Fluorinated maleimide-substituted porphyrins and chlorins: synthesis and characterization

• Valentina A. Ol’shevskaya,
• Elena G. Kononova and
• Andrei V. Zaitsev

Beilstein J. Org. Chem. 2019, 15, 2704–2709, doi:10.3762/bjoc.15.263

• . Maleimides are considered as a biologically important scaffold that possess almost all types of biological activities including antibacterial and antifungal activity [24], anticancer activity [25], cox-2 inhibitor and anti-inflammatory, antidiabetic activity [26] and photodynamic activity [27]. Attaching of

Nanangenines: drimane sesquiterpenoids as the dominant metabolite cohort of a novel Australian fungus, Aspergillus nanangensis

• Heather J. Lacey,
• Cameron L. M. Gilchrist,
• Andrew Crombie,
• John A. Kalaitzis,
• Daniel Vuong,
• Peter J. Rutledge,
• Peter Turner,
• John I. Pitt,
• Ernest Lacey,
• Yit-Heng Chooi and
• Andrew M. Piggott

Beilstein J. Org. Chem. 2019, 15, 2631–2643, doi:10.3762/bjoc.15.256

• activity against human and murine tumour cell lines. This suggests that the regioisomeric lactone moiety could play an important role in the observed cytotoxicity. Interestingly, 3 (SF002-96-1 [4]) was previously shown to inhibit survivin, which is a member of the inhibitor of apoptosis (IAP) family and a

α,ß-Didehydrosuberoylanilide hydroxamic acid (DDSAHA) as precursor and possible analogue of the anticancer drug SAHA

• Shital K. Chattopadhyay,
• Subhankar Ghosh,
• Sarita Sarkar and
• Kakali Bhadra

Beilstein J. Org. Chem. 2019, 15, 2524–2533, doi:10.3762/bjoc.15.245

• refractory cutaneous T-cell lymphoma (CTCL) [3]. Moreover, it also shows anticancer activity against a large number of hematological and solid malignancies [4][5]. Its anticancer activity is related to inhibition of histone deacetylase inhibitor (HDACi) at nanomolar concentrations (IC50 < 86 nM). Although

• , originally recognized as a pan-inhibitor, recent studies have established that it is unable to inhibit Class IIA lysine deacetylases (HDAC/4/5/79), thus showing some selectivity profile [6][7]. Moreover, pan-inhibition is also a cause of increased concern due to adverse side effects [8]. The closely related

• hydroxamic acid derivative belinostat (2) is also approved for the treatment of peripheral T-cell lymphoma (PTCL) [9]. On the other hand, trichostatin A (3), containing an α,ß-unsaturated hydroxamic acid unit is the best known HDAC inhibitor which shows antifungal activities [10][11]. Because of the

Current understanding and biotechnological application of the bacterial diterpene synthase CotB2

• Ronja Driller,
• Daniel Garbe,
• Norbert Mehlmer,
• Monika Fuchs,
• Keren Raz,
• Dan Thomas Major,
• Thomas Brück and
• Bernhard Loll

Beilstein J. Org. Chem. 2019, 15, 2355–2368, doi:10.3762/bjoc.15.228

• -crystallized with AHD, a compound that mimics the diphosphate group of GGDP and acts as a suicide inhibitor. The crystal structure of CotB2wt·Mg2+3·AHD (PDB-ID 6GGJ; [37]) confirmed the active site architecture as observed in the structure of CotB2wt·Mg2+3·F-Dola and more importantly, that the folding of the C

Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors

• Christoph W. Grathwol,
• Nathalie Wössner,
• Sören Swyter,
• Adam C. Smith,
• Enrico Tapavicza,
• Robert K. Hofstetter,
• Anja Bodtke,
• Manfred Jung and
• Andreas Link

