Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14
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Graphical contents list ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14
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Selective GPCR ligands ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Peter Gmeiner
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GPCR crystal structures: Medicinal chemistry in the pocket ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Jeremy Shonberg , Ralf C. Kling , Peter Gmeiner , Stefan Löber Recent breakthroughs in GPCR structural biology have significantly increased our understanding of drug action at these therapeutically relevant receptors, and this will undoubtedly lead to the design of better therapeutics. In recent years, crystal structures of GPCRs from classes A, B, C and F have been solved, unveiling a precise snapshot of ligand–receptor interactions. Furthermore, some receptors have been crystallized in different functional states in complex with antagonists, partial agonists, full agonists, biased agonists and allosteric modulators, providing further insight into the mechanisms of ligand-induced GPCR activation. It is now obvious that there is enormous diversity in the size, shape and position of the ligand binding pockets in GPCRs. In this review, we summarise the current state of solved GPCR structures, with a particular focus on ligand–receptor interactions in the binding pocket, and how this can contribute to the design of GPCR ligands with better affinity, subtype selectivity or efficacy. Graphical abstract image
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Structure versus function—The impact of computational methods on the discovery of specific GPCR–ligands ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Marcel Bermudez , Gerhard Wolber Over the past decades, computational methods have become invaluable for drug design campaigns but also as auxiliary tool for structural biology. The combination of experimental and in silico methods in the field of G protein coupled receptors (GPCRs) is indispensable. Despite recent groundbreaking achievements in GPCR crystallography, structural information for the vast majority of this physiologically important protein class is only accessible through homology models. Since the understanding of the conformational changes resulting in multiple activation pathways is incomplete, the design of specific GPCR modulating drugs remains a major challenge. However, due to the highly interdisciplinary requirements for the investigation of receptor function and the necessity of joining scientist from different fields, computational approaches gain importance in rationalizing and illustrating certain specific effects. In silico methods, such as molecular dynamics (MD) simulations, pharmacophore modeling or docking, proved to be suitable to complement experimental approaches. In this review, we highlight recent examples of in silico studies that were successfully applied in the field of GPCR research. Those approaches follow two main goals: Firstly, structural investigations that help to understand the receptor function and the characterization of ligand binding and secondly the identification of novel GPCR modulators as potential drugs. Graphical abstract image
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Novel 3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]propanamides as selective agonists of human formyl-peptide receptor 2 ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Enza Lacivita , Igor A. Schepetkin , Madia L. Stama , Liliya N. Kirpotina , Nicola A. Colabufo , Roberto Perrone , Andrei I. Khlebnikov , Mark T. Quinn , Marcello Leopoldo N-Formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) that play critical roles in inflammatory reactions, and FPR-specific interactions can possibly be used to facilitate the resolution of pathological inflammatory reactions. We here report the synthesis and biological evaluation of six pairs of chiral ureidopropanamido derivatives as potent and selective formyl peptide receptor-2 (FPR2) agonists that were designed starting from our lead agonist (S)-3-(1H-indol-3-yl)-2-[3-(4-methoxyphenyl)ureido]-N-[[1-(5-methoxy-2-pyridinyl)cyclohexyl]methyl]propanamide ((S)-9a). The new compounds were obtained in overall yields considerably higher than (S)-9a. Several of the new compounds showed agonist properties comparable to that of (S)-9a along with higher selectivity over FPR1. Molecular modeling was used to define chiral recognition by FPR2. In vitro metabolic stability of selected compounds was also assessed to obtain preliminary insight on drug-like properties of this class of compounds. Graphical abstract image
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High metabolic in vivo stability and bioavailability of a palmitoylated ghrelin receptor ligand assessed by mass spectrometry ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Katja B. Kostelnik , Sylvia Els-Heindl , Nora Klöting , Sven Baumann , Martin von Bergen , Annette G. Beck-Sickinger The constitutive activity of the ghrelin receptor is of high physiological and pathophysiological relevance. In-depth structure–activity relationship studies revealed a palmitoylated ghrelin receptor ligand that displays an in vitro binding affinity in the low nanomolar range. Activity studies revealed inverse agonistic as well as antagonistic properties and in vitro metabolic analysis indicated a high stability in blood serum and liver homogenate. For metabolic testing in vivo, a combined approach of stable isotopic labeling and mass spectrometry-based analysis was established. Therefore, a heavy isotopic version of the peptide containing a 13C-labeled palmitic acid was synthesized and a 1:1 ratio of a 12C/13C-peptide mixture was injected into rats. Biological samples were analyzed by multiple reaction monitoring allowing simultaneous peptide detection and quantification. Measurements revealed a suitable bioavailability over 24h in rat serum and subsequent high-resolution mass spectrometry investigations showed only negligible degradation and slow body clearance. Hence, this method combination allowed the identification and evaluation of a highly potent and metabolically stable ghrelin receptor ligand in vivo. Graphical abstract image
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Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Martin Hansen , Stine Engesgaard Jacobsen , Shane Plunkett , Gudrun Eckhard Liebscher , John D. McCorvy , Hans Bräuner-Osborne , Jesper Langgaard Kristensen N-Benzyl substitution of phenethylamine 5-HT2A receptor agonists has dramatic effects on binding affinity, receptor selectivity and agonist activity. In this paper we examine how affinity for the 5-HT2A/2C receptors are influenced by N-benzyl substitution of 4-bromo-2,5-dimethoxyphenethylamine derivatives. Special attention is given to the 2′ and 3′-position of the N-benzyl as such compounds are known to be very potent. We found that substitutions in these positions are generally well tolerated. The 2′-position was further examined using a range of substituents to probe the hydrogen bonding requirements for optimal affinity and selectivity, and it was found that small changes in the ligands in this area had a profound effect on their affinities. Furthermore, two ligands that lack a 2′-benzyl substituent were also found to have high affinity contradicting previous held notions. Several high-affinity ligands were identified and assayed for functional activity at the 5-HT2A and 5-HT2C receptor, and they were generally found to be less efficacious agonists than previously reported N-benzyl phenethylamines. Graphical abstract image
