Structural diversity in the host–guest complexes of the antifolate pemetrexed with native cyclodextrins: gas phase, solution and solid state studies

• Magdalena Ceborska,
• Magdalena Zimnicka,
• Aneta Aniela Kowalska,
• Kajetan Dąbrowa and
• Barbara Repeć

Beilstein J. Org. Chem. 2017, 13, 2252–2263, doi:10.3762/bjoc.13.222

• ; pemetrexed; supramolecular chemistry; Introduction Herein, supramolecular host–guest complexes of the potent folic acid inhibitor pemetrexed (PTX, Figure 1a) with native cyclodextrins (α-, β- and γ-CDs, Figure 1b) in the gas phase (MS), in solution (NMR, UV–vis) and in the solid state (Raman, FTIR–ATR) were

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

• prepare phosphohomocysteine 30 [141], the arginine mimetic 31 that was developed as a potent metallo-aminopeptidase inhibitor [142] or the aminophosphonic acid 32 [143] (Figure 10B). The mechanism of hydrolysis of diphenyl phosphonate in acidic conditions is likely different to the one occurring with

• inhibitor of the human farnesyl pyrophosphate synthase (hFPPS) [181] were prepared from their corresponding diethylphosphonates (Figure 18). Nucleotide analogues were also prepared by this methodology as exemplified by the compound 54 [176] or 55 [182]. For these last two examples, the bromotrimethylsilane

• 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

Difunctionalization of alkenes with iodine and tert-butyl hydroperoxide (TBHP) at room temperature for the synthesis of 1-(tert-butylperoxy)-2-iodoethanes

• Hao Wang,
• Cui Chen,
• Weibing Liu and
• Zhibo Zhu

Beilstein J. Org. Chem. 2017, 13, 2023–2027, doi:10.3762/bjoc.13.200

• product formation efficiency. We investigated the addition of the radical inhibitor TEMPO (2,2,6,6-tetramethylpiperididine-N-oxyl) to gain an insight into the mechanism of this reaction. The reaction was completely inhibited in the presence of TEMPO, suggesting that a radical pathway may be operating in

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

• Johannes Schörgenhumer,
• Maximilian Tiffner and
• Mario Waser

Beilstein J. Org. Chem. 2017, 13, 1753–1769, doi:10.3762/bjoc.13.170

• inhibitor Ranirestat, but also because it presents an early and pioneering report on the use of chiral tetraalkylphosphonium salts as asymmetric PTCs. Just a year later, the same group then also succeeded in using the chiral spirocyclic quaternary ammonium salts B for the same transformation, which

Block copolymers from ionic liquids for the preparation of thin carbonaceous shells

• Sadaf Hanif,
• Bernd Oschmann,
• Dmitri Spetter,
• Muhammad Nawaz Tahir,
• Wolfgang Tremel and
• Rudolf Zentel

Beilstein J. Org. Chem. 2017, 13, 1693–1701, doi:10.3762/bjoc.13.163

• dopamine (4) as the anchoring unit. Dopamine has been proven to coordinate well on transition metal oxide surfaces [29][31][32]. This route was chosen because dopamine cannot be polymerized in a radical process due to its phenolic structure that would act as an inhibitor. Hence we use the reactive ester

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

• pharmaceutical ingredients. The following section will describe a few of such efforts. In 2013, Witt et al. reported a scalable process for the synthesis of GSK3B inhibitor AZD8926, 103 [99]. The drug is therapeutically useful for the treatment of CNS disorder viz. Alzheimer’s disease (AD), Schizophrenia and

• et al. utilized a modular catalytic system comprised of C-quinones for the oxidative dehydrogenation of tetrahydroquinolines 104 to an (2,1-c)quinoline 105. This was further transformed to 106, an antiprotozoal agent, and 107, a topoisomerase inhibitor, presently in the phase II clinical trial

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

• within 4 h [35]. Interestingly, the addition of the pan-caspase inhibitor Boc-Asp(OMe)-fluoromethylketone [84] prevented apoptosis, while a normal cytopathogenic effect and subsequent cell death by necrosis was observed. Mycolactone A/B is also highly cytotoxic to keratinocytes [85], dendritic [81], and

• fluorescent mycolactone-derived probe, which co-localized with active WASP to a small but significant extent in Jurkat T cells. At the same time, wiskostatin, a known N-WASP inhibitor [97] was found to counteract some of the effects of mycolactone (e.g., impaired cell adhesion in HeLa cells). Wiskostatin also