Beilstein J. Org. Chem. 2019, 15, 2170–2183, doi:10.3762/bjoc.15.214

• bioactivity, allows the probing of pharmacologically relevant systems with spatiotemporal resolution. A hetero-stilbene lead resulting from the screening of a compound that was originally designed as kinase inhibitor served as a starting point for the design of photoswitchable sirtuin inhibitors. Because the

• selective Sirt1 inhibitor, passed phase II clinical trials as a disease-modifying therapeutic for Huntington’s disease (HD) and was acquainted by AOP Orphan Pharmaceuticals AG for phase III trials in 2017 [9][10]. Its structure comprises a carboxamide moiety, which mimics the amide group of the endogenous

• pan-sirtuin inhibitor nicotinamide (Figure 1). Likewise Sirt2 inhibition was shown to have beneficial effects in animal and cell models of neurodegenerative diseases like HD and Parkinson’s disease [11][12]. Sirt3 activity recently was found to play an important role in cardiovascular diseases and

Characterization of two new degradation products of atorvastatin calcium formed upon treatment with strong acids

• Jürgen Krauß,
• Monika Klimt,
• Markus Luber,
• Peter Mayer and
• Franz Bracher

Beilstein J. Org. Chem. 2019, 15, 2085–2091, doi:10.3762/bjoc.15.206

• , Germany 10.3762/bjoc.15.206 Abstract Atorvastatin calcium (Lipitor®, Sortis®) is a well-established cholesterol synthesis enzyme (CSE) inhibitor commonly used in the therapy of hypercholesterolemia. This drug is known to be sensitive to acid treatment, but only little data has been published on the

Regioselective Pd-catalyzed direct C1- and C2-arylations of lilolidine for the access to 5,6-dihydropyrrolo[3,2,1-ij]quinoline derivatives

• Hai-Yun Huang,
• Haoran Li,
• Thierry Roisnel,
• Jean-François Soulé and
• Henri Doucet

Beilstein J. Org. Chem. 2019, 15, 2069–2075, doi:10.3762/bjoc.15.204

• ; Introduction Lilolidine (Figure 1, left), which is a commercially available compound, contains a 5,6-dihydropyrrolo[3,2,1-ij]quinoline skeleton found in several bioactive molecules. For example, tivantinib (Figure 1, middle) exhibits MET inhibitor properties [1]; whereas tarazepide (Figure 1, right) is being

Bipolenins K–N: New sesquiterpenoids from the fungal plant pathogen Bipolaris sorokiniana

• Chin-Soon Phan,
• Hang Li,
• Simon Kessler,
• Peter S. Solomon,
• Andrew M. Piggott and
• Yit-Heng Chooi

Beilstein J. Org. Chem. 2019, 15, 2020–2028, doi:10.3762/bjoc.15.198

• effects on cells infected with respiratory syncytial virus [22][23], induction of aerial mycelium formation in Fusarium culmorum [24], and as an inhibitor of ubiquinol-cytochrome c reductase binding protein, blocking mitochondrial ROS-mediated vascular endothelial growth factor receptor type 2 signalling

A review of the total syntheses of triptolide

• Xiang Zhang,
• Zaozao Xiao and
• Hongtao Xu

Beilstein J. Org. Chem. 2019, 15, 1984–1995, doi:10.3762/bjoc.15.194

• pathways involved in the regulation of reactive oxygen species (ROS) and/or nitric oxide (NO) [9], histone methyltransferase [10], HSP70 [11], Jak2, Bcl-2/Bax [12], caspase 8 [13], NF-κB [14], X-linked inhibitor of apoptosis protein (XIAP) [15], MAPK, PI3K [16], and MPK1, ERK-1/2, and JNK-1/2 [17]. The

Archangelolide: A sesquiterpene lactone with immunobiological potential from Laserpitium archangelica

• Silvie Rimpelová,
• Michal Jurášek,
• Lucie Peterková,
• Jiří Bejček,
• Vojtěch Spiwok,
• Miloš Majdl,
• Michal Jirásko,
• Miloš Buděšínský,
• Juraj Harmatha,
• Eva Kmoníčková,
• Pavel Drašar and
• Tomáš Ruml

