains one of the important scientific challenges in

• organic chemistry [13][14][15][16][17][18][19][20][21][22][23]. Anion-receptor biomimetics aimed at developing synthetic analogs of the natural compounds that offer a deeper understanding of a number of biological processes. The design of anion receptors is quite a challenge for several reasons. The

Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz–Fritsch–Bobbitt reaction with non-activated and moderately-activated systems

• Marco Mottinelli,
• Mathew P. Leese and
• Barry V. L. Potter

Beilstein J. Org. Chem. 2017, 13, 1871–1878, doi:10.3762/bjoc.13.182

• to access libraries of regioisomeric N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives that might facilitate the design of new structural templates for steroid-binding receptors. We thus evaluated the robustness and flexibility of this approach to the THIQ system and considered, in particular, the

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• purity of the sample was satisfactory enough to be further used as-synthesized, an analytically pure sample could easily be obtained by simple washing with CH2Cl2. The mechanochemically prepared urea 33 was next used in the synthesis of tri- and tetrapodal anion receptors, again by exploiting the solid

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• alkaloids such as luotonin A, tryptanthrin and many more (Figure 1) [11][12]. Quinazoline derivatives work as potential inhibitors of epidermal growth factor (EGF) and tyrosine kinase receptors and also display antibacterial, antitubercular and antiviral properties [13][14][15][16]. Last but not the least

Synthesis and metal binding properties of N-alkylcarboxyspiropyrans

• Alexis Perry and
• Christina J. Kousseff

Beilstein J. Org. Chem. 2017, 13, 1542–1550, doi:10.3762/bjoc.13.154

• Alexis Perry Christina J. Kousseff Biosciences, University of Exeter, Stocker Road, Exeter EX4 4QD, UK 10.3762/bjoc.13.154 Abstract Spiropyrans bearing an N-alkylcarboxylate tether are a common structure in dynamic, photoactive materials and serve as colourimetric/fluorimetric cation receptors

• been extensively exploited [2]. Spiropyrans bearing an N-alkylcarboxylate tether are photo-reversible colourimetric/fluorimetric receptors for metal cations [3][4][5] and amino acids [6], and serve as convenient building blocks in the synthesis of dynamic materials [7] (Figure 1). In this latter role

• /fluorimetric receptors for metal cations via complexation of the merocyanine isomer. Consequently, we have assessed the metal binding behaviour of spiropyrans bearing N-acetic acid through to N-dodecanoic acid tethers by 1H NMR and UV–vis spectroscopy. All compounds tested displayed a strong preference for

Syntheses of 3,4- and 1,4-dihydroquinazolines from 2-aminobenzylamine

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

Beilstein J. Org. Chem. 2017, 13, 1470–1477, doi:10.3762/bjoc.13.145

• heterocylic amidines (1,4,5,6-tetrahydropyrimidines) display biological activity as anthelmintics used in medical practice (pyrantel, morantel and oxantel) [5][6], nicotinic agonists [7], antidepressants [8] and selective inhibitors of M1 acetylcholine receptors [9][10], among others. Their benzannulated