Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17
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Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17
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Sulfonamide inhibition study of the carbonic anhydrases from the bacterial pathogen Porphyromonas gingivalis: The β-class (PgiCAb) versus the γ-class (PgiCA) enzymes ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Sonia Del Prete , Daniela Vullo , Sameh M. Osman , Andrea Scozzafava , Zeid AlOthman , Clemente Capasso , Claudiu T. Supuran The oral pathogenic bacterium Porphyromonas gingivalis, encodes for two carbonic anhydrases (CAs, EC 4.2.1.1) one belonging to the γ-class (PgiCA) and another one to the β-class (PgiCAb). This last enzyme has been cloned and characterized here for its inhibition profile with the main class of CA inhibitors, the sulfonamides. Many of the clinically used sulfonamides as well as simple aromatic/heterocyclic sulfonamides were ineffective as PgiCAb inhibitors whereas better inhibition was observed with simple derivatives such as sulfanilamide, metanilamide, 4-aminoalkylbenzenesulfonamides (K Is of 364–475nM). The halogenosulfanilamides incorporating heavy halogens, 4-hydroxy- and 4-hydroxyalkyl-benzenesulfonamides, were also micromolar, ineffective PgiCAb inhibitors. The best inhibitors of the β-class enzyme were acetazolamide and ethoxzolamide, with K Is of 214–280nM. Interestingly, the γ-class enzyme was much more sensitive to sulfonamide inhibitors compared to the β-class one, PgiCAb. Identification of potent and possibly selective inhibitors of PgiCAb/PgiCA may lead to pharmacological tools useful for understanding the physiological role(s) of these enzymes, since this bacterium is the main causative agent of periodontitis and few treatment options are presently available. Graphical abstract image
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Development of novel membrane active lipidated peptidomimetics active against drug resistant clinical isolates ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Sandeep Lohan , Arneesh Kalanta , Praveen Sonkusre , Swaranjit Singh Cameotra , Gopal Singh Bisht A new series of small cationic lipidated peptidomimetics have been synthesized and found to be highly active against several susceptible as well as drug resistant clinical isolates of bacteria and fungi. All lipidated peptidomimetics do not cause significant lysis of human erythrocytes (HC50 >200μg/mL). Calcein dye leakage experiment revealed membranolytic effect of LPEP08 which was further confirmed by scanning electron microscopy (SEM). The involvement of intracellular targets as an alternate mode of action was precluded by DNA retardation assay. Additionally, LPEP08 exhibit high proteolytic stability and dose not elicit resistance against drug resistant clinical isolate of Staphylococcus aureus, even after 16 rounds of passaging. These results demonstrate the potential of lipidated peptidomimetics as biocompatible anti-infective therapeutics. Graphical abstract image
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Ethyl 2-(benzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate analogues as a new scaffold for protein kinase casein kinase 2 inhibitor ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Cheng-Hao Jin , Kyu-Yeon Jun , Eunjung Lee , Seongrak Kim , Youngjoo Kwon , Kunhong Kim , Younghwa Na Protein kinase casein kinase 2 (PKCK2) is a constitutively active, growth factor-independent serine/threonine kinase, and changes in PKCK2 expression or its activity are reported in many cancer cells. To develop a novel PKCK2 inhibitor(s), we first performed cell-based phenotypic screening using 4000 chemicals purchased from ChemDiv chemical libraries (2000: randomly selected; 2000: kinase-biased) and performed in vitro kinase assay-based screening using hits found from the first screening. We identified compound 24 (C24)[(Z)-ethyl 5-(4-chlorophenyl)-2-(3,4-dihydroxybenzylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a] pyrimidine-6-carboxylate] as a novel inhibitor of PKCK2 that is more potent and selective than 4,5,6,7-tetrabromobenzotriazole (TBB). In particular, compound 24 [half maximal inhibitory concentration (IC50)=0.56μM] inhibited PKCK2 2.2-fold more efficiently than did TBB (IC50 =1.24μM), which is quite specific toward PKCK2 with respect to ATP binding, in a panel of 31 human protein kinases. The K i values of compound 24 and TBB for PKCK2 were 0.78μM and 2.70μM, respectively. Treatment of cells with compound 24 inhibited endogenous PKCK2 activity and showed anti-proliferative and pro-apoptotic effects against stomach and hepatocellular cancer cell lines more efficiently than did TBB. As expected, compound 24 also enabled tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-resistant cancer cells to be sensitive toward TRAIL. In comparing the molecular docking of compound 24 bound to PKCK2α versus previously reported complexes of PKCK2 with other inhibitors, our findings suggest a new scaffold for specific PKCK2α inhibitors. Thus, compound 24 appears to be a selective, cell-permeable, potent, and novel PKCK2 inhibitor worthy of further characterization. Graphical abstract image
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Identification of novel inhibitors of phospho-MurNAc-pentapeptide translocase MraY from library screening: Isoquinoline alkaloid michellamine B and xanthene dye phloxine B ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Agnes Mihalyi , Shirin Jamshidi , Justinas Slikas , Timothy D.H. Bugg The National Cancer Institute (NCI) Diversity Set was screened for potential inhibitors of phospho-MurNAc-pentapeptide translocase MraY from Escherichia coli using a primary fluorescence enhancement assay, followed by a secondary radiochemical assay. One new MraY inhibitor was identified from this screen, a naphthylisoquinoline alkaloid michellamine B, which inhibited E. coli MraY (IC50 456μM) and Bacillus subtilis MraY (IC50 386μM), and which showed antimicrobial activity against B. subtilis (MIC 16μg/mL). Following an earlier report of halogenated fluoresceins identified from a combined MraY/MurG screen, three halogenated fluoresceins were tested as inhibitors of E. coli MraY and E. coli MurG, and phloxine B was identified as an inhibitor of E. coli MraY (IC50 32μM). Molecular docking of inhibitor structures against the structure of Aquifex aeolicus MraY indicates that phloxine B appears to bind to the Mg2+ cofactor in the enzyme active site, while michellamine B binds to a hydrophobic groove formed between transmembrane helices 5 and 9. Graphical abstract image
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Endoperoxide polyketides from a Chinese Plakortis simplex: Further evidence of the impact of stereochemistry on antimalarial activity of simple 1,2-dioxanes ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Giuseppina Chianese , Marco Persico , Fan Yang , Hou-Wen Lin , Yue-Wei Guo , Nicoletta Basilico , Silvia Parapini , Donatella Taramelli , Orazio Taglialatela-Scafati , Caterina Fattorusso Chemical investigation of the organic extract obtained from the sponge Plakortis simplex collected in the South China Sea afforded five new polyketide endoperoxides (2 and 4–7), along with two known analogues (1 and 3). The stereostructures of these metabolites have been deduced on the basis of spectroscopic analysis and chemical conversion. The isolated endoperoxide derivatives have been tested for their in vitro antimalarial activity against Plasmodium falciparum strains, showing IC50 values in the low micromolar range. The structure–activity relationships were analyzed by means of a detailed computational investigation and rationalized in the light of the mechanism of action proposed for this class of simple antimalarials. The relative orientation of the atoms involved in the putative radical generation and transfer reaction was demonstrated to have a great impact on the antimalarial activity. The resulting 3D pharmacophoric model can be a useful guide to design simple and effective antimalarial lead compounds belonging to the class of 1,2-dioxanes. Graphical abstract image