Beilstein J. Org. Chem. 2019, 15, 1933–1944, doi:10.3762/bjoc.15.189

• evokes the synthesis of IL-6, INF-γ and TNF-α (see section “Abbreviations” at the end of the text). Furthermore, compound 2 has a very similar structure to the well-described SL thapsigargin, which is the best-known inhibitor of sarcoplasmic/endoplasmic reticular calcium ATPase (SERCA) with Ki values in

• reticulum and mitochondrial markers were performed. As it is apparent from Figure 3 and Figure S20 (Supporting Information File 1), compound 5 localized in the endoplasmic reticulum, which is in agreement with the site of localization of another SL, the SERCA inhibitor compound 2 [8]. However, we observed

• that this SL does not act as SERCA inhibitor. Therefore, we proceeded to confirm this hypothesis by a molecular dynamics simulation study. Molecular dynamics simulation of compounds 1 and 2 with SERCA The binding cavity for thapsigargin and compound 2 in the SERCA protein lies in the transmembrane

Installation of -SO₂F groups onto primary amides

• Jing Liu,
• Shi-Meng Wang,
• Njud S. Alharbi and
• Hua-Li Qin

Beilstein J. Org. Chem. 2019, 15, 1907–1912, doi:10.3762/bjoc.15.186

• binding sites (Figure 1) [20]. The smallest member of this family, methyl sulfonyl fluoride (MSF), is known as a selective and irreversible inhibitor of acetylcholinesterase (AChE) [21][22]. The sulfonyl fluoride inhibitors NSC 127755 was found for specifically modifying tyrosine-31 of DHFR in chicken

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

• )-7 (Scheme 6) which was found to be an effective inhibitor of the mitotic kinesin. The biologically active enantiomer of mexiletine (R)-24 was efficiently synthesized from the alcohol (2R,1'R)-7 (Scheme 7) [45]. When the respective tosylate (2R,1'R)-25 was treated with 2,6-dimethylphenoxide two

• protected diamine (R)-80a. Removal of the chiral auxiliary yielded the diamine (R)-80b which after acylation provided analogues (R)-76. Compound (R)-76 (R = C9H19) appeared inactive as inhibitor of human sphingosine kinases 1 and 2. 1,2-Diamino-3-hydroxy derivatives The interest in sphingoid analogues stems

• from the involvement of sphingolipid metabolites in an array of important cell processes. ᴅ-threo-PDMP (1R,2R)-81 is a ceramide analogue identified as an inhibitor of glucosylceramide synthase (GCS) at micromolar concentrations [66][67]. It was efficiently synthesized [68][69] employing the alcohol (2R

Synthesis of 9-O-arylated berberines via copper-catalyzed C_Ar–O coupling reactions

• Qiaoqiao Teng,
• Xinhui Zhu,
• Qianqian Guo,
• Weihua Jiang,
• Jiang Liu and
• Qi Meng

Beilstein J. Org. Chem. 2019, 15, 1575–1580, doi:10.3762/bjoc.15.161

• elaborate motifs such as heterocycles [10][11][12], glucose [13], nitric oxide [14], and the multidrug-resistance pump inhibitor 5-nitro-2-phenylindole (INF55) [15] have been covalently attached to BBR, further widening its pharmacological spectrum. Aromatic rings are another family of substituents having

Synthesis and biological evaluation of truncated derivatives of abyssomicin C as antibacterial agents

• Leticia Monjas,
• Peter Fodran,
• Johanna Kollback,
• Carlo Cassani,
• Thomas Olsson,
• Maja Genheden,
• D. G. Joakim Larsson and
• Carl-Johan Wallentin

Beilstein J. Org. Chem. 2019, 15, 1468–1474, doi:10.3762/bjoc.15.147

• covalent inhibitor of 4-amino-4-deoxychorismate (ADC) synthase, which is the enzyme that catalyzes the conversion of chorismate and glutamine into ADC and glutamate, the first step in the biosynthesis of p-aminobenzoic acid (PABA) in bacteria [6]. Specifically, AbC binds via a Michael addition between a

