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

• Abstract In this study, we explored Heck- and Suzuki-coupling methodology to modify the template 2,5-di-tert-butylhydroquinone (BHQ, 2), an inhibitor of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA). We found that by utilizing Suzuki coupling, we could successfully attach a six-carbon

• cytotoxic agent. The problem of concomitant toxicity to healthy cells has been circumvented by attaching a short peptide (His-Ser-Ser-Lys-Leu-Gln-Leu) to a tether at TG’s C-8 position (1b). This modification renders the inhibitor inactive [3]. Prostate cancer cells produce on their surface the serine

• inhibiting SERCA and preventing it from loading intracellular calcium stores. No other major proteases share the specificity of PSA, which prevents premature inhibitor activation in healthy cells. Moreover, as PSA is deactivated by inhibitors present in the blood serum, potential detrimental effects on other

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

• pH 7.4 containing 0.05% (v/v) Tween 20). This washing procedure was repeated after each incubation step. The coated microtiter plates were then blocked with BSA in PBS (3% w/v, 1 h at 37 °C, 100 μL per well). Serial two-fold dilutions of each inhibitor were pre-incubated 1 h at 37 °C in PBS-DMSO (9:1

• using the following equation, where A is absorbance. % Inhibition = [(A(no inhibitor) – A(with inhibitor)/A(no inhibitor)] × 100. The percent of inhibition was plotted against the logarithm of the concentration of the sugar derivatives. The sigmoidal curves were fitted and the concentration at 50

Synthesis of (macro)heterocycles by consecutive/repetitive isocyanide-based multicomponent reactions

• Angélica de Fátima S. Barreto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2019, 15, 906–930, doi:10.3762/bjoc.15.88

• synthesis of telaprevir 64, a protease inhibitor used in the treatment of hepatitis C, through a very short and efficient synthetic strategy involving as key steps two IMCRs (Ugi and Passerini) [28]. The strategy involved the synthesis of isocyanide 58 via a Passerini reaction using aldehyde 56, cyclopropyl

Efficient synthesis of pyrazolopyridines containing a chromane backbone through domino reaction

• Razieh Navari,
• Saeed Balalaie,
• Saber Mehrparvar,
• Fatemeh Darvish,
• Frank Rominger,
• Fatima Hamdan and
• Sattar Mirzaie

Beilstein J. Org. Chem. 2019, 15, 874–880, doi:10.3762/bjoc.15.85

• tracazolate, cartazolate, and etazolate [22]. Other pyrazolopyridine-containing bioactive compounds include a GSK-3 inhibitor [23] and BAY 41-2272, [24][25] and could be used as cardiovascular therapeutic agents (Figure 1). Moreover, pyrazolopyridine derivatives also have industrial importance as fluorophores

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

• PTP1B inhibitory assay, the inhibitory effects of compounds 1–8 were evaluated against PTP1B, and the result showed that compounds 1, 2 and 4 had a moderate PTP1B inhibitory activity with IC50 values of 18.8, 21.8 and 15.6 μM, respectively. The known PTP1B inhibitor oleanolic acid (IC50 = 3.0 μM) were

• inhibitor concentration [I] by using the following equation: % inhibition = 1/(1 + [IC50/[I]]k), where k is the Hill coefficient; IC50 ≥ 50 μM was considered inactive. NF-κB signaling pathway inhibitory activity assays NF-κB signaling pathway inhibitory activity was evaluated according to the previously

• 4 software (Graphpad, San Diego, CA) from the nonlinear curve fitting of the percentage of inhibition (% inhibition) versus the inhibitor concentration [I] by using the following equation: % inhibition = 100/(1 + [IC50/[I]]k), where k is the Hill coefficient. Bortezomib was used as a positive

Cyclopropene derivatives of aminosugars for metabolic glycoengineering

• Jessica Hassenrück and
• Valentin Wittmann

Beilstein J. Org. Chem. 2019, 15, 584–601, doi:10.3762/bjoc.15.54

Synthesis and SAR of the antistaphylococcal natural product nematophin from Xenorhabdus nematophila

• Frank Wesche,
• Hélène Adihou,
• Thomas A. Wichelhaus and
• Helge B. Bode

Beilstein J. Org. Chem. 2019, 15, 535–541, doi:10.3762/bjoc.15.47

• described as a potent inhibitor of various proteases, in particular trypsin and thrombin [17][18][19]. Hereby, the α-keto amide covalently binds to the serine oxygen in the active site under formation of a stable tetrahedral hemiketal. Furthermore, substitution of the indole hydrogen by alkyl, aryl or