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‘Carba’-carfentanil (trans isomer): A μ opioid receptor (MOR) partial agonist with a distinct binding mode ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Grazyna Weltrowska , Carole Lemieux , Nga N. Chung , Jason J. Guo , Brian C. Wilkes , Peter W. Schiller There is strong evidence to indicate that a positively charged nitrogen of endogenous and exogenous opioid ligands forms a salt bridge with the Asp residue in the third transmembrane helix of opioid receptors. To further examine the role of this electrostatic interaction in opioid receptor binding and activation, we synthesized ‘carba’-analogues of the highly potent μ opioid analgesic carfentanil (3), in which the piperidine nitrogen was replaced with a carbon. The resulting trans isomer (8b) showed reduced, but still significant MOR binding affinity (K i μ =95.2nM) with no MOR versus DOR binding selectivity and was a MOR partial agonist. The cis isomer (8a) was essentially inactive. A MOR docking study indicated that 8b bound to the same binding pocket as parent 3, but its binding mode was somewhat different. A re-evaluation of the uncharged morphine derivative N-formylnormorphine (9) indicated that it was a weak MOR antagonist showing no preference for MOR over KOR. Taken together, the results indicate that deletion of the positively charged nitrogen in μ opioid analgesics reduces MOR binding affinity by 2–3 orders of magnitude and may have pronounced effects on the intrinsic efficacy and on the opioid receptor selectivity profile. Graphical abstract image
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Novel N-biphenyl-2-ylmethyl 2-methoxyphenylpiperazinylalkanamides as 5-HT7R antagonists for the treatment of depression ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Youngjae Kim , Jinsung Tae , Kangho Lee , Hyewhon Rhim , Il Han Choo , Heeyeong Cho , Woo-Kyu Park , Gyochang Keum , Hyunah Choo 5-HT7 receptor (5-HT7R) is a promising target for the treatment of depression and neuropathic pain. 5-HT7R antagonists exhibited antidepressant effects, while the agonists produced strong anti-hyperalgesic effects. In our efforts to discover selective 5-HT7R antagonists or agonists, N-biphenylylmethyl 2-methoxyphenylpiperazinylalkanamides 1 were designed, synthesized, and biologically evaluated against 5-HT7R. Among the synthesized compounds, N-2′-chlorobiphenylylmethyl 2-methoxyphenylpiperazinylpentanamide 1–8 showed the best binding affinity with a K i value of 8.69nM and it was verified as a novel antagonist according to functional assays. The compound 1–8 was very selective over 5-HT1DR, 5-HT2AR, 5-HT3R, 5-HT5AR and 5-HT6R and moderately selective over 5-HT1AR, 5-HT1BR and 5-HT2CR. The novel 5-HT7R antagonist 1–8 exhibited an antidepressant effect at a dose of 25mg/kg in the forced swimming test in mice and showed a U-shaped dose–response curve which typically appears in 5-HT7R antagonists such as SB-269970 and lurasidone. Graphical abstract image
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Ricinine: A pyridone alkaloid from Ricinus communis that activates the Wnt signaling pathway through casein kinase 1α ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Kensuke Ohishi , Kazufumi Toume , Midori A. Arai , Samir K. Sadhu , Firoj Ahmed , Takamasa Mizoguchi , Motoyuki Itoh , Masami Ishibashi Wnt signaling plays important roles in proliferation, differentiation, development of cells, and various diseases. Activity-guided fractionation of the MeOH extract of the Ricinus communis stem led to the isolation of four compounds (1–4). The TCF/β-catenin transcription activities of 1 and 3 were 2.2 and 2.5 fold higher at 20 and 30μM, respectively. Cells treated with ricinine (1) had higher β-catenin and lower of p-β-catenin (ser 33, 37, 45, Thr 41) protein levels, whereas glycogen synthase kinase 3β (GSK3β) and casein kinase 1α (CK1α) protein levels remained unchanged. Cells treated with pyrvinium, an activator of CK1α, had lower β-catenin levels. However, the combined treatment of pyrvinium and 1 led to higher β-catenin levels than those in cells treated with pyrvinium alone, which suggested that 1 inhibited CK1α activity. Furthermore, 1 increased β-catenin protein levels in zebrafish embryos. These results indicated that 1 activated the Wnt signaling pathway by inhibiting CK1α. Graphical abstract image
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Design, synthesis, and in vitro evaluation of an activity-based protein profiling (ABPP) probe targeting agmatine deiminases ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Andrew Thomson , Sean O’Connor , Bryan Knuckley , Corey P. Causey Agmatine deiminases (AgDs) belong to a family of enzymes known as guanidinium group modifying enzymes (GMEs). Many pathogenic bacteria encode an AgD that participates in the catabolism of agmatine (decarboxylated arginine). This catabolism may confer a competitive survival advantage, by virtue of energy production and increased acid tolerance, making this sub-family of enzymes a potential therapeutic target that warrants further study. Herein we report the development of an activity-based protein profiling (ABPP) probe that selectively targets the AgD from Streptococcus mutans. Due to the selectivity and covalent nature of the modification, this probe could prove to be a valuable tool for the study of other AgD family members. Graphical abstract image
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2-Phenylaminonaphthoquinones and related compounds: Synthesis, trypanocidal and cytotoxic activities ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Ivan Sieveking , Pablo Thomas , Juan C. Estévez , Natalia Quiñones , Mauricio A. Cuéllar , Juan Villena , Christian Espinosa-Bustos , Angélica Fierro , Ricardo A. Tapia , Juan D. Maya , Rodrigo López-Muñoz , Bruce K. Cassels , Ramon J. Estévez , Cristian O. Salas A series of new 2-aminonaphthoquinones and related compounds were synthesized and evaluated in vitro as trypanocidal and cytotoxic agents. Some tested compounds inhibited epimastigote growth and trypomastigote viability. Several compounds showed similar or higher activity and selectivity as compared with current trypanocidal drug, nifurtimox. Compound 4l exhibit higher selectivity than nifurtimox against Trypanosoma cruzi in comparison with Vero cells. Some of the synthesized quinones were tested against cancer cells and normal fibroblasts, showing that certain chemical modifications on the naphthoquinone moiety induce and excellent increase the selectivity index of the cytotoxicity (4g and 10). The results presented here show that the anti-T. cruzi activity of 2-aminonaphthoquinones derivatives can be improved by the replacement of the benzene ring by a pyridine moiety. Interestingly, the presence of a chlorine atom at C-3 and a highly lipophilic alkyl group or aromatic ring are newly observed elements that should lead to the discovery of more selective cytotoxic and trypanocidal compounds. Graphical abstract image