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of β-ketosulfones

• Alexander N. Reznikov,
• Anastasiya E. Sibiryakova,
• Marat R. Baimuratov,
• Eugene V. Golovin,
• Victor B. Rybakov and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2019, 15, 1289–1297, doi:10.3762/bjoc.15.127

• frequently used in the synthesis of organic fine chemicals and natural compounds. In addition to using the sulfonyl group as an auxiliary, it is also included in some chiral bioactive molecules, such as remikiren (1, renin inhibitor for the treatment of hypertension) [5][6], eletriptan (2, Relpax®, serotonin

• 5-HT1 receptor agonist for the treatment of migraine) [7], and apremilast (3, Otezla®, inhibitor of the PDE4 for the treatment of certain types of psoriasis and psoriatic arthritis) [8] (Figure 1). Recently we have shown that racemic sulfone 4 exhibits high antiviral activity against BVDV with low

Phylogenomic analyses and distribution of terpene synthases among Streptomyces

• Lara Martín-Sánchez,
• Kumar Saurabh Singh,
• Mariana Avalos,
• Gilles P. van Wezel,
• Jeroen S. Dickschat and
• Paolina Garbeva

Beilstein J. Org. Chem. 2019, 15, 1181–1193, doi:10.3762/bjoc.15.115

• the recombinant enzyme from Streptomyces malaysiensis [43]. The diterpene 7 is a precursor to the lysophospholipase inhibitor cyclooctatin (20) formed by the action of two genetically clustered cytochrome P450 monooxygenases CotB3 and CotB4 (Scheme 4) [40][44], while no derivatives from 8 are

Insertion of [1.1.1]propellane into aromatic disulfides

• Robin M. Bär,
• Gregor Heinrich,
• Martin Nieger,
• Olaf Fuhr and
• Stefan Bräse

Beilstein J. Org. Chem. 2019, 15, 1172–1180, doi:10.3762/bjoc.15.114

• ) [1]. In their pioneering work Stepan et al. replaced a para-substituted fluorophenyl ring in the γ-secretase inhibitor BMS-708,163 with a BCP whereby the oral absorption and in vitro metabolic stability could be significantly increased [2]. BCPs are usually derived from [1.1.1]propellane (1) [7

Synthesis of aryl cyclopropyl sulfides through copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid

• Emeline Benoit,
• Ahmed Fnaiche and
• Alexandre Gagnon

Beilstein J. Org. Chem. 2019, 15, 1162–1171, doi:10.3762/bjoc.15.113

• ]. Roniciclib, also named BAY 1000394, is a pan-cyclin-dependant kinase (CDK) inhibitor that contains an aryl cyclopropyl sulfoximine and that was developed to treat patients with untreated small cell lung cancer [6][9]. Aryl cyclopropyl sulfides 1 are also remarkable synthons in organic synthesis (Scheme 1

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

• most potent galectin-1 inhibitor 1b has at least fiftyfold better affinity than the reference monosaccharide methyl β-D-galactoside (11) and a similar affinity as the reference disaccharide methyl β-lactoside (12). Hence, the 4-fluorophenyltriazol moiety of 1b efficiently replaces the galectin-1

• -interacting glucose unit in methyl β-lactoside (12) and at the same time induces a significantly better selectivity than that of methyl β-lactoside (12). Taken together, the 4-fluorophenyltriazole 1b represents the most potent mono-galactoside-derived galectin-1 inhibitor, albeit with an apparently lower

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

• -dihydro analogs are represented only by several substances [33][34]. Partially hydrogenated pyrrolo[1,2-c]imidazole is a part of (±)-axinellamines 11. 4-[(5R)-6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]-3-fluorobenzonitrile (LCI-699, osilodrostat) is considered as an inhibitor of aldosterone synthase

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