• . Consistent with this, mycolactone treatment in the presence of a proteasome inhibitor restored COX2 and TNF production in RAW264.7 cells and both proteins were found in the cytosol. Translocation of secretory proteins into the ER is mediated by the Sec61 complex, a protein conducting channel that consists of

Grip on complexity in chemical reaction networks

• Albert S. Y. Wong and
• Wilhelm T. S. Huck

Beilstein J. Org. Chem. 2017, 13, 1486–1497, doi:10.3762/bjoc.13.147

• *. In the reaction network, trypsin (Tr) catalyzes its own formation from the precursor trypsinogen (Tg). Opposed to this positive feedback, Tr is inhibited by the negative feedback that is composed of three sequential steps (Figure 5b). In the activation step, Tr converts a pro-inhibitor into an

• intermediate inhibitor (Int-Inh), which consists of a glutamine (Gln) residue attached to a potent inhibitor for Tr. Another enzyme, aminopeptidase N (Ap), controls the release of the inhibitor moiety by cleaving off Gln in the delay step. In the final step, Tr recognition of the active inhibitor (Inh) closes

• amplified. Similarly, the design is used to create an analog-to-digital output by introducing a trypsin inhibitor (soybean trypsin inhbitor (STI)) in the second CSTR (Figure 6b). The STI effectively thresholds the local minima in the initial oscillations, converting the initial signal into a switch-like

Mechanochemical borylation of aryldiazonium salts; merging light and ball milling

• José G. Hernández

Beilstein J. Org. Chem. 2017, 13, 1463–1469, doi:10.3762/bjoc.13.144

• the presence of 1,1-diphenylethene (4) as a radical inhibitor was conducted. After the standard 1 h of milling, the formation of 3a was slowed down and the analysis of the reaction mixture by gas chromatography–mass spectrometry showed the presence of the phenyl radical trapping adduct 5 (Scheme 1

1-Imidoalkylphosphonium salts with modulated C_α–P⁺ bond strength: synthesis and application as new active α-imidoalkylating agents

• Jakub Adamek,
• Roman Mazurkiewicz,
• Anna Węgrzyk and
• Karol Erfurt

Beilstein J. Org. Chem. 2017, 13, 1446–1455, doi:10.3762/bjoc.13.142

• Otezla), a tumor necrosis factor-α (TNF-α) inhibitor used for the treatment of psoriasis, psoriatic dermatitis and other inflammatory diseases related to the immune system [31]. Results and Discussion 1-Imidoalkylphosphonium salts 5 were synthesized in a three-step procedure starting from α-amino acids

Total syntheses of the archazolids: an emerging class of novel anticancer drugs

• Stephan Scheeff and
• Dirk Menche

Beilstein J. Org. Chem. 2017, 13, 1085–1098, doi:10.3762/bjoc.13.108

• these scarce natural products for biological evaluation, but also in supplying novel analogues with tailored functional properties to decipher the target inhibitor interactions at a molecular level. Finally, the total syntheses of the Menche and Trauner group were also of key importance to assign the

Cycloheximide congeners produced by Streptomyces sp. SC0581 and photoinduced interconversion between (E)- and (Z)-2,3-dehydroanhydrocycloheximides

• Li Yang,
• Ping Wu,
• Jinghua Xue,
• Huitong Tan,
• Zheng Zhang and
• Xiaoyi Wei

Beilstein J. Org. Chem. 2017, 13, 1039–1049, doi:10.3762/bjoc.13.103

• a multitude of biological activities. The most famous representative of this family, cycloheximide (5), has been used for decades as an inhibitor of eukaryotic translation elongation [1][2][3]. Other members of this family show potent cell migration inhibition and antiviral activity [4][5][6], which

Synthesis of tetrasubstituted pyrazoles containing pyridinyl substituents

• Josef Jansa,
• Ramona Schmidt,
• Ashenafi Damtew Mamuye,
• Laura Castoldi,
• Alexander Roller,
• Vittorio Pace and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2017, 13, 895–902, doi:10.3762/bjoc.13.90

• ], agrochemicals [5], dyes [6], fluorescent materials [7][8] and ligands of complexing agents [9][10][11]. Multiaryl-substituted pyrazoles are of special interest, with some drug molecules such as the nonsteroidal anti-inflammatory agent Lonazolac [12] or the well-known COX-2 inhibitor Celecoxib [13] as prominent