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Stereoselective synthesis of lanthionine derivatives in aqueous solution and their incorporation into the peptidoglycan of Escherichia coli ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Thibaut Denoël , Astrid Zervosen , Thomas Gerards , Christian Lemaire , Bernard Joris , Didier Blanot , André Luxen The three diastereoisomers—(R,R), (S,S) and meso—of lanthionine were synthesized in aqueous solution with high diastereoselectivity (>99%). The (S) and (R) enantiomers of two differently protected sulfamidates were opened by nucleophilic attack of (R) or (S)-cysteine. Acidification and controlled heating liberated the free lanthionines. Using the same chemistry, an α-benzyl lanthionine was also prepared. The proposed method, which avoids the need of enrichment by recrystallization, opens the way to the labelling of these compounds with 35S. Furthermore, in vivo bioincorporation into Escherichia coli W7 was studied. No incorporation of α-benzyl lanthionine was observed. In contrast, meso-lanthionine can effectively replace meso-diaminopimelic acid in vivo, while in the presence of (R,R)-lanthionine the initial increase of bacterial growth was followed by cell lysis. In the future, meso-[35S]lanthionine could be used to study the biosynthesis of peptidoglycan and its turnover in relation to cell growth and division. Graphical abstract image
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Synthesis and antifungal activity of substituted salicylaldehyde hydrazones, hydrazides and sulfohydrazides ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Gregory L. Backes , Donna M. Neumann , Branko S. Jursic Efficient synthetic procedures for the preparation of acid hydrazines and hydrazides were developed by converting the corresponding carboxylic acid into the methyl ester catalyzed by Amberlyst-15, followed by a reaction with hydrazine monohydrate. Sulfohydrazides were prepared from the corresponding sulfonyl chlorides and hydrazine monohydrate. Both of these group of compounds were condensed with substituted salicylaldehydes using gradient concentration methods that generated a large library of hydrazone, hydrazide and sulfohydrazide analogs. Antifungal activity of the prepared analogs showed that salicylaldehyde hydrazones and hydrazides are potent inhibitors of fungal growth with little to no mammalian cell toxicity, making these analogs promising new targets for future therapeutic development. Graphical abstract image
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Competitive antagonism of insect GABA receptors by 4-substituted 5-(4-piperidyl)-3-isothiazolols ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Genyan Liu , Kenjiro Furuta , Hiromitsu Nakajima , Fumiyo Ozoe , Yoshihisa Ozoe γ-Aminobutyric acid (GABA) receptors are important targets of parasiticides/insecticides. Several 4-substituted analogs of the partial GABAA receptor agonist 5-(4-piperidyl)-3-isothiazolol (Thio-4-PIOL) were synthesized and examined for their antagonism of insect GABA receptors expressed in Drosophila S2 cells or Xenopus oocytes. Thio-4-PIOL showed weak antagonism of three insect GABA receptors. The antagonistic activity of Thio-4-PIOL was enhanced by introducing bicyclic aromatic substituents into the 4-position of the isothiazole ring. The 2-naphthyl and the 3-biphenylyl analogs displayed antagonist potencies with half maximal inhibitory concentrations in the low micromolar range. The 2-naphthyl analog induced a parallel rightward shift of the GABA concentration–response curve, suggesting competitive antagonism by these analogs. Both compounds exhibited weak insecticidal activities against houseflies. Thus, the orthosteric site of insect GABA receptors might be a potential target site of insecticides. Graphical abstract image
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Sequence-specific DNA alkylation and transcriptional inhibition by long-chain hairpin pyrrole–imidazole polyamide–chlorambucil conjugates targeting CAG/CTG trinucleotide repeats ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Sefan Asamitsu , Yusuke Kawamoto , Fumitaka Hashiya , Kaori Hashiya , Makoto Yamamoto , Seiichiro Kizaki , Toshikazu Bando , Hiroshi Sugiyama Introducing novel building blocks to solid-phase peptide synthesis, we readily synthesized long-chain hairpin pyrrole–imidazole (PI) polyamide–chlorambucil conjugates 3 and 4 via the introduction of an amino group into a GABA (γ-turn) contained in 3, to target CAG/CTG repeat sequences, which are associated with various hereditary disorders. A high-resolution denaturing polyacrylamide sequencing gel revealed sequence-specific alkylation both strands at the N3 of adenines or guanines in CAG/CTG repeats by conjugates 3 and 4, with 11bp recognition. In vitro transcription assays using conjugate 4 revealed that specific alkylation inhibited the progression of RNA polymerase at the alkylating sites. Chiral substitution of the γ-turn with an amino group resulted in higher binding affinity observed in SPR assays. These assays suggest that conjugates 4 with 11bp recognition has the potential to cause specific DNA damage and transcriptional inhibition at the alkylating sites. Graphical abstract image
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Exploiting the anti-HIV 6-desfluoroquinolones to design multiple ligands ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Luca Sancineto , Nunzio Iraci , Maria Letizia Barreca , Serena Massari , Giuseppe Manfroni , Gianmarco Corazza , Violetta Cecchetti , Alessandro Marcello , Dirk Daelemans , Christophe Pannecouque , Oriana Tabarrini It is getting clearer that many drugs effective in different therapeutic areas act on multiple rather than single targets. The application of polypharmacology concepts might have numerous advantages especially for disease such as HIV/AIDS, where the rapid emergence of resistance requires a complex combination of more than one drug. In this paper, we have designed three hybrid molecules combining WM5, a quinolone derivative we previously identified as HIV Tat-mediated transcription (TMT) inhibitor, with the tricyclic core of nevirapine and BILR 355BS (BILR) non-nucleoside reverse transcriptase inhibitors (NNRTIs) to investigate whether it could be possible to obtain molecules acting on both transcription steps of the HIV replicative cycle. One among the three designed multiple ligands, reached this goal. Indeed, compound 1 inhibited both TMT and reverse transcriptase (RT) activity. Unexpectedly, while the anti-TMT activity exerted by compound 1 resulted into a selective inhibition of HIV-1 reactivation from latently infected OM10.1 cells, the anti-RT properties shown by all of the synthesized compounds did not translate into an anti-HIV activity in acutely infected cells. Thus, we have herein produced the proof of concept that the design of dual TMT–RT inhibitors is indeed possible, but optimization efforts are needed to obtain more potent derivatives. Graphical abstract image
