Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction

• Maryna V. Murlykina,
• Oleksandr V. Kolomiets,
• Maryna M. Kornet,
• Yana I. Sakhno,
• Sergey M. Desenko,
• Victoriya V. Dyakonenko,
• Svetlana V. Shishkina,
• Oleksandr A. Brazhko,
• Vladimir I. Musatov,
• Alexander V. Tsygankov,
• Erik V. Van der Eycken and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2019, 15, 1281–1288, doi:10.3762/bjoc.15.126

• ]pyridine-4-carboxamides being SMYD2 inhibitors (an oncogenic methyltransferase that represses the functional activity of the tumor suppressor proteins p53 and RB); the similar structures can be obtained using the methodology of sequential Doebner- and Ugi-type MCRs. In the present work we combined several

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• , nintedanib is employed against pulmonary fibrosis [32], tenidap [33] is a nonsteroidal anti-inflammatory drug (NSAID), while indolidan [34] and adibendan [35] are potent long-acting cardiotonic agents and SM-130686 is a GHSR agonist [36] (Figure 5). Other kinase inhibitors such as sunitinib [37] and

Stereo- and regioselective hydroboration of 1-exo-methylene pyranoses: discovery of aryltriazolylmethyl C-galactopyranosides as selective galectin-1 inhibitors

• Alexander Dahlqvist,
• Axel Furevi,
• Niklas Warlin,
• Hakon Leffler and
• Ulf J. Nilsson

Beilstein J. Org. Chem. 2019, 15, 1046–1060, doi:10.3762/bjoc.15.102

• /bjoc.15.102 Abstract Galectins are carbohydrate recognition proteins that bind carbohydrates containing galactose and are involved in cell signaling and cellular interactions, involving them in several diseases. We present the synthesis of (aryltriazolyl)methyl galactopyranoside galectin inhibitors

• using a highly diastereoselective hydroboration of C1-exo-methylene pyranosides giving inhibitors with fourfold or better selectivity for galectin-1 over galectin-3, -4C (C-terminal CRD), -4N (N-terminal CRD), -7, -8C, -8N, -9C, and -9N and dissociation constants down to 170 µM. Keywords: C-galactoside

• uptake and breakdown, respectively. The association of galectins to cell signaling and adhesion gives them roles in several different pathological processes, such as pulmonary fibrosis [6][10], pathological lymphangiogenesis [11], inflammation [12] and cancer [13], with galectin inhibitors demonstrated

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

• Victoria V. Lipson,
• Tetiana L. Pavlovska,
• Nataliya V. Svetlichnaya,
• Anna A. Poryvai,
• Nikolay Yu. Gorobets,
• Erik V. Van der Eycken,
• Irina S. Konovalova,
• Svetlana V. Shiskina,
• Alexander V. Borisov,
• Vladimir I. Musatov and
• Alexander V. Mazepa

Beilstein J. Org. Chem. 2019, 15, 1032–1045, doi:10.3762/bjoc.15.101

• antagonists [8], cyclin-dependent kinases GSK-3β, CK1 [9] and nitric oxide synthase activity inhibitors [10][11], as well as antibacterial [2], antifungal [12], antihistamine [13] and antitumor activities [14]. Remarkable immunosuppressive properties are inherent to palau’amine (VI) [15]. Ceratamines XIII are

Heck- and Suzuki-coupling approaches to novel hydroquinone inhibitors of calcium ATPase

• Robert J. Kempton,
• Taylor A. Kidd-Kautz,
• Soizic Laurenceau and
• Stefan Paula

Beilstein J. Org. Chem. 2019, 15, 971–975, doi:10.3762/bjoc.15.94

• convey specificity for prostate cancer cells. Keywords: calcium ATPase inhibitors; Heck- and Suzuki-coupling reactions; hydroquinones; prostate cancer; tethered amino acid; Introduction Sarco/endoplasmic reticulum calcium ATPase (SERCA) is an integral protein that resides in the membrane of the

• sarcoplasmic reticulum (SR) within muscle cells. It transfers Ca2+ from the cytosol to the lumen of the SR at the expense of ATP hydrolysis. Specific inhibitors of SERCA are of significance to human health because of their well-documented value as research tools and their potential as novel anticancer agents

• [1][2]. The natural product thapsigargin (TG, 1a, Figure 1) is one of the most frequently used SERCA inhibitors because of its high specificity and potency. Both cancerous and healthy cells undergo apoptosis after exposure to low concentrations of TG, making TG a highly potent but nonselective

Towards the preparation of synthetic outer membrane vesicle models with micromolar affinity to wheat germ agglutinin using a dialkyl thioglycoside

• Dimitri Fayolle,
• Nathalie Berthet,
• Bastien Doumeche,
• Olivier Renaudet,
• Peter Strazewski and
• Michele Fiore