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Fluoro-substituted phenylazocarboxamides: Dopaminergic behavior and N-arylating properties for irreversible binding ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Amelie L. Bartuschat , Tamara Schellhorn , Harald Hübner , Peter Gmeiner , Markus R. Heinrich Phenylazocarboxamides can serve as bioisosteres for cinnamides, which are widely occurring substructures in medicinal chemistry. Starting from our lead compound 2, the introduction of additional fluoro substituents and the exchange of the methoxyphenylpiperazine head group by an aminoindane moiety was investigated resulting in dopamine D3 receptor antagonists and agonists with K i values in the sub- and low-nanomolar range. As a potentially irreversible ligand, the 3,4,5-trifluoro-substituted phenylazocarboxamide 7 was investigated for its N-arylating properties by incubation with the protected lysine analog 18 and with the L89K mutant of the dopamine D3 receptor. Whereas covalent bond formation with the lysine unit in TM2 of D3 could not be detected, substantial N-arylation of the side chain of the model compound 18 has been observed. Graphical abstract image
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Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Kevin J. Frankowski , Stephen R. Slauson , Kimberly M. Lovell , Angela M. Phillips , John M. Streicher , Lei Zhou , David A. Whipple , Frank J. Schoenen , Thomas E. Prisinzano , Laura M. Bohn , Jeffrey Aubé Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure–activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists. Graphical abstract image
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Dimeric carbamoylguanidine-type histamine H2 receptor ligands: A new class of potent and selective agonists ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Nicole Kagermeier , Kristin Werner , Max Keller , Paul Baumeister , Günther Bernhardt , Roland Seifert , Armin Buschauer The bioisosteric replacement of the acylguanidine moieties in dimeric histamine H2 receptor (H2R) agonists by carbamoylguanidine groups resulted in compounds with retained potencies and intrinsic activities, but considerably improved stability against hydrolytic cleavage. These compounds achieved up to 2500 times the potency of histamine when studied in [35S]GTPγS assays on recombinant human and guinea pig H2R. Unlike 3-(imidazol-4-yl)propyl substituted carbamoylguanidines, the corresponding 2-amino-4-methylthiazoles revealed selectivity over histamine receptor subtypes H1R, H3R and H4R in radioligand competition binding studies. H2R binding studies with three fluorescent compounds and one tritium-labeled ligand, synthesized from a chain-branched precursor, failed due to pronounced cellular accumulation and high non-specific binding. However, the dimeric H2R agonists proved to be useful pharmacological tools for functional studies on native cells, as demonstrated for selected compounds by cAMP accumulation and inhibition of fMLP-stimulated generation of reactive oxygen species in human monocytes. Graphical abstract image
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M2 Subtype preferring dibenzodiazepinone-type muscarinic receptor ligands: Effect of chemical homo-dimerization on orthosteric (and allosteric?) binding ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Max Keller , Christian Tränkle , Xueke She , Andrea Pegoli , Günther Bernhardt , Armin Buschauer , Roger W. Read A series of new dibenzodiazepinone-type muscarinic receptor ligands, including two homo-dimeric compounds, was prepared. Sixteen representative compounds were characterized in equilibrium binding studies with [3H]N-methylscopolamine ([3H]NMS) at the muscarinic receptor subtype M2, and seven selected compounds were additionally investigated at M1, M3, M4 and M5 with respect to receptor subtype selectivity. The side chain of the known M2 preferring muscarinic receptor antagonist DIBA was widely varied with respect to chain length and type of the basic group (amine, imidazole, guanidine and piperazine). Most of the structural changes were well tolerated with respect to muscarinic receptor binding, determined by displacement of [3H]NMS. Compounds investigated at all subtypes shared a similar selectivity profile, which can be summarized as M2 >M1 ≈M4 >M3 ≈M5 (46, 50, 57, 62–64) and M2 >M1 ≈M4 >M3 >M5 (1, 58). The homo-dimeric dibenzodiazepinone derivatives UNSW-MK250 (63) and UNSW-MK262 (64) exhibited the highest M2 receptor affinities (pIC50 =9.0 and 9.2, respectively). At the M2 receptor a steep curve slope of −2 was found for the dimeric ligand 63, which cannot be described according to the law of mass action, suggesting a more complex mechanism of binding. In addition to equilibrium binding studies, for selected ligands, we determined pEC50,diss, an estimate of affinity to the allosteric site of M2 receptors occupied with [3H]NMS. Compounds 58 and 62–64 were capable of retarding [3H]NMS dissociation by a factor >10 (E max,diss >92%), with highest potency (pEC50,diss =5.56) residing in the dimeric compound 64. As the monomeric counterpart of 64 was 100 times less potent (62: pEC50,diss =3.59), these data suggest that chemical dimerization of dibenzodiazepinone-type M receptor ligands can enhance allosteric binding. Graphical abstract image
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Cell-based and virtual fragment screening for adrenergic α2C receptor agonists ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Edit Szőllősi , Amrita Bobok , László Kiss , Márton Vass , Dalma Kurkó , Sándor Kolok , András Visegrády , György M. Keserű Fragment-based drug discovery has emerged as an alternative to conventional lead identification and optimization strategies generally supported by biophysical detection techniques. Membrane targets like G protein-coupled receptors (GPCRs), however, offer challenges in lack of generic immobilization or stabilization methods for the dynamic, membrane-bound supramolecular complexes. Also modeling of different functional states of GPCRs proved to be a challenging task. Here we report a functional cell-based high concentration screening campaign for the identification of adrenergic α2C receptor agonists compared with the virtual screening of the same ligand set against an active-like homology model of the α2C receptor. The conventional calcium mobilization-based assay identified active fragments with a similar incidence to several other reported fragment screens on GPCRs. 16 out of 3071 screened fragments turned out as specific ligands of α2C, two of which were identified by virtual screening as well and several of the hits possessed surprisingly high affinity and ligand efficiency. Our results indicate that in vitro biological assays can be utilized in the fragment hit identification process for GPCR targets. Graphical abstract image
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Using click chemistry toward novel 1,2,3-triazole-linked dopamine D3 receptor ligands ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Thomas M. Keck , Ashwini K. Banala , Rachel D. Slack , Caitlin Burzynski , Alessandro Bonifazi , Oluyomi M. Okunola-Bakare , Martin Moore , Jeffrey R. Deschamps , Rana Rais , Barbara S. Slusher , Amy Hauck Newman The dopamine D3 receptor (D3R) is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, Parkinson’s disease, restless leg syndrome, and drug addiction. A common molecular template used in the development of D3R-selective antagonists and partial agonists incorporates a butylamide linker between two pharmacophores, a phenylpiperazine moiety and an extended aryl ring system. The series of compounds described herein incorporates a change to that chemical template, replacing the amide functional group in the linker chain with a 1,2,3-triazole group. Although the amide linker in the 4-phenylpiperazine class of D3R ligands has been previously deemed critical for high D3R affinity and selectivity, the 1,2,3-triazole moiety serves as a suitable bioisosteric replacement and maintains desired D3R-binding functionality of the compounds. Additionally, using mouse liver microsomes to evaluate CYP450-mediated phase I metabolism, we determined that novel 1,2,3-triazole-containing compounds modestly improves metabolic stability compared to amide-containing analogues. The 1,2,3-triazole moiety allows for the modular attachment of chemical subunit libraries using copper-catalyzed azide-alkyne cycloaddition click chemistry, increasing the range of chemical entities that can be designed, synthesized, and developed toward D3R-selective therapeutic agents. Graphical abstract image