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Design, stereoselective synthesis, configurational stability and biological activity of 7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Marina Maria Carrozzo , Umberto Maria Battisti , Giuseppe Cannazza , Giulia Puia , Federica Ravazzini , Aurelia Falchicchio , Serena Perrone , Cinzia Citti , Krzysztof Jozwiak , Daniela Braghiroli , Carlo Parenti , Luigino Troisi Chiral 5-arylbenzothiadiazine derivatives have recently attracted particular attention because they exhibit an interesting pharmacological activity as AMPA receptor (AMPAr) positive modulators. However, investigations on their configurational stability suggest a rapid enantiomerization in physiological conditions. In order to enhance configurational stability, preserving AMPAr activity, we have designed the novel compound (R,S)-7-chloro-9-(furan-3-yl)-2,3,3a,4-tetrahydro-1H-benzo[e]pyrrolo[2,1-c][1,2,4]thiadiazine 5,5-dioxide bearing a pyrrolo moiety coupled with the 5-(furan-3-yl) substituent on benzothiadiazine core. A stereoselective synthesis was projected to obtain single enantiomer of the latter compound. Absolute configuration was assigned by X-ray crystal structure. Patch clamp experiments evaluating the activity of single enantiomers as AMPAr positive allosteric modulator showed that R stereoisomer is the active component. Molecular modeling studies were performed to explain biological results. An on-column stopped-flow bidimensional recycling HPLC procedure was applied to obtain on a large scale the active enantiomer with enantiomeric enrichment starting from the racemic mixture of the compound. Graphical abstract image
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Inhibitory effects of p-alkylaminophenol on melanogenesis ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Noriko Takahashi , Masahiko Imai , Yu Komori Melanin protects the skin against ultraviolet (UV) rays. It is produced in excess by UV radiation, which causes skin disorders and pigmentation. Retinoic acid (RA) decreases the levels of epidermal melanin by suppressing the expression of melanogenic enzymes including tyrosinase, which is the rate-limiting enzyme in melanin synthesis. However, RA shows inflammatory effects on the skin. In an effort to develop potent inhibitors of melanin synthesis, new aminophenol derivatives were synthesized based on structure–activity relationship studies of N-(4-hydroxyphenyl)retinamide (1), a derivative of RA. We investigated the inhibitory effects of a series of aminophenols on melanogenesis using B16 melanoma cells. p-Decylaminophenol (3) was the most potent agent examined, showing significant inhibition of B16 tyrosinase activities at concentrations less than what was required to achieve a similar level of inhibition by the well-known tyrosinase inhibitor, kojic acid. Compound 3 decreased melanin content and inhibited protein and mRNA expression for the tyrosinase-related protein-1 (TRP-1). It also inhibited the microphthalmia-associated transcription factor (MITF), a master transcription factor in melanogenesis. Compound 3 suppressed MEK/ERK signal pathways involved in the activation and expression of MITF. The data indicate that 3 inhibits TRP-1 expression by decreasing MITF expression through suppressing MEK/ERK signal pathways. This results in the reduction of melanin in B16 cells. Compound 3 might be an alternative to RA as a potent inhibitor of melanogenesis. Graphical abstract image
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Novel 3,6-bis(imidazolidine)acridines as effective photosensitizers for photodynamic therapy ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): L. Čižeková , A. Grolmusová , Z. Ipóthová , Z. Barbieriková , V. Brezová , L’. Hunáková , J. Imrich , L. Janovec , I. Dovinová , H. Paulíková The photoeffect of new proflavine derivatives with DNA-binding and antitumour activities, 3,6-bis((1-alkyl-5-oxo-imidazolidin-2-yliden)imino)acridine hydrochlorides (AcrDIMs), was studied to evaluate them as potential photosensitizers for photodynamic antitumor therapy. EPR measurements showed that superoxide radical anion and singlet oxygen were produced upon irradiation of AcrDIMs with UV-A light (>300nm) in the presence of molecular oxygen. This indicates that AcrDIMs may act as photosensitizers. The most active pentyl-AcrDIM and hexyl-AcrDIM displayed photocytotoxic effect toward the mouse lymphocytic leukemia cell line L1210 and human ovarian cancer cells A2780. Antitumor activity of pentyl-AcrDIM increased as high as about 12 times (72h incubation) after irradiation of A2780 cells (365nm, 1.05J/cm2). The photocytotoxicity seems to be associated with oxidative stress. Concerning the cell cycle, flow cytometry showed an arrest in the S-phase already 4h after irradiation. In a comet assay, no genotoxicity of AcrDIMs was found. Typical morphologic changes and formation of DNA-ladders indicated induction of apoptotic cell death, though no activation of caspase-3 was observed. Investigation of intracellular localization of pentyl-AcrDIM confirmed its partial accumulation in mitochondria and lysosomes. After irradiation of the A2780 cells, colocalization of pentyl-AcrDIM with monodansylcadaverine, a lysosomal dye, was proven, suggesting that lysosomes in the irradiated cells may be involved in the cell death. Graphical abstract image
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Discovery, structure–activity relationship studies, and anti-nociceptive effects of 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one as novel opioid receptor agonists ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Ming-Fu Cheng , Li-Chin Ou , Shu-Chun Chen , Wan-Ting Chang , Ping-Yee Law , Horace H. Loh , Yu-Sheng Chao , Chuan Shih , Shiu-Hwa Yeh , Shau-Hua Ueng The μ-opioid receptor (MOR) is the major opioid receptor targeted by most analgesics in clinical use. However, the use of all known MOR agonists is associated with severe adverse effects. We reported that the 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-ones are novel opioid receptor agonists. Subsequent structural modification resulted in the potent MOR/KOR (κ-opioid receptor) agonists 19, 20, and 21. Testing the analgesic effect of these in WT B6 mice (tail-flick test) gave ED50 values of 8.4, 10.9, and 26.6mg/kg, respectively. The 1-phenyl-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one core could be addressed in 1 or 2 synthetic steps with moderate to high percent of yield. In the adenylyl cyclase assay, compound 19 displayed a MOR/KOR agonist profile, with IC50 values of 0.73 and 0.41μM, respectively. Current results suggest that compound 19 is a promising lead to go further development and in vitro/in vivo adverse effects studies. Graphical abstract image
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Synthesis of pyrazolo[4,3-a]phenanthridines, a new scaffold for Pim kinase inhibition ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Virginie Suchaud , Laurent Gavara , Francis Giraud , Lionel Nauton , Vincent Théry , Fabrice Anizon , Pascale Moreau A new series of nitro or amino substituted pyrazolo[4,3-a]phenanthridines was synthesized in 6 steps from 5-bromo-6-nitroindazole. The evaluation of their inhibitory potency toward Pim kinases demonstrated that the nitro series could be considered as an interesting starting point for the development of new Pim kinase inhibitors, especially Pim-3. A preferential binding mode was suggested by molecular modeling experiments for nitro series and Pim-1/Pim-3 ATP-binding sites. Moreover, the most active compounds exhibited antiproliferative activities toward PC3 cells in the micromolar range. Graphical abstract image