Expression, purification and structural analysis of functional GABA transporter 1 using the baculovirus expression system

• Jing Hu,
• Chris Weise,
• Christoph Böttcher,
• Hua Fan and
• Jian Yin

Beilstein J. Org. Chem. 2017, 13, 874–882, doi:10.3762/bjoc.13.88

• dithiothreitol (DTT) and protease inhibitor cocktail (1:500) (Merck). After a 4 × 30 s sonication step, the cells were incubated overnight at 4 °C with agitation. The solubilized protein was fractionated by 45 min of centrifugation at 18,000 rpm. The cell lysate was added directly to the immunoaffinity

New approach toward the synthesis of deuterated pyrazolo[1,5-a]pyridines and 1,2,4-triazolo[1,5-a]pyridines

• Aleksey Yu. Vorob’ev,
• Vyacheslav I. Supranovich,
• Gennady I. Borodkin and
• Vyacheslav G. Shubin

Beilstein J. Org. Chem. 2017, 13, 800–805, doi:10.3762/bjoc.13.80

• antiviral [7][8], antimalarial [9] and antitubercular [10] agents. Also they were applied in the development of FIXa [11], PI3K [12], EGFR [13] and PDE [14] inhibitors and dopamine receptor ligands [15]. The nonselective PDE3,4 inhibitor ibudilast (MN-166) has been marketed in Japan for over 25 years for

Isoxazole derivatives as new nitric oxide elicitors in plants

• Anca Oancea,
• Emilian Georgescu,
• Florentina Georgescu,
• Alina Nicolescu,
• Elena Iulia Oprita,
• Catalina Tudora,
• Lucian Vladulescu,
• Marius-Constantin Vladulescu,
• Florin Oancea and
• Calin Deleanu

Beilstein J. Org. Chem. 2017, 13, 659–664, doi:10.3762/bjoc.13.65

• ], antinociceptive [12] and anticancer [13] activities. Several isoxazole derivatives have GABAA antagonist [14] and T-type Ca2+ channel blocking activities [15]. Commercial drugs featuring an isoxazole moiety include the COX-2 inhibitor Valdecoxib and the β-lactam antibiotics Cloxacillin and Dicloxacillin. An

N-Propargylamines: versatile building blocks in the construction of thiazole cores

• S. Arshadi,
• E. Vessally,
• L. Edjlali,
• R. Hosseinzadeh-Khanmiri and
• E. Ghorbani-Kalhor

Beilstein J. Org. Chem. 2017, 13, 625–638, doi:10.3762/bjoc.13.61

• pharmacological activities. For example, abafungin (Figure 1) is an antifungal drug marketed worldwide for the treatment of dermatomycoses. It works by inhibiting the enzyme sterol 24-C-methyltransferase [1][2][3][4]. Febuxostat, also known by its brand name adenuric is a xanthine oxidase inhibitor that helps to

• prevent gout flare-ups [5][6][7]. Ritonavir (norvir), is an HIV protease inhibitor. It works by blocking the growth of HIV [8][9]. Tiazofurin is a C-nucleoside analogue with antineoplastic activity and acts by inhibition of the guanosine triphosphate (GTP) biosynthesis through a reduction of PI and PIP

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

• -indanone derivatives 66 were obtained in 13–86% yields (Scheme 22). This method was further applied to the synthesis of biologically active compounds, such as 1-tetralones, 1-benzosuberones and donepezil (a potent acetylcholinesterase inhibitor used in the treatment of Alzheimer’s disease). Halo-1

Silyl-protective groups influencing the reactivity and selectivity in glycosylations

• Mikael Bols and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2017, 13, 93–105, doi:10.3762/bjoc.13.12

• glycosylation with a TES-protected glycosyl donor has also been performed in a case where the target contained a 6-O-acylglucoside and hence protective groups that could be removed under mild acidic conditions were needed [9]. This was for example used for the synthesis of the serine protease inhibitor

Biochemical and structural characterisation of the second oxidative crosslinking step during the biosynthesis of the glycopeptide antibiotic A47934