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Affinity and kinetics study of anthranilic acids as HCA2 receptor agonists ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Jacobus P.D. van Veldhoven , Rongfang Liu , Stephanie A. Thee , Yessica Wouters , Sanne J.M. Verhoork , Christiaan Mooiman , Julien Louvel , Adriaan P. IJzerman Structure–affinity relationship (SAR) and structure–kinetics relationship (SKR) studies were combined to investigate a series of biphenyl anthranilic acid agonists for the HCA2 receptor. In total, 27 compounds were synthesized and twelve of them showed higher affinity than nicotinic acid. Two compounds, 6g (IC50 =75nM) and 6z (IC50 =108nM) showed a longer residence time profile compared to nicotinic acid, exemplified by their kinetic rate index (KRI) values of 1.31 and 1.23, respectively. The SAR study resulted in the novel 2-F, 4-OH derivative (6x) with an IC50 value of 23nM as the highest affinity HCA2 agonist of the biphenyl series, although it showed a similar residence time as nicotinic acid. The SAR and SKR data suggest that an early compound selection based on binding kinetics is a promising addition to the lead optimization process. Graphical abstract image
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Improved radiosynthesis and preliminary in vivo evaluation of a 18F-labeled glycopeptide–peptoid hybrid for PET imaging of neurotensin receptor 2 ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Simone Maschauer , Cornelia Greff , Jürgen Einsiedel , Julian Ott , Philipp Tripal , Harald Hübner , Peter Gmeiner , Olaf Prante The neurotensin receptor 2 (NTS2) is an attractive target for cancer imaging, as it is overexpressed in a variety of tumor types including prostate, pancreas and breast carcinoma. The aim of this study was the development of the first NTS2 subtype selective 18F-labeled radioligand for imaging NTS2 expression in vivo by positron emission tomography (PET). The radiosynthesis of glycopeptoid 18 F-4 was realized by copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC), applying the prosthetic group 6-deoxy-6-[18F]fluoroglucosyl azide for 18F-fluoroglycosylation of the alkyne-terminated NT(8–13) analog Pra-N-Me-Arg-Arg-Pro-N-homo-Tyr-Ile-Leu-OH. The binding affinity of the peptide–peptoid 4 for NTS2 was 7nM with excellent subtype selectivity over NTS1 (260-fold). In vitro autoradiography studies of rat brain slices confirmed the high selectivity of 18 F-4 for NTS2. Biodistribution experiments using HT29 and PC3 tumor-bearing nude mice revealed high renal and only moderate tumor uptake, while PET imaging experiments revealed specific binding of 18F-4 in NTS2-positive tumors. As 18F-4 displayed high stability in vitro but fast degradation in vivo, future work will focus on the development of metabolically more stable NT(8–13) analogs. Graphical abstract image
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Synthesis and biological evaluation of spirocyclic antagonists of CCR2 (chemokine CC receptor subtype 2) ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Ann Kathrin Strunz , Annelien J.M. Zweemer , Christina Weiss , Dirk Schepmann , Anna Junker , Laura H. Heitman , Michael Koch , Bernhard Wünsch Activation of chemokine CC receptors subtype 2 (CCR2) plays an important role in chronic inflammatory processes such as atherosclerosis, multiple sclerosis and rheumatoid arthritis. A diverse set of spirocyclic butanamides 4 (N-benzyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4′-piperidin]-1′-yl)butanamides) was prepared by different combination of spirocyclic piperidines 8 (3,4-dihydrospiro[[2]benzopyran-1,4′-piperidines]) and γ-halobutanamides 11. A key step in the synthesis of spirocyclic piperidines 8 was an Oxa-Pictet–Spengler reaction of β-phenylethanols 5 with piperidone acetal 6. The substituted γ-hydroxybutanamides 11c–e were prepared by hydroxyethylation of methyl acetates 13 with ethylene sulfate giving the γ-lactones 14c and 14e. Aminolysis of the γ-lactones 14c and 14e with benzylamines provided the γ-hydroxybutanamides 15c–e, which were converted into the bromides 11c–e by an Appel reaction using polymer-bound PPh3. In radioligand binding assays the spirocyclic butanamides 4 did not displace the iodinated radioligand 125I-CCL2 from the human CCR2. However, in the Ca2+-flux assay using human CCR2 strong antagonistic activity of butanamides 4 was detected. Analysis of the IC50-values led to clear relationships between the structure and the inhibition of the Ca2+-flux. 4g (4-(3,4-dihydrospiro[[2]benzopyran-1,4′-piperidin]-1′-yl)-N-[3,5-bis(trifluoromethylbenzyl)]-2-(4-fluorophenyl)butanamide) and 4o (N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4′-piperidin]-1′-yl)butanamide) represent the most potent CCR2 antagonists with IC50-values of 89 and 17nM, respectively. Micromolar activities were found in the β-arrestin recruitment assay with murine CCR2, but the structure–activity-relationships detected in the Ca2+-flux assay were confirmed. Graphical abstract image
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Ligand selectivity of a synthetic CXCR4 mimetic peptide ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Andrea Groß , Regine Brox , Dominik Damm , Nuška Tschammer , Barbara Schmidt , Jutta Eichler The chemokine receptor CXCR4 belongs to the family of seven-transmembrane G-protein coupled receptors (GPCRs). It is activated by its natural ligand SDF-1α. In addition, CXCR4, along with CCR5, serve as coreceptors during HIV-1 entry into its target cell. Recently, we introduced a CXCR4 mimetic peptide, termed CX4-M1, which presents the three extracellular loops (ECLs) of the receptor. CX4-M1 was shown to selectively bind to gp120 of X4-tropic, that is, CXCR4 using, HIV-1, as well as to peptides that present the V3-loops of these gp120 proteins. Furthermore, CX4-M1 selectively inhibits infection of cells with X4-tropic HIV-1. We have now adapted the sequence of the ECLs presented by CX4-M1 to the recently published crystal structure of CXCR4. The binding behavior, as well as the effect on HIV-1 infection, of the resulting peptide (CX4-Mc) was very similar to CX4-M1, validating retrospectively the original design of CX4-M1. A peptide presenting the ECLs of CCR5 (CR5-M), on the other hand, did neither bind to gp120 from X4-tropic HIV-1, nor did it inhibit infection of cells with X4-tropic HIV-1. Furthermore, we could show that CX4-M1, as well as CX4-Mc, but not CR5-M, are selectively recognized by anti-CXCR4 antibodies, bind to SDF-1α, and also inhibit SDF-1α signaling, extending the scope of selective functional CXCR4 mimicry through CX4-M1. Graphical abstract image