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Formation of the carboxamidine precursor of cyanuric acid from guanine oxidative lesion dehydro-guanidinohydantoin ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Joris Irvoas , Jérôme Trzcionka , Geneviève Pratviel DNA damage under oxidative stress leads to oxidation of guanine base. The identification of the resulting guanine lesions in cellular DNA is difficult due to the sensitivity of the primary oxidation products to hydrolysis and/or further oxidation. We isolated dehydroguanidino-hydantoin (DGh) (or oxidized guanidinohydantoin), a secondary oxidation product of guanine, and showed that this lesion reacts readily with nucleophiles such as asymmetric peroxides and transforms to 2,4,6-trioxo-1,3,5-triazinane-1-carboxamidine residue. Further hydrolysis of this intermediate leads to cyanuric acid and finally to urea residue. This work demonstrates a new possible pathway for the formation of the well-known carboxamidine precursor of cyanuric acid lesion. Graphical abstract image
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Design, synthesis and evaluation of rivastigmine and curcumin hybrids as site-activated multitarget-directed ligands for Alzheimer’s disease therapy ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Yujie Li , Peng Peng , Li Tang , Yunzhen Hu , Yongzhou Hu , Rong Sheng A series of novel 2-methoxy-phenyl dimethyl-carbamate derivatives were designed, synthesized and evaluated as site-activated MTDLs based on rivastigmine and curcumin. Most of them exhibited good to excellent AChE and BuChE inhibitory activities with sub-micromolar IC50 values. Among all the compounds, 6a demonstrated the most potent AChE inhibition with IC50 value of 0.097μM, which is about 20-fold than that of rivastigmine. In addition, the three selected compounds 5a, 6a and 6e demonstrated inhibitory activity against Aβ self-aggregation similar to cucurmin in TEM assay, which is obviously different from the weak activity of rivastigmine. Moreover, the hydrolysate of 6a (compound 7) also showed potent ABTS + scavenging and moderate copper ion chelating activity in vitro. Graphical abstract image
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A semi-synthetic derivative of artemisinin, artesunate inhibits prostaglandin E2 production in LPS/IFNγ-activated BV2 microglia ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Uchechukwu P. Okorji , Olumayokun A. Olajide Artesunate is a semi-synthetic derivative of artemisinin used to treat malaria, and has been shown to possess anti-inflammatory activity. In this study, we have investigated the effect of artesunate on PGE2 production/COX-2 protein expression in LPS+IFNγ-activated BV2 microglia. To further understand the mechanism of action of this compound, we investigated its interference with NF-κB and p38 MAPK signalling pathways. PGE2 production was determined using EIA, while protein expressions of inflammatory targets like COX-2, mPGES-1, IκB, p38 and MAPKAPK2 were evaluated using western blot. An NF-κB-bearing luciferase reporter gene assay was used to test the effect of artesunate on NF-κB-mediated pro-inflammatory gene expression in HEK293 cells stimulated with TNFα (1ng/ml). Artesunate (2 and 4μM), significantly (p <0.01) suppressed PGE2 production in LPS+IFNγ-activated BV2 microglia. This effect was found to be mediated via reduction in COX-2 and mPGES-1 proteins. Artesunate also produced significant inhibition of TNFα and IL-6 production in activated BV2 microglia. Further investigations showed that artesunate (0.5–4μM) significantly (p <0.001) reduced NF-κB-driven luciferase expression, and inhibited IκB phosphorylation and degradation, through inhibition of IKK. Artesunate inhibited phosphorylation of p38 MAPK and its substrate MAPKAPK2 following stimulation of microglia with LPS+IFNγ. Taken together, we have shown that artesunate prevents neuroinflammation in BV2 microglia by interfering with NF-κB and p38 MAPK signalling. Graphical abstract image
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Discovery of quinazolin-4-amines bearing benzimidazole fragments as dual inhibitors of c-Met and VEGFR-2 ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Lei Shi , Ting-Ting Wu , Zhi Wang , Jia-Yu Xue , Yun-Gen Xu Both c-Met and VEGFR-2 are important targets for the treatment of cancers. In this study, a series of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinazolin-4-amine derivatives were designed and identified as dual c-Met and VEGFR-2 inhibitors. Among these compounds bearing quinazoline and benzimidazole fragments, compound 7j exhibited the most potent inhibitory activity against c-Met and VEGFR-2 with IC50 of 0.05μM and 0.02μM, respectively. It also showed the highest anticancer activity against the tested cancer cell lines with IC50 of 1.5μM against MCF-7 and 8.7μM against Hep-G2. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, which demonstrates that compound 7j is a potential agent for cancer therapy deserving further researching. Graphical abstract image
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Synthesis of protoporphyrin–lipids and biological evaluation of micelles and liposomes ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Shoji Tachikawa , Mohamed E. El-Zaria , Ryu Inomata , Shinichi Sato , Hiroyuki Nakamura Protoporphyrin IX (PPIX) lipids were synthesized by introducing a long alkyl chain, such as C13, C15, and C17, at each vinyl group on PPIX via hydrobromination. The PPIX lipids exhibited a water-soluble property by forming their micelles in water and the PPIX–lipid micelles showed relatively low cytotoxicity toward HeLa cells (IC50 =151.7–379.9μM) without light irradiation. PL-C17 liposomes (post-inserted liposomes) were readily prepared by adding PL-C17 micelle solution to the liposome solution. The IC50 values of PPIX, PL-C17 micelles, and PL-C17 liposomes toward HeLa cells were 0.53, 5.65, and 12.9μM, respectively, after irradiation with a xenon lamp in the 400–800nm range for 2min. PL-C17 liposomes were selectively accumulated in the Golgi apparatus in cells. Graphical abstract image
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Mono- and di-halogenated histamine, histidine and carnosine derivatives are potent carbonic anhydrase I, II, VII, XII and XIV activators ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Mohamed-Chiheb Saada , Daniela Vullo , Jean-Louis Montero , Andrea Scozzafava , Claudiu T. Supuran , Jean-Yves Winum Mono- and di-halogenated histamines, l-histidine methyl ester derivatives and carnosine derivatives incorporating chlorine, bromine and iodine were prepared and investigated as activators of five carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic hCA I, II and VII, and the transmembrane hCA XII and XIV. All of them were activated in a diverse manner by the investigated compounds, with a distinct activation profile. Graphical abstract image
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Design, synthesis, and biological evaluation of scaffold-based tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4) ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Zack G. Zachariassen , Stefanie Thiele , Erik A. Berg , Pernille Rasmussen , Torgils Fossen , Mette M. Rosenkilde , Jon Våbenø , Bengt Erik Haug Structure–activity relationship studies of the cyclopentapeptide CXCR4 antagonists (cyclo(-l-/d-Arg1-Arg2-2-Nal3-Gly4-d-Tyr5-)) suggest that the l-/d-Arg1-Arg2-2-Nal3 tripeptide sequence contained within these cyclopentapeptides serves as a recognition motif for peptidic CXCR4 antagonists. Starting by dissecting the cyclopentapeptide structure and reintroducing cyclic constraints in a stepwise manner, we here report a novel class of scaffold-based tripeptidomimetic CXCR4 antagonists based on the d-Arg-Arg-2-Nal motif. Biological testing of the prototype compounds showed that they represent new peptidomimetic hits; importantly, the modular nature of the scaffold provides an interesting starting point for future ligand optimization. Graphical abstract image