Beilstein J. Org. Chem. 2019, 15, 937–946, doi:10.3762/bjoc.15.90

• Fisher reaction between pyranoses and fatty alcohols of different lengths [8][9]. Alkyl thioglycosides are known for their properties as co-surfactants [10] and present interesting antimicrobial activities [11], acting as glycosidase inhibitors and being resistant towards glycoside hydrolases [12][13

New sesquiterpenoids from the South China Sea soft corals Clavularia viridis and Lemnalia flava

• Qihao Wu,
• Yuan Gao,
• Meng-Meng Zhang,
• Li Sheng,
• Jia Li,
• Xu-Wen Li,
• Hong Wang and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2019, 15, 695–702, doi:10.3762/bjoc.15.64

• bromine atom on the benzene ring may play the key functional role in the inhibitory activity. This study could thus provide a clue for the further biological study and structure modification of marine brominated laurane sesquiterpenoid derivatives towards new effective PTP1B and/or NF-κB inhibitors

Dirhodium(II)-catalyzed [3 + 2] cycloaddition of N-arylaminocyclopropane with alkyne derivatives

• Wentong Liu,
• Yi Kuang,
• Zhifan Wang,
• Jin Zhu and
• Yuanhua Wang

Beilstein J. Org. Chem. 2019, 15, 542–550, doi:10.3762/bjoc.15.48

• ciprofloxacin and moxifloxacin (Scheme 1), and reverse transcriptase inhibitors [2], such as nevirapine. Meanwhile, since 1 contains a three-membered ring with high tension [3][4][5][6] and a nitrogen prone to single-electron oxidation, ring opening readily occurs followed by N-centered radical formation. The

Selectivity in multiple multicomponent reactions: types and synthetic applications

• Ouldouz Ghashghaei,
• Francesca Seghetti and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2019, 15, 521–534, doi:10.3762/bjoc.15.46

• early example involves the synthesis of protease inhibitors by double Ugi 4CR using pyridine-2,6-dicarboxylic acid, isocyanides, amines and aldehydes (Scheme 2), and the combinatorial implications of this protocol were analyzed [6]. Ugi and Dömling soon realized the potential of such experiments, which

Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

• Constantinos G. Neochoritis,
• Maryam Kazemi Miraki,
• Eman M. M. Abdelraheem,
• Ewa Surmiak,
• Tryfon Zarganes-Tzitzikas,
• Beata Łabuzek,
• Tad A. Holak and
• Alexander Dömling

Beilstein J. Org. Chem. 2019, 15, 513–520, doi:10.3762/bjoc.15.45

• MDM2–p53 interaction could enable p53 and reverse tumor formation [26][27][28]. Based on our knowledge to antagonize the oncogenic protein–protein interaction p53–MDM2 [23][29][30][31][32][33][34][35][36][37][38][39][40] we designed macrocyclic inhibitors in continuation of our previous work [13][23

• indole-based macrocycles, a subset of them was screened searching for MDM2 inhibitors. Compared to our previous indole-based macrocycles 1 following a different strategy (employing a classical Ugi-4C as the key reaction) [23], this one-pot Ugi macrocyclization leading to macrocycles 2 offers speed (one

• basis of the evaluation of the current derivatives as potent inhibitors [33]. The indole moiety could be used not only to constrain the two other substituents but also as an “anchor” mimicking the Trp23. The bulky tert-butyl group would mimic the Phe19 and the macrocyclic ring would fill the Leu26 sub

Aqueous olefin metathesis: recent developments and applications

• Valerio Sabatino and
• Thomas R. Ward

Beilstein J. Org. Chem. 2019, 15, 445–468, doi:10.3762/bjoc.15.39

• the solid phase), this technology has been exploited to disrupt protein–protein interactions (PPIs) in cancer cells [94][95][96]. Aileron Therapeutics recently launched a stapled peptide platform aiming at developing molecules like ALRN-6924, a stapled peptide that interacts with p53 inhibitors MDMX

Asymmetric synthesis of a high added value chiral amine using immobilized ω-transaminases

• Antonella Petri,
• Valeria Colonna and
• Oreste Piccolo

Beilstein J. Org. Chem. 2019, 15, 60–66, doi:10.3762/bjoc.15.6

• mainly used for the synthesis of dipeptidyl peptidase IV (DPP-IV) inhibitors, such as alogliptin, linagliptin and other antidiabetic agents [15][17]. Over the years, numerous synthetic pathways were tested for the preparation of 3-aminopiperidine and its N-protected precursors in an optically active form