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Molecular modeling of the human P2Y14 receptor: A template for structure-based design of selective agonist ligands ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Kevin Trujillo , Silvia Paoletta , Evgeny Kiselev , Kenneth A. Jacobson The P2Y14 receptor (P2Y14R) is a Gi protein-coupled receptor that is activated by uracil nucleotides UDP and UDP-glucose. The P2Y14R structure has yet to be solved through X-ray crystallography, but the recent agonist-bound crystal structure of the P2Y12R provides a potentially suitable template for its homology modeling for rational structure-based design of selective and high-affinity ligands. In this study, we applied ligand docking and molecular dynamics refinement to a P2Y14R homology model to qualitatively explain structure–activity relationships of previously published synthetic nucleotide analogues and to probe the quality of P2Y14R homology modeling as a template for structure-based design. The P2Y14R model supports the hypothesis of a conserved binding mode of nucleotides in the three P2Y12-like receptors involving functionally conserved residues. We predict phosphate group interactions with R2536.55, K2777.35, Y2566.58 and Q2606.62, nucleobase (anti-conformation) π–π stacking with Y1023.33 and the role of F1915.42 as a means for selectivity among P2Y12-like receptors. The glucose moiety of UDP-glucose docked in a secondary subpocket at the P2Y14R homology model. Thus, P2Y14R homology modeling may allow detailed prediction of interactions to facilitate the design of high affinity, selective agonists as pharmacological tools to study the P2Y14R. Graphical abstract image
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Understanding allosteric interactions in G protein-coupled receptors using Supervised Molecular Dynamics: A prototype study analysing the human A3 adenosine receptor positive allosteric modulator LUF6000 ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Giuseppe Deganutti , Alberto Cuzzolin , Antonella Ciancetta , Stefano Moro The search for G protein-coupled receptors (GPCRs) allosteric modulators represents an active research field in medicinal chemistry. Allosteric modulators usually exert their activity only in the presence of the orthosteric ligand by binding to protein sites topographically different from the orthosteric cleft. They therefore offer potentially therapeutic advantages by selectively influencing tissue responses only when the endogenous agonist is present. The prediction of putative allosteric site location, however, is a challenging task. In facts, they are usually located in regions showing more structural variation among the family members. In the present work, we applied the recently developed Supervised Molecular Dynamics (SuMD) methodology to interpret at the molecular level the positive allosteric modulation mediated by LUF6000 toward the human adenosine A3 receptor (hA3 AR). Our data suggest at least two possible mechanisms to explain the experimental data available. This study represent, to the best of our knowledge, the first case reported of an allosteric recognition mechanism depicted by means of molecular dynamics simulations. Graphical abstract image
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Non-peptide ligand binding to the formyl peptide receptor FPR2—A comparison to peptide ligand binding modes ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Tomasz M. Stepniewski , Slawomir Filipek Ligands of the FPR2 receptor initiate many signaling pathways including activation of phospholipase C, protein kinase C, the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase/protein kinase B pathway. The possible actions include also calcium flux, superoxide generation, as well as migration and proliferation of monocytes. FPR2 activation may induce a pro- and anti-inflammatory effect depending on the ligand type. It is also found that this receptor is involved in tumor growth. Most of currently known FPR2 ligands are agonists since they were designed based on N-formyl peptides, which are natural agonists of formyl receptors. Since the non-peptide drugs are indispensable for effective treatment strategies, we performed a docking study of such ligands employing a generated dual template homology model of the FPR2 receptor. The study revealed different binding modes of particular classes of these drugs. Based on the obtained docking poses we proposed a detailed location of three hydrophobic pockets in orthosteric binding site of FPR2. Our model emphasizes the importance of aromatic stacking, especially with regard to residues His1023.29 and Phe2576.51, for binding of FPR2 ligands. We also identified other residues important for non-peptide ligand binding in the binding site of FPR2. Graphical abstract image
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Promiscuity and selectivity of bitter molecules and their receptors ()
Publication date: 15 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 14 Author(s): Antonella Di Pizio , Masha Y. Niv Bitter taste is essential for survival, as it protects against consuming poisonous compounds, which are often bitter. Bitter taste perception is mediated by bitter taste receptors (TAS2Rs), a subfamily of G-protein coupled receptors (GPCRs). The number of TAS2R subtypes is species-dependent, and varies from 3 in chicken to 50 in frog. TAS2Rs present an intriguing case for studying promiscuity: some of the receptors are still orphan, or have few known agonists, while others can be activated by numerous, structurally dissimilar compounds. The ligands also vary in the repertoire of TAS2Rs that they activate: some bitter compounds are selective toward a single TAS2R, while others activate multiple TAS2Rs. Selectivity/promiscuity profile of bitter taste receptors and their compounds was explored by a chemoinformatic approach. TAS2R-promiscuous and TAS2R-selective bitter molecules were found to differ in chemical features, such as A log P, E-state, total charge, number of rings, globularity, and heavy atom count. This allowed the prediction of bitter ligand selectivity toward TAS2Rs. Interestingly, while promiscuous TAS2Rs are activated by both TAS2R-promiscuous and TAS2R-selective compounds, almost all selective TAS2Rs in human are activated by promiscuous compounds, which are recognized by other TAS2Rs anyway. Thus, unique ligands, that may have been the evolutionary driving force for development of selective TAS2Rs, still need to be unraveled. Graphical abstract image
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Editorial board ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13
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Graphical contents list ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13
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Thiazolidine-2,4-dione derivatives: Programmed chemical weapons for key protein targets of various pathological conditions ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Navriti Chadha , Malkeet Singh Bahia , Maninder Kaur , Om Silakari Thiazolidine-2,4-dione is an extensively explored heterocyclic nucleus for designing of novel agents implicated for a wide variety of pathophysiological conditions, that is, diabetes, diabetic complications, cancer, arthritis, inflammation, microbial infection, and melanoma, etc. The current paradigm of drug development has shifted to the structure-based drug design, since high-throughput screenings have continued to generate disappointing results. The gap between hit generation and drug establishment can be narrowed down by investigation of ligand interactions with its receptor protein. Therefore, it would always be highly beneficial to gain knowledge of molecular level interactions between specific protein target and developed ligands; since this information can be maneuvered to design new molecules with improved protein fitting. Thus, considering this aspect, we have corroborated the information about molecular (target) level implementations of thiazolidine-2,4-diones (TZD) derivatives having therapeutic implementations such as, but not limited to, anti-diabetic (glitazones), anti-cancer, anti-arthritic, anti-inflammatory, anti-oxidant and anti-microbial, etc. The structure based SAR of TZD derivatives for various protein targets would serve as a benchmark for the alteration of existing ligands to design new ones with better binding interactions. Graphical abstract image