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

• most of the human cancers have either mutated the p53 itself or the p53 pathway is inhibited. The latter group of tumors retains the wild type p53 (wt-p53) but its pathway is inactivated by negative regulators, mainly the MDM2 and MDMX proteins. Thus, the design and synthesis of an inhibitor of the

• Leu57. This pocket when filled with a smaller hydrophobic substituent such as -Cl boosts the inhibitor activity in accordance with literature [33]. Conclusion We effectively synthesized p53-MDM2 antagonists based on an artificial macrocyclic scaffold. 16 different derivatives were obtained and screened

• probing the subpockets of MDM2 and expansion of the chemistry compared to previous studies [13]. (A) Overlay of 1 H,15N-HSQC spectra of the reference MDM2 (red) and the titration steps with the 2i inhibitor. MDM2/2i ratios 4:1 (orange), 4:2 (yellow), 4:3 (green), 1:1 (light blue), 1:2 (blue), 1:5 (purple

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12

• Seema V. Kanojia,
• Sucheta Chatterjee,
• Subrata Chattopadhyay and
• Dibakar Goswami

Beilstein J. Org. Chem. 2019, 15, 490–496, doi:10.3762/bjoc.15.42

• (HPA-12, 1, Figure 1) as the first inhibitor of CERT-mediated ceramide transport [11]. However, the initially determined (1R,3R) configuration of the most active HPA-12 stereoisomer (compound 1, Figure 1) was later revised to (1R,3S) configuration (compound 2, Figure 1) by Berkeš et al. in 2011 [12

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

• [70]. α-Chymotrypsin is a serine protease that recognizes hydrophobic residues in one of its clefts. A modified HG-type catalyst (66) contains an L-phenyl chloromethyl ketone moiety that acts as inhibitor and is first recognized by supramolecular anchoring and then covalently attaches upon

• , entries 2, 7 and 12). Gebbink and co-workers anchored the HG-type catalyst 79 to cutinase, a serine hydrolase [75]. The phosphonate ester moiety acts as a suicide inhibitor forming an irreversible covalent bond to a serine residue present in the active site of the enzyme. Assembly of ArM 8 occurs at pH 5

Study on the regioselectivity of the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide

• Pedro N. Batalha,
• Luana da S. M. Forezi,
• Maria Clara R. Freitas,
• Nathalia M. de C. Tolentino,
• Ednilsom Orestes,
• José Walkimar de M. Carneiro,
• Fernanda da C. S. Boechat and
• Maria Cecília B. V. de Souza

Beilstein J. Org. Chem. 2019, 15, 388–400, doi:10.3762/bjoc.15.35

• eigenvalue in the Hessian second order matrix) [28][38][39][40][41]. Structures of some bioactive 4-oxoquinoline-3-carboxamide derivatives 1–4 with different bioactive profiles. Ki = binding affinity; AHA = acetohydroxamic acid (standard urease inhibitor); SAHA = suberoylanilide hydroxamic acid (an FDA

Synthesis and biological activity of methylated derivatives of the Pseudomonas metabolites HHQ, HQNO and PQS

• Sven Thierbach,
• Max Wienhold,
• Susanne Fetzner and
• Ulrich Hennecke

Beilstein J. Org. Chem. 2019, 15, 187–193, doi:10.3762/bjoc.15.18

• metabolites [16]. For example, Mycobacterium abscessus, which like P. aeruginosa and S. aureus can occur in the lung of cystic fibrosis patients [17][18][19], is able to methylate HQNO to give 2-heptyl-1-methoxy-4(1H)-quinolone (HMOQ). HMOQ is a significantly less efficient inhibitor of the respiratory chain

Computational characterization of enzyme-bound thiamin diphosphate reveals a surprisingly stable tricyclic state: implications for catalysis

• Ferran Planas,
• Michael J. McLeish and
• Fahmi Himo

Beilstein J. Org. Chem. 2019, 15, 145–159, doi:10.3762/bjoc.15.15

• inhibitor). Overall, the calculations reveal that the relative stabilities of the cofactor states are greatly affected by the presence and identity of the bound ligands. A surprising finding is that benzoylformate binding, while favoring ylide formation, provided even greater stabilization to a

• catalytically inactive tricyclic state. Conversely, the inhibitor binding greatly destabilized the ylide formation. Together, these observations have significant implications for the reaction kinetics of the ThDP-dependent enzymes, and, potentially, for the use of unnatural substrates in such reactions