New standards for collecting and fitting steady state kinetic data

• Kenneth A. Johnson

Beilstein J. Org. Chem. 2019, 15, 16–29, doi:10.3762/bjoc.15.2

• -reciprocal plot, and including a kind of global analysis in resolving steady state inhibition patterns, which are defined by the effects of inhibitors on the slope and intercept, i.e., kcat and kcat/Km. However, there are serious disadvantages in using a double reciprocal plot due to the unequal weighting of

Cross metathesis-mediated synthesis of hydroxamic acid derivatives

• Shital Kumar Chattopadhyay,
• Subhankar Ghosh and
• Suman Sil

Beilstein J. Org. Chem. 2018, 14, 3070–3075, doi:10.3762/bjoc.14.285

• advantage. In continuation of our earlier studies [26][27] on HDAC inhibitors, we herein report a direct access to α,ß-unsaturated hydroxamates through cross-metathesis reaction. Results and Discussion It is known that a CM reaction between a class-I olefin and a class-II olefin proceeds better in the

• of the important cyclic peptide Chap-31 may encourage the preparation of cyclic peptide based HDAC inhibitors. The developed methodology may hence complement the existing literature on the preparation of such class of compounds and may find applications. Experimental General procedure for cross

Volatiles from the hypoxylaceous fungi Hypoxylon griseobrunneum and Hypoxylon macrocarpum

• Jan Rinkel,
• Alexander Babczyk,
• Tao Wang,
• Marc Stadler and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2018, 14, 2974–2990, doi:10.3762/bjoc.14.277

• mycotoxins [2], a class of highly bioactive secondary metabolites that belong to the strongest known inhibitors of protein biosynthesis in eukaryotes [3]. Similarly, the sesquiterpene aristolochene (2) is the parent hydrocarbon of PR toxin [4][5] and has been used as a marker to differentiate between toxin

Synthesis of indole–cycloalkyl[b]pyridine hybrids via a four-component six-step tandem process

• Muthumani Muthu,
• Rakkappan Vishnu Priya,
• Abdulrahman I. Almansour,
• Raju Suresh Kumar and
• Raju Ranjith Kumar

Beilstein J. Org. Chem. 2018, 14, 2907–2915, doi:10.3762/bjoc.14.269

• ]pyridine has been reported as inhibitors of cytochrome P450 [33]. Furthermore, muscopyridine is being used in perfume industry [34]. Among the several methods available for the synthesis of pyridines or cycloalkyl-fused pyridines [23][24][25][26][27][35][36][37][38][39][40][41][42][43][44], the one-pot

Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

• Laura Carro

Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

• to develop novel anti-infective drugs which can combat the ever-increasing rate of multidrug-resistant bacteria. This review describes the progress achieved towards the discovery of molecules that disrupt PPI systems in bacteria for which inhibitors have been identified and whose targets could

• interface in both Gram-negative and Gram-positive microorganisms. In order to encourage prospective drug discovery endeavours in this field, this study focuses on four examples of bacterial PPIs for which inhibitors with promising activities have been reported. For each of the targets the structural

• (bromodomain and extra terminal) molibresib (4, Figure 2), developed by GSK and currently in phase I for the treatment of several carcinomas [30]. It is also worth highlighting two PPI inhibitors that have recently been approved: lifitegrast (5, Figure 2) is an anti-inflammatory integrin antagonist that

Olefin metathesis catalysts embedded in β-barrel proteins: creating artificial metalloproteins for olefin metathesis

• Daniel F. Sauer,
• Johannes Schiffels,
• Takashi Hayashi,
• Ulrich Schwaneberg and
• Jun Okuda

Beilstein J. Org. Chem. 2018, 14, 2861–2871, doi:10.3762/bjoc.14.265

• active site from the protein easier as compared to supramolecular anchoring. However, the design of catalysts capable of undergoing dative anchoring is usually based on interactions of inhibitors with the active site of the protein. This makes the catalyst design challenging and the application is

Pd-Catalyzed microwave-assisted synthesis of phosphonated 13α-estrones as potential OATP2B1, 17β-HSD1 and/or STS inhibitors

• Rebeka Jójárt,
• Szabolcs Pécsy,
• György Keglevich,
• Mihály Szécsi,
• Réka Rigó,
• Csilla Özvegy-Laczka,
• Gábor Kecskeméti and
• Erzsébet Mernyák

Beilstein J. Org. Chem. 2018, 14, 2838–2845, doi:10.3762/bjoc.14.262

• the test compounds inhibited the STS markedly. The structure–activity relationship evaluation revealed that 2-substituted 3-hydroxy derivatives are able to inhibit the 17β-HSD1 enzyme with submicromolar IC50 values. Dual OATP2B1 and 17β-HSD1 inhibitors have been identified. Keywords: catalysis

• estrone derivatives, including estrone-3-sulfate could be blocked. Inhibitors based on the estrane core could have multiple inhibitory properties concerning the two enzymatic steps of the sulfatase pathway and OATP2B1-mediated membrane transport of estrone-sulfate. The inhibitor design is usually based on