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New amide derivatives of Probenecid as selective inhibitors of carbonic anhydrase IX and XII: Biological evaluation and molecular modelling studies ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Simone Carradori , Adriano Mollica , Mariangela Ceruso , Melissa D’Ascenzio , Celeste De Monte , Paola Chimenti , Rocchina Sabia , Atilla Akdemir , Claudiu T. Supuran Novel amide derivatives of Probenecid were synthesized and discovered to act as potent and selective inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII. The proposed chemical transformation of the carboxylic acid into an amide group led to a complete loss of hCA I and II inhibition (K is >10,000nM) and enhanced the inhibitory activity against hCA IX and XII, with respect to the parent compound (incorporating a COOH function). These promising biological results have been corroborated by molecular modelling studies within the active sites of the four studied human carbonic anhydrases, which enabled us to rationalize both the isoform selectivity and high activity against the tumor-associated isoforms hCA IX/XII. Graphical abstract image
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Design and synthesis of novel ROR inverse agonists with a dibenzosilole scaffold as a hydrophobic core structure ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Hirozumi Toyama , Masaharu Nakamura , Yuichi Hashimoto , Shinya Fujii Molecular structure calculations indicated that the dibenzosilole skeleton could be well superposed on phenanthridinone, which is a structural component of ligands of retinoic acid receptor-related orphan receptors (RORs). Therefore, we designed, synthesized and biologically evaluated a series of novel ROR ligands based on the dibenzosilole scaffold as a hydrophobic core structure. Dibenzosilole derivatives bearing a hexafluoro-2-hydroxypropyl group on the benzene ring exhibited significant ROR-inhibitory activity, comparable to that of the lead phenanthridinone derivative 5. Our results indicate that the dibenzosilole skeleton would be a useful scaffold for developing novel biologically active compounds, and that cis-amide structure can be replaced by an alkylsilyl functionality. Graphical abstract image
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Novel Raman-tagged sphingomyelin that closely mimics original raft-forming behavior ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Jin Cui , Shigeru Matsuoka , Masanao Kinoshita , Nobuaki Matsumori , Fuminori Sato , Michio Murata , Jun Ando , Hiroyuki Yamakoshi , Kosuke Dodo , Mikiko Sodeoka Three Raman probes of sphingomyelin (SM) were synthesized and evaluated for their applicability to imaging experiments. One probe containing a hydroxymethyl-1,3-butadiyne moiety in the polar head group showed strong scattering. The solid-state 2H NMR spectra of this probe in oriented bilayer membrane revealed excellent compatibility with natural SM in phase behavior since the probe undergoes phase separation to form raft-like liquid ordered (Lo) domains in the raft-mimicking mixed bilayers. Graphical abstract image
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Cloning, characterization and anion inhibition study of a β-class carbonic anhydrase from the caries producing pathogen Streptococcus mutans ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Nurcan Dedeoglu , Viviana De Luca , Semra Isik , Hatice Yildirim , Feray Kockar , Clemente Capasso , Claudiu T. Supuran The oral pathogenic bacterium involved in human dental caries formation Streptococcus mutans, encodes for two carbonic anhydrase (CA, EC 4.2.1.1) one belonging to the α- and the other one to the β-class. This last enzyme (SmuCA) has been cloned, characterized and investigated for its inhibition profile with a major class of CA inhibitors, the inorganic anions. Here we show that SmuCA has a good catalytic activity for the CO2 hydration reaction, with k cat 4.2×105 s−1 and k cat/K m of 5.8×107 M−1 ×s−1, being inhibited by cyanate, carbonate, stannate, divannadate and diethyldithiocarbamate in the submillimolar range (K Is of 0.30–0.64mM) and more efficiently by sulfamide, sulfamate, phenylboronic acid and phenylarsonic acid (K Is of 15–46μM). The anion inhibition profile of the S. mutans enzyme is very different from other α- and β-CAs investigated earlier. Identification of effective inhibitors of this new enzyme may lead to pharmacological tools useful for understanding the role of S. mutans CAs in dental caries formation, and eventually the development of pharmacological agents with a new mechanism of antibacterial action. Graphical abstract image
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Simple structural modifications confer cytotoxicity to allobetulin ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Lucie Heller , Anja Obernauer , René Csuk A variety of allobetulin derivatives was synthesized from allobetulin or allobetulone. These compounds were screened for their cytotoxic activity using a photometric SRB assay employing six different human tumor cell lines. In summary, opening of ring A of allobetulin in general lowers the cytotoxicity, but the 2,3-seco diethyl ester was highly cytotoxic and remarkable selective for A549 lung carcinoma cells while being significantly less cytotoxic for non-malignant mouse fibroblasts. The introduction of an amino group at position C-3 in the allobetulin skeleton enhances cytotoxicity and furnishes highly cytotoxic compounds. Their selectivity to distinguish between cancer cell and non-malignant cell depends on the configuration at position C-3. Graphical abstract image
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Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Katerina Kumpan , Amit Nathubhai , Chenlu Zhang , Pauline J. Wood , Matthew D. Lloyd , Andrew S. Thompson , Teemu Haikarainen , Lari Lehtiö , Michael D. Threadgill The tankyrases are members of the PARP superfamily; they poly(ADP-ribosyl)ate their target proteins using NAD+ as a source of electrophilic ADP-ribosyl units. The three principal protein substrates of the tankyrases (TRF1, NuMA and axin) are involved in replication of cancer cells; thus inhibitors of the tankyrases may have anticancer activity. Using structure-based drug design and by analogy with known 3-arylisoquinolin-1-one and 2-arylquinazolin-4-one inhibitors, series of arylnaphthyridinones, arylpyridinopyrimidinones and their tetrahydro-derivatives were synthesised and evaluated in vitro. 7-Aryl-1,6-naphthyridin-5-ones, 3-aryl-2,6-naphthyridin-1-ones and 3-aryl-2,7-naphthyridin-1-ones were prepared by acid-catalysed cyclisation of the corresponding arylethynylpyridinenitriles or reaction of bromopyridinecarboxylic acids with β-diketones, followed by treatment with NH3. The 7-aryl-1,6-naphthyridin-5-ones were methylated at 1-N and reduced to 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones. Cu-catalysed reaction of benzamidines with bromopyridinecarboxylic acids furnished 2-arylpyrido[2,3-d]pyrimidin-4-ones. Condensation of benzamidines with methyl 1-benzyl-4-oxopiperidine-3-carboxylate and deprotection gave 2-aryl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ones, aza analogues of the known inhibitor XAV939. Introduction of the ring-N in the arylnaphthyridinones and the arylpyridopyrimidinones caused >1000-fold loss in activity, compared with their carbocyclic isoquinolinone and quinazolinone analogues. However, the 7-aryl-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-ones showed excellent inhibition of the tankyrases, with some examples having IC50 =2nM. One compound (7-(4-bromophenyl)-1-methyl-1,2,3,4-tetrahydro-1,6-naphthyridin-5-one) showed 70-fold selectivity for inhibition of tankyrase-2 versus tankyrase-1. The mode of binding was explored through crystal structures of inhibitors in complex with tankyrase-2. Graphical abstract image