• the substrate analog inhibitor, (R)-mandelate. In that study all intermediates and transition states were located and characterized. Intriguingly, we identified the tricyclic TCH+ state of the cofactor as an off-cycle intermediate species. It was found to be about 5 kcal/mol lower in energy than the

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

• recently been approved or reached clinical validation can be found in Figure 2. If we analyze their mechanism of action, nearly all of them are currently being investigated as oncological treatments. For example, navitoclax (1, Figure 2), a Bcl-2/Bcl-XL inhibitor developed by Abbot Laboratories is

• ]. LCL-161 (3, Figure 2), an inhibitor of the interaction between Smac (second mitochondria-derived activator of caspases) and IAP (inhibitor of apoptosis proteins) developed by Novartis, has recently entered phase II for the treatment of leukaemia [29]. Another example is the inhibitor of the BET

• disrupts the LFA-1/ICAM-1 interaction used for the treatment of dry eye disease [31][32], and tirofiban (6, Figure 2), a platelet glycoprotein IIb/IIIa inhibitor indicated in acute coronary syndrome [33]. In addition to small molecules, natural products have been shown to be able to modulate protein

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

• 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

• -sulfate uptake by OATP2B1 [6]. None of the steroidal STS or 17β-HSD1 inhibitors reached the clinical trial, which is mainly due to their retained estrogenic activity. This side-effect could be eliminated by the inhibitor design based on the 13-epimer of natural estrone (13α-estrone, 13αE1OH) [17][18

• of the steroid to the transporter protein. Additionally, inhibitory potencies of the newly-synthesized compounds on human placental STS and 17β-HSD1 have been tested in vitro (Table 3). None of the newly-synthesized derivatives proved to be a potent STS inhibitor, since the compounds suppressed the

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

• ), an inhibitor of the RAP/TRAP (RNAIII-activating protein/target of RAP) quorum sensing system in S. aureus (Figure 1) [12][13][14]. Furthermore, hamamelitannin has been shown to inhibit biofilm formation and to potentiate the activity of antibiotics against staphylococcal biofilms in vitro and in vivo

• optimal side chain substituents are an o-chlorobenzamide on the 5-position and a non-substituted benzamide on the 2’-position. In absence of any structural information of the inhibitor–target interaction, we were interested in replacing the core tetrahydrofuran scaffold by a pyrrolidine ring in order to

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

• Jacqueline Pollini Valentina Bragoni Lukas J. Goossen Lehrstuhl für Organische Chemie I, Ruhr-Universität Bochum, ZEMOS, Universitätsstraße 150, 44801 Bochum, Germany 10.3762/bjoc.14.252 Abstract A convenient and sustainable three-step synthesis of the tyrosinase inhibitor 2-hydroxy-6

• subsequent hydrogenation step. Overall, the target compound was obtained in an overall yield of 61% based on the unsaturated anacardic acid content and 34% based on the crude CNSL. Keywords: cashew nutshell liquid; cross-metathesis; renewable feedstock; sustainable chemistry; tyrosinase inhibitor

• synthesis of the most potent tyrosinase inhibitor among them, the ginkgolic acid (13:0), starting from crude CNSL (Scheme 1, left). Tyrosinase is an enzyme [28] which is responsible for browning of fruits and vegetables as well as skin pigmentation [29]. Furthermore, it is linked to several

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

• 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

• , is a potent inhibitor of QscR [64]. A set of other compounds containing aryl tails with large substituents (such as Br, I, and SCH3) also partially inhibit SdiA; specifically, thiolactone 16 (mBTL), which has a long (4 atom) linker between the amide and phenyl, inhibited SdiA activity by 89% with an

• sub-micromolar IC50 (318 nM). Compound 11 was originally designed by the Meijler lab to react with a cysteine in the AHL-binding pocket of LasR, thereby acting as an irreversible inhibitor [44]. SdiA does have a cysteine in the binding pocket (Cys45, see Figure 1D), but it is positioned near carbons 3

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

• intermediate between PqsD and anthraniloyl-CoA [54]. Upon simplification and rigidification through reduction in size as well as removal of rotatable bonds inhibitor 13 was obtained carrying the characteristic secondary alcohol of this class. Notably, both enantiomers of 13 show similar potency, but different

• the substrate tunnel [57]. The binding models of the ureidothiophene and nitrophenylmethanol classes even allowed for the generation of a merged inhibitor [58]. One major liability of this class, however, was the general inefficacy in whole cell assays, which could not be improved, even through the