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Structure–affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Antonella Brizzi , Francesca Aiello , Pietro Marini , Maria Grazia Cascio , Federico Corelli , Vittorio Brizzi , Luciano De Petrocellis , Alessia Ligresti , Livio Luongo , Stefania Lamponi , Sabatino Maione , Roger G. Pertwee , Vincenzo Di Marzo In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB1 and CB2 receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands (K i in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB1 and CB2 ligand, with K i values similar to WIN 55,212, exhibiting a CB1 and CB2 agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower affinity but higher CB2 selectivity than 11, proved to behave as a weak CB2 competitive inverse agonist. Graphical abstract image
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Syntheses of coumarin–tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aβ aggregation, and β-secretase ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Qi Sun , Da-Yong Peng , Sheng-Gang Yang , Xiao-Lei Zhu , Wen-Chao Yang , Guang-Fu Yang Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer’s disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine–coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (K i =16.7nM) against human AChE and about 2-fold lower potency (K i =16.1nM) against BChE than tacrine (K i =35.7nM for AChE, K i =8.7nM for BChE), respectively. In addition, some of the tacrine–coumarin hybrids showed simultaneous inhibitory effects against both Aβ aggregation and β-secretase. We therefore conclude that tacrine–coumarin hybrid is an interesting multifunctional lead for the AD drug discovery. Graphical abstract image
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Synthesis and biological evaluation of new simple indolic non peptidic HIV Protease inhibitors: The effect of different substitution patterns ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): C. Bonini , L. Chiummiento , N. Di Blasio , M. Funicello , P. Lupattelli , F. Tramutola , F. Berti , A. Ostric , S. Miertus , V. Frecer , D.-X. Kong New structurally simple indolic non peptidic HIV Protease inhibitors were synthesized from (S)-glycidol by regioselective methods. Following the concept of targeting the protein backbone, different substitution patterns were introduced onto the common stereodefined isopropanolamine core modifying the type of functional group on the indole, the position of the functional group on the indole and the type of the nitrogen containing group (sulfonamides or perhydroisoquinoline), alternatively. The systematic study on in vitro inhibition activity of such compounds confirmed the general beneficial effect of the 5-indolyl substituents in presence of arylsulfonamide moieties, which furnished activities in the micromolar range. Preliminary docking analysis allowed to identify several key features of the binding mode of such compounds to the protease. Graphical abstract image
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Antinociceptive and antidepressant-like action of endomorphin-2 analogs with proline surrogates in position 2 ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Renata Perlikowska , Justyna Piekielna , Marzena Mazur , Robert Koralewski , Jacek Olczak , Jean-Claude do Rego , Jakub Fichna , Jakub Modranka , Tomasz Janecki , Anna Janecka In our efforts to develop new candidate drugs with antinociceptive and/or antidepressant-like activity, two novel endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2) analogs, containing proline surrogates in position 2 were synthesized using commercially available racemic trans-4-phenylpyrrolidine-3-carboxylic acid (4-Ph-β-Pro). The obtained mixture of two diastereoisomeric peptides (2a and 2b) was separated by HPLC and both enantiopure analogs were used in the in vitro and in vivo studies. To assign the absolute configuration to the 4-Ph-β-Pro residues in both peptides, the stereoselective synthesis of (3R,4S)-4-phenylpyrrolidine-3-carboxylic acid was performed and this enantiomer was introduced into position 2 of EM-2 sequence. Based on the HPLC retention times we were able to assign the absolute configuration of 4-Ph-β-Pro residues in both peptide analogs. Analog 2a incorporating (3R,4S)-4-Ph-β-Pro residue produced strong analgesia in mice after intracerebroventricular (icv) administration which was antagonized by the μ-opioid receptor (MOR) antagonist, β-funaltrexamine (β-FNA). This analog also influenced an emotion-related behavior of mice, decreasing immobility time in the forced swimming and tail suspension tests, without affecting locomotor activity. The antidepressant-like effect was reversed by the δ-selective antagonist, naltrindole (NLT) and κ-selective nor-binaltorphimine (nor-BNI). Thus, the experiments with selective opioid receptor antagonists revealed that analgesic action of analog 2a was mediated through the MOR, while the δ- and κ-receptors (DOR and KOR, respectively) were engaged in the antidepressant-like activity. Analog 2b with (3S,4R)-4-Ph-β-Pro in position 2 showed no antinociceptive or antidepressant-like activity in animal studies. Graphical abstract image
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Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-d-glucopyranosylamines ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Vanessa Parmenopoulou , Anastassia L. Kantsadi , Vicky G. Tsirkone , Demetra S.M. Chatzileontiadou , Stella Manta , Spyros E. Zographos , Christina Molfeta , Georgios Archontis , Loranne Agius , Joseph M. Hayes , Demetres D. Leonidas , Dimitri Komiotis Glycogen phosphorylase (GP) is a validated target for the development of new type 2 diabetes treatments. Exploiting the Zinc docking database, we report the in silico screening of 1888 N-acyl-β-d-glucopyranosylamines putative GP inhibitors differing only in their R groups. CombiGlide and GOLD docking programs with different scoring functions were employed with the best performing methods combined in a ‘consensus scoring’ approach to ranking of ligand binding affinities for the active site. Six selected candidates from the screening were then synthesized and their inhibitory potency was assessed both in vitro and ex vivo. Their inhibition constants’ values, in vitro, ranged from 5 to 377μM while two of them were effective at causing inactivation of GP in rat hepatocytes at low μM concentrations. The crystal structures of GP in complex with the inhibitors were defined and provided the structural basis for their inhibitory potency and data for further structure based design of more potent inhibitors. Graphical abstract image
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A new Rhodamine B-based ‘on–off’ chemical sensor with high selectivity and sensitivity toward Fe3+ and its imaging in living cells ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Xiaofeng Bao , Jiaxin Shi , Xuemei Nie , Baojing Zhou , Xinlong Wang , Luyong Zhang , Hong Liao , Tao Pang A new fluorescent chemosensor based on a Rhodamine B and pyrrole conjugate (RBPY) has been designed and synthesized. UV–vis absorption and fluorescence spectroscopic studies show that RBPY exhibits a high selectivity and sensitivity toward Fe3+ among many other metal cations in a MeOH/H2O solution (3:2, v/v, pH 7.10, HEPES buffer, 0.1mM) by forming a 1:1 complex with Fe3+. Furthermore, results reveal that the formation of the RBPY–Fe3+ complex is fully reversible in the presence of sulfide anions and could also be used as an efficient sensor for S2−. Importantly, fluorescence microscopy experiments further demonstrated that RBPY can be utilized as a fluorescent probe for the detection of Fe3+ in human liver (L-02) cells. Graphical abstract image