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Glycosyl hydroperoxides: A new class of potential antimalarial agents ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Barbara Szechner , Anna Jaromin , Silvia Parapini , Nicoletta Basilico , Barbara Grzeszczyk , Bartłomiej Furman , Marek Chmielewski Motivated by the antimalarial properties observed in organic peroxides, an extensive series of glycosyl hydroperoxides was prepared with the aim of identifying new bioactive molecules. Selected compounds were tested against a Plasmodium falciparum culture (chloroquine-susceptible strain D10 and chloroquine-resistant strain W2). Screening results indicated that the factors critical for antimalarial activity were the presence of a hydroperoxide moiety and solubility in water at pH 5.0. Moreover, the ability to inhibit β-hematin formation in vitro has been evaluated (BHIA Assay). Graphical abstract image
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Insights into the interaction of negative allosteric modulators with the metabotropic glutamate receptor 5: Discovery and computational modeling of a new series of ligands with nanomolar affinity ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Andrew Anighoro , Davide Graziani , Ilaria Bettinelli , Antonio Cilia , Carlo De Toma , Matteo Longhi , Fabio Mangiarotti , Sergio Menegon , Lorenza Pirona , Elena Poggesi , Carlo Riva , Giulio Rastelli Metabotropic glutamate receptor 5 (mGlu5) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu5. A homology model of the 7TM receptor domain built on the crystal structure of the mGlu1 template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu5 crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure–activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu5 were extended to include important non-aryl alkyne mGlu5 NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu5 and may facilitate the design of new modulators for this class of receptors. Graphical abstract image
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Anti-arthritic agents: Progress and potential ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Sergey S. Laev , Nariman F. Salakhutdinov Osteoarthritis and rheumatoid arthritis are the two most common types of arthritis. Cartilage breakdown is a key feature of both diseases which contributes to the pain and joint deformity experienced by patients. Therefore, anti-arthritis drugs are of great importance. The aim of this review is to present recent progress in studies of various agents against osteoarthritis and rheumatoid arthritis. The structures and activities of anti-arthritic agents, which used in medical practice or are in development, are presented and discussed. The effects and mechanisms of action of opioids, glucocorticoids, non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, natural products derived from plants, nutraceuticals, and a number of new and perspective agents are considered. Various perspective targets for the treatment of osteoarthritis and rheumatoid arthritis are also discussed. Trials of good quality are needed to draw solid conclusions regarding efficacy of many of the studied agents. Unfortunately, to date, there is no pharmacologic agent proven to prevent the progression of both diseases, and there is an urgent need for further development of better anti-arthritic agents. Graphical abstract image
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Selective inhibition of prolyl 4-hydroxylases by bipyridinedicarboxylates ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): James D. Vasta , Ronald T. Raines Collagen is the most abundant protein in animals. A variety of indications are associated with the overproduction of collagen, including fibrotic diseases and cancer metastasis. The stability of collagen relies on the posttranslational modification of proline residues to form (2S,4R)-4-hydroxyproline. This modification is catalyzed by collagen prolyl 4-hydroxylases (CP4Hs), which are Fe(II)- and α-ketoglutarate (AKG)-dependent dioxygenases located in the lumen of the endoplasmic reticulum. Human CP4Hs are validated targets for treatment of both fibrotic diseases and metastatic breast cancer. Herein, we report on 2,2′-bipyridinedicarboxylates as inhibitors of a human CP4H. Although most 2,2′-bipyridinedicarboxylates are capable of inhibition via iron sequestration, the 4,5′- and 5,5′-dicarboxylates were found to be potent competitive inhibitors of CP4H, and the 5,5′-dicarboxylate was selective in its inhibitory activity. Our findings clarify a strategy for developing CP4H inhibitors of clinical utility. Graphical abstract image
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Synthesis and evaluation of tamoxifen derivatives with a long alkyl side chain as selective estrogen receptor down-regulators ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Takuji Shoda , Masashi Kato , Rintaro Harada , Takuma Fujisato , Keiichiro Okuhira , Yosuke Demizu , Hideshi Inoue , Mikihiko Naito , Masaaki Kurihara Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. An antagonist that acts as not only an inhibitor of ligand binding but also an inducer of the down-regulation of ER would be useful for the treatment for ER-positive breast cancer. We previously reported the design and synthesis of a selective estrogen receptor down-regulator (SERD), (E/Z)-4-(1-{4-[2-(dodecylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl)phenol (C12), which is a tamoxifen derivative having a long alkyl chain on the amine moiety. This compound induced degradation of ERα via a proteasome-dependent pathway and showed an antagonistic effect in MCF-7 cells. With the aim of increasing the potency of SERDs, we designed and synthesized various tamoxifen derivatives that have various lengths and terminal groups of the long alkyl side chain. During the course of our investigation, C10F having a 10-fluorodecyl group on the amine moiety of 4-OHT was shown to be the most potent compound among the tamoxifen derivatives. Moreover, computational docking analysis suggested that the long alkyl chain interacted with the hydrophobic region on the surface of the ER, which is a binding site of helix 12 and coactivator. These results provide useful information to develop promising candidates as SERDs. Graphical abstract image
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Selective induction of oxidative stress in cancer cells via synergistic combinations of agents targeting redox homeostasis ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Fady N. Akladios , Scott D. Andrew , Christopher J. Parkinson Cancer cell resistance to chemotherapy is still a heavy burden that impairs the response of many cancer patients to conventional chemotherapy. Using drug combinations is one therapeutic approach to overcome the developing resistance to any one drug. Oxidative stress is now a generally regarded hallmark of cancer that can be one approach to selectively target cancer cells while sparing normal cells. With the aim of increasing oxidative stress in cancer cells to a lethal set point, we have generated and combined several series of redox active compounds that act at different points of the cellular oxidative cascade. The premise of such combinations is to deplete of endogenous antioxidant defence proteins (e.g., Glutathione) while concomitantly increasing the generation of ROS via metal redox recycling and Fenton chemistry which eventually leads to the disruption of cellular redox homeostasis and induction of cell death. Through this approach, we have identified highly synergistic combinations of two distinctive classes of compounds (Azines and Copper(II) complexes of 2-pyridyl ketone thiosemicarbazones) which are capable of eliminating cancer cells without concomitant increase in toxicity toward normal cells. In one of our most potent combinations, a combination index (CI) value of 0.056 was observed, representing a 17 fold enhancement in activity beyond additive effects. Such new combination regimen of redox active compounds can be one step closer to potentially safer low dose chemotherapy. Graphical abstract image