• Veronika Ulrich,
• Clara Brieke and
• Max J. Cryle

Beilstein J. Org. Chem. 2016, 12, 2849–2864, doi:10.3762/bjoc.12.284

• expression was induced with 0.1% rhamnose and 0.1 mM IPTG. After overnight expression, cells were harvested at 5000g and 4 °C for 10 min and resuspended in lysis buffer (50 mM Tris pH 8, 50 mM NaCl, 10 mM imidazole, 0.5 mM DTE, EDTA-free SIGMAFAST™ Protease Inhibitor Cocktail Tablet). All purification steps

New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

• Pavel Nagorny and
• Zhankui Sun

Beilstein J. Org. Chem. 2016, 12, 2834–2848, doi:10.3762/bjoc.12.283

• found to be particularly good in promoting the formation of benzhydryl acetamide (95% after 96 h). Due to the formation of the strong inhibitor, hydrobromic acid that acts as the source of bromide anion as the reaction progresses, the aforementioned studies required a stoichiometric amount of halogen

cis-Diastereoselective synthesis of chroman-fused tetralins as B-ring-modified analogues of brazilin

• Dimpee Gogoi,
• Runjun Devi,
• Pallab Pahari,
• Bipul Sarma and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2016, 12, 2816–2822, doi:10.3762/bjoc.12.280

• potentially important biological activities including the abilities to act as telomerase inhibitor and to produce DNA nicks [5][6][7]. Also, haematoxylin has recently been demonstrated to be a potent inhibitor of protein tyrosine kinase [8]. Given the broad and interesting biological activities of these two

Synthesis of spiro[isoindole-1,5’-isoxazolidin]-3(2H)-ones as potential inhibitors of the MDM2-p53 interaction

• Salvatore V. Giofrè,
• Santa Cirmi,
• Raffaella Mancuso,
• Francesco Nicolò,
• Giuseppe Lanza,
• Laura Legnani,
• Agata Campisi,
• Maria A. Chiacchio,
• Michele Navarra,
• Bartolo Gabriele and
• Roberto Romeo

Beilstein J. Org. Chem. 2016, 12, 2793–2807, doi:10.3762/bjoc.12.278

• that plays a key role in the regulation of several cellular processes, including apoptosis, DNA repair, and angiogenesis [1][2][3][4]. The murine double minute 2 (MDM2) protein is the primary cellular inhibitor of p53, functioning through direct interaction with p53 [5]: tumoral cells show an

• inhibitory [32] and cytotoxic activity. Recently, MDM2-p53 inhibitors based on an isoindolinone scaffold [33][34] have been reported. These latter results demonstrate the versatility of the isoindolinone scaffold as MDM2-p53 inhibitor and show that significant improvements in potency may be gained by modest

• antitumor activity could be linked to the inhibition of the protein–protein p53-MDM2 interaction. Docking measurements support the biological data. Further studies are needed to better clarify the role played by the new synthesized compounds in SH-SY5Y cancer cell lines as inhibitor of MDM2-p53 interaction

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• deprotonation by His257 [23]. Our results may also partially explain the potent inhibition of a PqsD inhibitor described in the literature which was discovered in silico and had been equipped with an α-chloroacetyl group [24]. Inhibition of PqsD has been proposed as promising antivirulence strategy leading to

• disruption of AQ signaling and thereby to global down-regulation of virulence factor production [11]. Consequently, PqsD has become a highly attractive target and a great amount of work pioneered by the Hartmann group has resulted in inhibitor discovery using a combination of in vitro assay, in silico

• inhibitors based on these leads have been described and importantly, some of them also displayed in situ activity by reducing signal production and biofilm formation in live cultures of P. aeruginosa [28][31]. Recently, a synergistic dual PqsD and PqsR inhibitor was developed which also led to a marked

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

• ]. In another study, structure-based computational methods have been used to predict binding sites, which are important for inhibitor binding, in AmpC beta lactamase which have been experimentally verified [17]. FDA approved Dorzolamide is a carbonic anhydrase II inhibitor which is used in the treatment

• phosphate probe which are used to identify the binding sites for drug-like molecules and phosphorylated ligands (such as ATP) respectively [92]. The best ligand binding site identified in HIV-1 protease by SiteHound is shown in Figure 4. This ligand binding site is the known inhibitor binding site in HIV-1

• that no single docking method performs well for all targets and the quality of docking results is highly dependent on the ligand and the binding site of interest [148][149][150]. The best four binding poses predicted for the known inhibitor Dorzolamide binding to carbonic anhydrase II obtained by