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Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Daniel W. Carney , Christian D.S. Nelson , Bennett D. Ferris , Julia P. Stevens , Alex Lipovsky , Teymur Kazakov , Daniel DiMaio , Walter J. Atwood , Jason K. Sello Human polyoma- and papillomaviruses are non-enveloped DNA viruses that cause severe pathologies and mortalities. Under circumstances of immunosuppression, JC polyomavirus causes a fatal demyelinating disease called progressive multifocal leukoencephalopathy (PML) and the BK polyomavirus is the etiological agent of polyomavirus-induced nephropathy and hemorrhagic cystitis. Human papillomavirus type 16, another non-enveloped DNA virus, is associated with the development of cancers in tissues like the uterine cervix and oropharynx. Currently, there are no approved drugs or vaccines to treat or prevent polyomavirus infections. We recently discovered that the small molecule Retro-2cycl, an inhibitor of host retrograde trafficking, blocked infection by several human and monkey polyomaviruses. Here, we report diversity-oriented syntheses of Retro-2cycl and evaluation of the resulting analogs using an assay of human cell infections by JC polyomavirus. We defined structure–activity relationships and also discovered analogs with significantly improved potency as suppressors of human polyoma- and papillomavirus infection in vitro. Our findings represent an advance in the development of drug candidates that can broadly protect humans from non-enveloped DNA viruses and toxins that exploit retrograde trafficking as a means for cell entry. Graphical abstract image
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Active immunisation of mice with GnRH lipopeptide vaccine candidates: Importance of T helper or multi-dimer GnRH epitope ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Daryn Goodwin , Pavla Simerska , Cheng-Hung Chang , Friederike M. Mansfeld , Pegah Varamini , Michael J. D’Occhio , Istvan Toth Active immunisation against gonadotropin releasing hormone (GnRH) is a potential alternative to surgical castration. This study focused on the development of a GnRH subunit lipopeptide vaccine. A library of vaccine candidates that contained one or more (up to eight) copies of monomeric or dimeric GnRH peptide antigen, an adjuvanting lipidic moiety based on lipoamino acids, and an additional T helper epitope, was synthesised by solid phase peptide synthesis. The candidates were evaluated in vivo in order to determine the minimal components of this vaccine necessary to induce a systemic immune response. BALB/c mice were immunised with GnRH lipopeptide conjugates, co-administered with or without Complete Freund’s Adjuvant, followed by two additional immunisations. Significant GnRH-specific IgG titres were detected in sera obtained from mice immunised with four of the seven lipopeptides tested, with an increase in titres observed after successive immunisations. This study highlights the importance of for epitope optimisation and delivery system design when producing anti-hapten antibodies in vivo. The results of this study also contribute to the development of future clinical and veterinary immunocontraceptives. Graphical abstract image
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Click approach to the discovery of 1,2,3-triazolylsalicylamides as potent Aurora kinase inhibitors ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Doohee Song , Yunjeong Park , Jieun Yoon , Waqar Aman , Jung-Mi Hah , Jae-Sang Ryu A series of 1,2,3-triazolylsalicylamide derivatives has been developed from the antiproliferative agent 7 and was evaluated for their Aurora kinase inhibitory activity. The novel 1,2,3-triazolylsalicylamide scaffold could be readily assembled by Cu(I)-catalyzed azide–alkyne 1,3-dipolar cycloaddition, allowing rapid access to the structurally diverse analogues. The synthesized 1,2,3-triazolylsalicylamide derivatives revealed a significant Aurora kinase inhibitory activity. In particular, 8g inhibited Aurora A with IC50 values of 0.37μM. The critical role of phenolic –OH in the binding was confirmed by a molecular modeling study. Graphical abstract image
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Amine substitution of quinazolinones leads to selective nanomolar AChE inhibitors with ‘inverted’ binding mode ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Fouad H. Darras , Sarah Wehle , Guozheng Huang , Christoph A. Sotriffer , Michael Decker Selective and nanomolar acetylcholinesterase inhibitors were obtained by connecting tri- and tetracyclic quinazolinones—previously described as moderately active and unselective cholinesterase (ChE) inhibitors—via a hydroxyl group in para position to an anilinic nitrogen with different amines linked via a three carbon atom spacer. These tri- and tetracyclic quinazolinones containing different alicyclic ring sizes and connected to tertiary amines were docked to a high-resolution hAChE crystal structure to investigate the preferred binding mode in relation to results obtained by experimental structure–activity relationships. While the ‘classical orientation’ locating the heterocycle in the active site was rarely found, an alternative binding mode with the basic aliphatic amine in the active center (‘inverted’ orientation) was obtained for most compounds. Analyses of extended SARs based on this inverted binding mode are able to explain the compounds’ binding affinities at AChE. Graphical abstract image
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Design, synthesis and biological evaluation of thienopyridinones as Chk1 inhibitors ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Pinrao Song , Peng Peng , Mengmeng Han , Xianchao Cao , Xiaodong Ma , Tao Liu , Yubo Zhou , Yongzhou Hu A series of thienopyridinone derivatives was designed and synthesized as inhibitors of checkpoint kinase 1 (Chk1). Most of them exhibited moderate to good Chk1 inhibitory activities. Among them, compounds 8q, 8t, and 8w with excellent Chk1 inhibitory activities (IC50 values of 4.05, 6.23, and 2.33nM, respectively) displayed strong synergistic effects with melphalan, a DNA-damaging agent in the cell-based assay. Further kinase profiling indicated that compound 8t was highly selective against CDK2/cyclinA, Aurora A, and PKC. Graphical abstract image
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Antiviral activity of benzimidazole derivatives. III. Novel anti-CVB-5, anti-RSV and anti-Sb-1 agents ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Michele Tonelli , Federica Novelli , Bruno Tasso , Iana Vazzana , Anna Sparatore , Vito Boido , Fabio Sparatore , Paolo La Colla , Giuseppina Sanna , Gabriele Giliberti , Bernardetta Busonera , Pamela Farci , Cristina Ibba , Roberta Loddo A library of eighty-six assorted benzimidazole derivatives was screened for antiviral activity against a panel of ten RNA and DNA viruses. Fifty-two of them displayed different levels of activity against one or more viruses, among which CVB-5, RSV, BVDV and Sb-1 were the most frequently affected. In particular, fourteen compounds exhibited an EC50 in the range 9–17μM (SI from 6 to >11) versus CVB-5, and seven compounds showed an EC50 in the range 5–15μM (SI from 6.7 to ⩾20) against RSV, thus resulting comparable to or more potent than the respective reference drugs (NM108 and ribavirin). Most of these compounds derive from 2-benzylbenzimidazole, but also other molecular scaffolds [as 1-phenylbenzimidazole (2), 2-trifluoromethylbenzimidazole (69), dihydropyrido[3′,2′:4,5]imidazo[1,2-a][1,4]benzodiazepin-5-one (3), dibenzo[c,e]benzimidazo[1,2-a]azepine (22), and 2-(tetrahydropyran-2-yl)benzimidazole (81, 82 and 86)] are related to interesting levels of activity against these or other viruses (BVDV, Sb-1). Thus, these scaffolds (some of which, so far unexplored), represent valid starting points to develop more efficient agents against pathologies caused by CVB-5, RSV, BVDV and Sb-1 viruses. Graphical abstract image