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Influence of linker length in shape recognition of B∗ DNA by dimeric aminoglycosides ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Sunil Kumar , Meredith Newby Spano , Dev P. Arya DNA-protein recognition has shown us the importance of DNA shapes in the recognition process. Specific high-affinity targeting of DNA shapes by small molecules is desirable for many biological applications that involve regulation of DNA based processes. Here, the effect of linker length and rigidity on the affinity of a conjugated neomycin dimer for a specific DNA shape (B∗ form) AT-rich DNA was explored. Binding constants approximating 108 M−1 for optimal linker lengths of 18–19 atoms are reported herein. Graphical abstract image
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(−)-Meptazinol–melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-β aggregation with high antioxidant potency for Alzheimer’s therapy ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Shaobing Cheng , Wei Zheng , Ping Gong , Qiang Zhou , Qiong Xie , Lining Yu , Peiyi Zhang , Liangkang Chen , Juan Li , Jianxing Chen , Hailin Chen , Hongzhuan Chen The multifactorial pathogenesis of Alzheimer’s disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-β (Aβ) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (−)-meptazinol–melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7–7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Aβ self-aggregation, showed favorable safety and the blood–brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD. Graphical abstract image
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Novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone: A new class of β-glucuronidase inhibitors and in silico studies ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Nik Khairunissa Nik Abdullah Zawawi , Muhammad Taha , Norizan Ahmat , Abdul Wadood , Nor Hadiani Ismail , Fazal Rahim , Muhammad Ali , Norishah Abdullah , Khalid Mohammed Khan A library of novel 2,5-disubtituted-1,3,4-oxadiazoles with benzimidazole backbone (3a–3r) was synthesized and evaluated for their potential as β-glucuronidase inhibitors. Several compounds such as 3a–3d, 3e–3j, 3l–3o, 3q and 3r showed excellent inhibitory potentials much better than the standard (IC50 =48.4±1.25μM: d-saccharic acid 1,4-lactone). All the synthesized compounds were characterized satisfactorily by using different spectroscopic methods. We further evaluated the interaction of the active compounds and the enzyme active site with the help of docking studies. Graphical abstract image
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Isolation of cholinesterase and β-secretase 1 inhibiting compounds from Lycopodiella cernua ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Van Thu Nguyen , Dao Cuong To , Manh Hung Tran , Sang Ho Oh , Jeong Ah Kim , Md Yousof Ali , Mi-Hee Woo , Jae Sue Choi , Byung Sun Min Three new serratene-type triterpenoids (1–3) and a new hydroxy unsaturated fatty acid (13) together with nine known compounds (4–12) were isolated from Lycopodiella cernua. The chemical structures were established using NMR, MS, and Mosher’s method. Compound 13 showed the most potent inhibitory activity against acetylcholinesterase (AChE) with an IC50 value of 0.22μM. For butyrylcholinesterase (BChE) inhibitory activity, 5 showed the most potent activity with an IC50 value of 0.42μM. Compound 2 showed the most potent activity with an IC50 of 0.23μM for BACE-1 inhibitory activity. The kinetic activities were investigated to determine the type of enzyme inhibition involved. The types of AChE inhibition shown by compounds 4, 5, and 13 were mixed; BChE inhibition by 5 was competitive, while 2 and 6 showed mixed-types. In addition, molecular docking studies were performed to investigate the interaction of these compounds with the pocket sites of AChE. The docking results revealed that the tested inhibitors 3, 4, and 13 were stably present in several pocket domains of the AChE residue. Graphical abstract image
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Design, antiviral and cytostatic properties of isoxazolidine-containing amonafide analogues ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Kamil Kokosza , Graciela Andrei , Dominique Schols , Robert Snoeck , Dorota G. Piotrowska A novel series of 5-arylcarbamoyl- and 5-arylmethyl-2-methylisoxazolidin-3-yl-3-phosphonates have been synthesized via cycloaddition of N-methyl-C-(diethoxyphosphoryl)nitrone with N-substituted naphthalimide acrylamides and N-allylnaphthalimides. All cis- and trans-isoxazolidine phosphonates obtained herein were assessed for antiviral activity against a broad range of DNA and RNA viruses. Isoxazolidines trans-9d and trans-9f exhibited the highest activity (EC50 =8.9μM) toward cytomegalovirus. Compounds cis- and trans-9d as well as cis- and trans-9f were found potent against HSV and Vaccinia viruses (EC50 in the 45–58μM range), whereas isoxazolidines 10a and 10d suppressed replication of Coxsackie B4 and Punta Toro viruses (EC50 in the 45–73μM range). Antiproliferative evaluation of all obtained isoxazolidines revealed the promising activity of cis-9b, cis-9d, trans-9d, cis-9e, trans-9e, cis-9f and trans-9f toward tested cancer cell lines with IC50 in the 1.1–19μM range. Graphical abstract image
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Design, synthesis, and biological activity of phenyl-pyrazole derivatives as BCR–ABL kinase inhibitors ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Liming Hu , Yuyan Zheng , Zhipeng Li , Yujie Wang , Yongjuan Lv , Xuemei Qin , Chengchu Zeng 4-(Pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives have been proposed as new BCR–ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. In the present study, a series of 4-(pyridin-3-yl)-1H-pyrazol-1-yl-phenyl-3-benzamide derivatives were synthesized and their activities against BCR–ABL1 kinase in vitro were evaluated by using Kinase-Glo assay. All new compounds showed from moderate to potent activities against wild-type (wt) BCR–ABL1 kinase with an IC50 range from 14.2 to 326.0nM. Among them, seven compounds exhibited BCR–ABL1 kinase inhibitory activities with IC50 values less than 50nM. Compound 7a displayed the most potent inhibitory activity to BCR–ABL kinase (IC50: 14.2nM). Docking simulation was performed for compounds 7a and 7i into the BCR–ABL kinase structure active site to determine the probable binding model. The preliminary structure–activity relationship was discussed. The interesting activities of these compounds may make them promising candidates as therapeutic agents for chronic myelogenous leukemia. Graphical abstract image
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Trichormamides C and D, antiproliferative cyclic lipopeptides from the cultured freshwater cyanobacterium cf. Oscillatoria sp. UIC 10045 ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Shangwen Luo , Hahk-Soo Kang , Aleksej Krunic , Wei-Lun Chen , Jilai Yang , John L. Woodard , James R. Fuchs , Sang Hyun Cho , Scott G. Franzblau , Steven M. Swanson , Jimmy Orjala Extract from the cultured freshwater cf. Oscillatoria sp. UIC 10045 showed antiproliferative activity against HT-29 cell line. Bioassay-guided fractionation led to the isolation of two new cyclic lipopeptides, named trichormamides C (1) and D (2). The planar structures were determined by combined analyses of HRESIMS, Q-TOF ESIMS/MS, and 1D and 2D NMR spectra. The absolute configurations of the amino acid residues were assigned by advanced Marfey’s analysis after partial and complete acid hydrolysis. Trichormamides C (1) is a cyclic undecapeptide and D (2) is a cyclic dodecapeptide, both containing a lipophilic β-aminodecanoic acid residue. Trichormamide C (1) displayed antiproliferative activities against HT-29 and MDA-MB-435 cancer cell lines with IC50 values of 1.7 and 1.0μM, respectively, as well as anti-Mycobacterium tuberculosis activity with MIC value of 23.8μg/mL (17.3μM). Trichormamide D (2) was found to be less potent against both HT-29 and MDA-MB-435 cancer cell lines with IC50 values of 11.5 and 11.7μM, respectively. Graphical abstract image