• ]. Starting from a PqsR inhibitor, changes of the electronic properties on the benzimidazole by introducing an electron-donating group led to a higher PqsBC inhibitory activity, while decreasing the affinity to PqsR (compound 28). Nevertheless, it was shown that blockage of PqsBC leads to a reduction of HHQ

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

• of LecA with its electrophilic epoxide warhead [40]. It could be demonstrated that 11 is a covalent lectin inhibitor, which provided the first proof-of-concept for this new approach to lectin inhibition. To date, the most potent LecA inhibitor 12 has been designed by the Pieters group, where two

Microwave-assisted synthesis of biologically relevant steroidal 17-exo-pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence

• Gergő Mótyán,
• László Mérai,
• Márton Attila Kiss,
• Zsuzsanna Schelz,
• Izabella Sinka,
• István Zupkó and
• Éva Frank

Beilstein J. Org. Chem. 2018, 14, 2589–2596, doi:10.3762/bjoc.14.236

• hormones, and therefore, in the development of prostate cancer [1]. According to extensive structure–activity relationship and docking studies, a potent steroidal inhibitor should possess certain structural characteristics for efficient P45017α inhibition [1][2][3], such as (i) a five or six-membered non

Synthesis of 3-aminocoumarin-N-benzylpyridinium conjugates with nanomolar inhibitory activity against acetylcholinesterase

• Nisachon Khunnawutmanotham,
• Cherdchai Laongthipparos,
• Patchreenart Saparpakorn,
• Nitirat Chimnoi and
• Supanna Techasakul

Beilstein J. Org. Chem. 2018, 14, 2545–2552, doi:10.3762/bjoc.14.231

• potent activities with inhibitory concentration (IC50) values in the nanomolar concentration range. Among them, the 2,3-difluorobenzylpyridinium-containing compound was the most potent inhibitor with an IC50 value of 1.53 ± 0.01 nM. Docking studies revealed that the synthesized compounds inhibit the

• target enzyme by a dual binding site mechanism whereby the coumarin portion binds with the peripheral anionic site while the N-benzylpyridinium residue binds with the catalytic anionic site of the enzyme. Keywords: acetylcholinesterase inhibitor; 3-aminocoumarin; N-benzylpyridinium; dual binding site

• inhibitor; synthesis; Introduction An increasing number of countries are facing a rapid growth of the elderly population. The birth rates of many countries, such as China, Japan, and Thailand are lower than the number theoretically required for the replacement of successive generations, resulting in an

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

• =Aoa) could be attributed to the presence of butyrate, which has been demonstrated to inhibit the proliferation as well as to induce apoptosis and cell cycle arrest in different cell lines (e.g., colon carcinoma, melanoma, T-cell lymphoma) as a histone deacetylase inhibitor and/or via activation of

Synthesis of 1,4-imino-L-lyxitols modified at C-5 and their evaluation as inhibitors of GH38 α-mannosidases

• Maroš Bella,
• Sergej Šesták,
• Ján Moncoľ,
• Miroslav Koóš and
• Monika Poláková

Beilstein J. Org. Chem. 2018, 14, 2156–2162, doi:10.3762/bjoc.14.189

• swainsonine, interferes with the glycosylation pathway where it specifically inhibits GH38 glycoside hydrolases [23][24]. Up to date, swainsonine is the most potent Golgi mannosidase II (GMII) inhibitor. It is known that inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences

• structure and related pyrrolidines are of particular interest as potential candidates for cancer treatment [26][27]. Our research interest has been focused on searching for efficient inhibitors of α-mannosidases from the GH38 family. Another important feature required for such a potential inhibitor is its

Synthesis of trifluoromethylated 2H-azirines through Togni reagent-mediated trifluoromethylation followed by PhIO-mediated azirination

• Jiyun Sun,
• Xiaohua Zhen,
• Huaibin Ge,
• Guangtao Zhang,
• Xuechan An and
• Yunfei Du

Beilstein J. Org. Chem. 2018, 14, 1452–1458, doi:10.3762/bjoc.14.123

• agents [7][8][9][10][11][12][13][14][15][16]. For example, fluoxetine hydrochloride (Figure 1, A) [4][9][10] (Prozac®, an antidepressant and a selective serotonin reuptake inhibitor for the treatment of major depressive disorders, obsessive–compulsive disorders, etc.), teriflunomide (Figure 1, B) [11][12