• the substrate of the target protein. The literature reveals diverse synthetic estrone derivatives as STS or 17β-HSD1 inhibitors [1][14], but to the best of our knowledge, there are no reports on estrone-based OATP2B1 inhibitors. Note that estrone itself has been shown to slightly inhibit estrone-3

Synthesis of pyrrolidine-based hamamelitannin analogues as quorum sensing inhibitors in Staphylococcus aureus

• Jakob Bouton,
• Kristof Van Hecke,
• Reuven Rasooly and
• Serge Van Calenbergh

Beilstein J. Org. Chem. 2018, 14, 2822–2828, doi:10.3762/bjoc.14.260

• product hamamelitannin and several of its analogues have been identified as quorum sensing inhibitors. In this paper the synthesis of pyrrolidine-based analogues of a more lead-like hamamelitannin analogue is reported. A convergent synthetic route based on a key ring-closing metathesis reaction was

Synthesis of a tyrosinase inhibitor by consecutive ethenolysis and cross-metathesis of crude cashew nutshell liquid

• Jacqueline Pollini,
• Valentina Bragoni and
• Lukas J. Gooßen

Beilstein J. Org. Chem. 2018, 14, 2737–2744, doi:10.3762/bjoc.14.252

• neurodegenerative diseases [30]. Therefore, the study and development of tyrosinase inhibitors from renewable resources is of particular interest for research and industry [31][32]. Fu et al. investigated naturally occurring ginkgolic acids which they selectively synthesized from 2,6-dihydroxybenzoic acid (4), and

Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis

• Robby Vroemans,
• Yenthel Verhaegen,
• My Tran Thi Dieu and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2689–2697, doi:10.3762/bjoc.14.246

• -known biologically active analogs (Scheme 5) [3]. Pd-catalyzed reactions were effected on bromotriazolochromene 5e. The piperazin-1-ylchromenes have been identified to be potent inhibitors at the 5-HT1A receptor and at the 5-HT transporter [45][46]. Thus, Buchwald–Hartwig amination of 1-phenylpiperazine

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

• against the EC90 of (enantiopure) L-OOHL (10 nM). Only 4 compounds (3% of the library) were able to inhibit SdiA activity in S. Typhimurium by greater than 65% under these conditions (Figure 2). This is a lower percentage of inhibitors than we typically identify for this AHL analog library, even with the

• compounds, R8 displayed the greatest inhibitory activity in SdiA – inhibition to 120% with an IC50 of 44 μM. Interestingly, similar compounds with shorter tail lengths are potent inhibitors in other receptors: R6, with a 9-carbon tail, is a potent inhibitor of QscR and LasR, and Q9, with an 8-carbon tail

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

• coordinate population-wide group behaviours in the infection process like concerted secretion of virulence factors. One very important signalling network is the Pseudomonas quinolone signal (PQS) QS. With the aim to devise novel and innovative anti-infectives, inhibitors have been designed to address the

• network with compensatory mechanisms ensuring environmental adaptability and fine-tuned control of associated virulence genes (Figure 1). All four have been studied in the pursuit of quorum sensing inhibitors (QSI) to be used as blockers of P. aeruginosa pathogenicity [11][23]. Typically, a QS system of

• treatment. PqsA inhibitors Anthranilic acid analogues Since anthranilic acid (1) serves as a PqsA substrate, the first compound reported to inhibit PqsA is 6-FABA (2, Figure 3), which was able to block this enzyme and successfully suppressed the production of DHQ in PA14 strains at a rather high

Pathoblockers or antivirulence drugs as a new option for the treatment of bacterial infections

• Matthew B. Calvert,
• Varsha R. Jumde and
• Alexander Titz

Beilstein J. Org. Chem. 2018, 14, 2607–2617, doi:10.3762/bjoc.14.239

• potential (RIP), which is benchmarked with the reference methyl α-D-mannoside (1a) defined as RIP = 1, was increased up to 6900-fold [17]. The biphenyl mannosides (e.g., 4, 5) have subsequently been identified by the Ernst and Hultgren/Janetka groups as promising inhibitors of FimH-mediated bacterial

• that are interconnected by a hinge region. Interestingly, in vitro binding studies have been performed with the lectin domain only. Recent works suggested that the conformation of the two domains influence the protein’s affinity towards inhibitors and the biologically relevant state is a matter of

• , Titz et al. have developed small molecule LecB inhibitors derived from mannose and obtained potent monovalent inhibitors (compound 15) of LecB-mediated bacterial adhesion [47]. The sulfonamide 15 and cinnamide 16 were developed to take advantage of interactions with a nearby shallow pocket, and indeed