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Synthesis and antimicrobial activity of chloramphenicol–polyamine conjugates ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): George E. Magoulas , Ourania N. Kostopoulou , Thomas Garnelis , Constantinos M. Athanassopoulos , Georgia G. Kournoutou , Michael Leotsinidis , George P. Dinos , Dionissios Papaioannou , Dimitrios L. Kalpaxis A series of chloramphenicol (CAM) amides with polyamines (PAs), suitable for structure–activity relationship studies, were synthesized either by direct attachment of the PA chain on the 2-aminopropane-1,3-diol backbone of CAM, previously oxidized selectively at its primary hydroxyl group, or from chloramphenicol base (CLB) through acylation with succinic or phthalic anhydride and finally coupling with a PA. Conjugates 4 and 5, in which the CLB moiety was attached on N4 and N1 positions, respectively, of the N 8,N 8-dibenzylated spermidine through the succinate linker, were the most potent antibacterial agents. Both conjugates were internalized into Escherichia coli cells by using the spermidine-preferential uptake system and caused decrease in protein and polyamine content of the cells. Noteworthy, conjugate 4 displayed comparable activity to CAM in MRSA or wild-type strains of Staphylococcus aureus and Escherichia coli, but superior activity in E. coli strains possessing ribosomal mutations or expressing the CAM acetyltransferase (cat) gene. Lead compounds, and in particular conjugate 4, have been therefore discovered during the course of the present work with clinical potential. Graphical abstract image
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Synthesis of C-5″ and C-6″-modified α-GalCer analogues as iNKT-cell agonists ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Joren Guillaume , Nora Pauwels , Sandrine Aspeslagh , Dirk M. Zajonc , Dirk Elewaut , Serge Van Calenbergh Alpha-galactosyl ceramide (α-GalCer) is a prototypical synthetic ligand of invariant natural killer T (iNKT) cells. Upon presentation by the MHC class I-like molecule CD1d, this glycolipid stimulates iNKT cells to secrete a vast amount of both pro-inflammatory Th1 and anti-inflammatory Th2 cytokines. Recently, we discovered that selected 6″-modified α-GalCer analogues may produce markedly Th1-biased responses due to the formation of either an additional anchor with CD1d or by establishing extra interactions with the T-cell receptor of iNKT cells. Here, we report a practical synthesis towards 6″-O-carbamate and galacturonamide analogues of α-GalCer and their evaluation as iNKT cell agonists in mice. Graphical abstract image
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Systematic assessment of scaffold hopping versus activity cliff formation across bioactive compound classes following a molecular hierarchy ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Dagmar Stumpfe , Dilyana Dimova , Jürgen Bajorath Scaffold hopping and activity cliff formation define opposite ends of the activity landscape feature spectrum. To rationalize these events at the level of scaffolds, active compounds involved in scaffold hopping were required to contain topologically distinct scaffolds but have only limited differences in potency, whereas compounds involved in activity cliffs were required to share the same scaffold but have large differences in potency. A systematic search was carried out for compounds involved in scaffold hopping and/or activity cliff formation. Results obtained for compound data sets covering more than 300 human targets revealed clear trends. If scaffolds represented multiple but fewer than 10 active compounds, nearly 90% of all scaffolds were exclusively involved in hopping events. With increasing compound coverage, the fraction of scaffolds involved in both scaffold hopping and activity cliff formation significantly increased to more than 50%. However, ∼40% of the scaffolds representing large numbers of active compounds continued to be exclusively involved in scaffold hopping. More than 200 scaffolds with broad target coverage were identified that consistently represented potent compounds and yielded an abundance of scaffold hops in the low-nanomolar range. These and other subsets of scaffolds we characterized are of prime interest for structure–activity relationship (SAR) exploration and compound design. Therefore, the complete scaffold classification generated in the course of our analysis is made freely available. Graphical abstract image
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Exploring S1 plasticity and probing S1′ subsite of mammalian aminopeptidase N/CD13 with highly potent and selective aminobenzosuberone inhibitors ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Germain Revelant , Mira Al-Lakkis-Wehbe , Marjorie Schmitt , Sarah Alavi , Céline Schmitt , Lionel Roux , Mounir Al-Masri , Nadège Schifano-Faux , Carmen Maiereanu , Céline Tarnus , Sébastien Albrecht In order to probe the S1 and S1′ mammalian aminopeptidase N subsites, racemic 1- or 4-substituted 7-aminobenzocyclohepten-6-one derivatives were synthesized and evaluated for their ability to inhibit mammalian aminopeptidase N. We focused on improving the physicochemical and ADME properties of this series by targeting lipophilicity and LELP score. Some 4-heteroaryl substituted analogues displayed reduced lipophilicity and enhanced inhibition potency with K i values in the nanomolar range. Graphical abstract image
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Optimization of rhodanine scaffold for the development of protein–protein interaction inhibitors ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Stefania Ferro , Laura De Luca , Fatima Ezzahra Agharbaoui , Frauke Christ , Zeger Debyser , Rosaria Gitto Searching for novel protein–protein interactions inhibitors (PPIs) herein we describe the identification of a new series of rhodanine derivatives. The selection was performed by means virtual-screening, docking studies, Molecular Dynamic (MD) simulations and synthetic approaches. All the new obtained compounds were tested in order to evaluate their ability to inhibit the interaction between the HIV-1 integrase (IN) enzyme and the nuclear protein lens epithelium growth factor LEDGF/p75. Graphical abstract image
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In silico evaluation of human small heat shock protein HSP27: Homology modeling, mutation analyses and docking studies ()
Publication date: 1 July 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 13 Author(s): Paola Fossa , Elena Cichero Small heat-shock proteins, possessing chaperone-like activity, represented crucial proteins actively involved in maintain protein homeostasis, which act to prevent improper polypeptide aggregation and deposition of misfolded proteins. In this context, a number of mutations concerning the HspB1 protein proved to be associated with the development of several neuropathologies. Unfortunately, molecular mechanisms underlying the onset of these diseases and in particular the changes induced by the mutations in HspB1 structure, remain poorly characterized. On the other hand, more recent studies demonstrated that HspB1 overexpression leads to an overactive chaperone activity, which in turn contributes to the anticancer agent resistance. On these basis, Hsp27 could represent a good innovative target for development of novel cancer therapy. Therefore, in this work a computational study, based on the homology model of the complete Hsp27 protein and of several pathological mutant forms, was developed. Finally, the derived model was employed to perform, for the first time, docking simulations on a recently identified Hsp27 inhibitor, disclosing a new useful panorama to be exploited for the further development of new compounds. Graphical abstract image
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