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Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Ramakrishna Edupuganti , Qiantao Wang , Clint D.J. Tavares , Catrina A. Chitjian , James L. Bachman , Pengyu Ren , Eric V. Anslyn , Kevin N. Dalby A small molecule library of pyrido[2,3-d]pyrimidine-2,4-dione derivatives 6–16 was synthesized from 6-amino-1,3-disubstituted uracils 18, characterized, and screened for inhibitory activity against eukaryotic elongation factor-2 kinase (eEF-2K). To understand the binding pocket of eEF-2K, structural modifications of the pyrido[2,3-d]pyrimidine were made at three regions (R1, R2, and R3). A homology model of eEF-2K was created, and compound 6 (A-484954, Abbott laboratories) was docked in the catalytic domain of eEF-2K. Compounds 6 (IC50 =420nM) and 9 (IC50 =930nM) are found to be better molecules in this preliminary series of pyrido[2,3-d]pyrimidine analogs. eEF-2K activity in MDA-MB-231 breast cancer cells is significantly reduced by compound 6, to a lesser extent by compound 9, and is unaffected by compound 12. Similar inhibitory results are observed when eEF-2K activity is stimulated by 2-deoxy-d-glucose (2-DOG) treatment, suggesting that compounds 6 and 9 are able to inhibit AMPK-mediated activation of eEF-2K to a notable extent. The results of this work will shed light on the further design and optimization of novel pyrido[2,3-d]pyrimidine analogs as eEF-2K inhibitors. Graphical abstract image
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Concise syntheses of 7-anilino-indoline-N-benzenesulfonamides as antimitotic and vascular disrupting agents ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Samir Mehndiratta , Yi-Fang Chiang , Mei-Jung Lai , Hsueh-Yun Lee , Mei-Chuan Chen , Ching-Chuan Kuo , Chi-Yen Chang , Jang-Yang Chang , Jing-Ping Liou Described herein is the development of a novel series of 7-anilino-indoline-N-benzenesulfonamides, derived from ABT751 (1), as potent anticancer agents. Amongst the synthesized series, compounds 6, 12, 13, and 14 have shown comparable to better anticancer activity on comparing with compound 1. 7-(4-Cyanophenylamino)-1-(4-methoxybenzenesulfonyl)indoline (13) was found to be the most potent one with up to 6 fold better activity against KB, HT29, and MKN45 cancer cell lines with IC50 values of 49.7, 149, and 92nM, respectively. Compound 13 was also found inhibiting multidrug resistant cancer cell lines, blocking cell cycle at G2/M phase, and inhibiting tubulin polymerization. Capillary disruption assay results revealed that compound 13 was able to disrupt formed capillaries in a concentration-dependent manner without affecting cell viability. Graphical abstract image
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Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Janupally Renuka , Kummetha Indrasena Reddy , Konduri Srihari , Variam Ullas Jeankumar , Morla Shravan , Jonnalagadda Padma Sridevi , Perumal Yogeeswari , Kondra Sudhakar Babu , Dharmarajan Sriram DNA gyrase of Mycobacterium tuberculosis (MTB) is a type II topoisomerase and is a well-established and validated target for the development of novel therapeutics. By adapting the medium throughput screening approach, we present the discovery and optimization of ethyl 5-(piperazin-1-yl) benzofuran-2-carboxylate series of mycobacterial DNA gyraseB inhibitors, selected from Birla Institute of Technology and Science (BITS) database chemical library of about 3000 molecules. These compounds were tested for their biological activity; the compound 22 emerged as the most active potent lead with an IC50 of 3.2±0.15μM against Mycobacterium smegmatis DNA gyraseB enzyme and 0.81±0.24μM in MTB supercoiling activity. Subsequently, the binding of the most active compound to the DNA gyraseB enzyme and its thermal stability was further characterized using differential scanning fluorimetry method. Graphical abstract image
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Cytoprotective pyridinol antioxidants as potential therapeutic agents for neurodegenerative and mitochondrial diseases ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Mohammad Parvez Alam , Omar M. Khdour , Pablo M. Arce , Yana Chen , Basab Roy , Walter G. Johnson , Sriloy Dey , Sidney M. Hecht As part of our ongoing efforts to identify compounds having potential utility in treating neurodegenerative and mitochondrial disorders, a series of pyridinol analogues have been prepared. The synthetic route employed for the preparation of the new analogues is different, and considerably more efficient, than that used in previously reported studies. The new route yields a pair of pyridinol regioisomers that can be readily separated and evaluated. Their ability to quench lipid peroxidation and reactive oxygen species (ROS), and to preserve mitochondrial membrane potential (Δψ m) and support ATP synthesis is reported. The optimal side chain length was found to be 16 carbon atoms. The metabolic stability of those compounds having optimal biological activities was evaluated in vitro using bovine liver microsomes. The omission of any side chain hydroxyl group and introduction of an azetidine moiety at position 6 of the pyridinol redox core (8 and 9) increased their microsomal stability as compared to the exocyclic dimethylamino group. The favorable metabolic stability conferred by the azetidine moiety in compounds 8 and 9 makes these compounds excellent candidates for further evaluation. Graphical abstract image
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Apoptosis-inducing effect of a palladium(II) saccharinate complex of terpyridine on human breast cancer cells in vitro and in vivo ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Ferda Ari , Buse Cevatemre , Elif Ilkay Ikitimur Armutak , Nazlihan Aztopal , Veysel T. Yilmaz , Engin Ulukaya The anti-growth effect of a palladium(II) complex—[PdCl(terpy)](sac)·2H2O] (sac=saccharinate, and terpy=2,2′:6′,2″-terpyridine)—was tested against human breast cancer cell lines, MCF-7 and MDA-MB-231. Anti-growth effect was assayed by the MTT and ATP viability assays in vitro and then confirmed on Balb/c mice in vivo. The mode of cell death was determined by both histological and biochemical methods. The Pd(II) complex had anti-growth effect on a dose dependent manner in vitro and in vivo. The cells died by apoptosis as evidenced by the pyknotic nucleus, cleavage of poly-(ADP-ribose) polymerase (PARP) and induction of active caspase-3. These results suggest that the palladium(II) saccharinate complex of terpyridine represents a potentially active novel complex for the breast cancer treatment, thus warrants further studies. Graphical abstract image
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Synthesis of fluorinated agonist of sphingosine-1-phosphate receptor 1 ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Lucie Aliouane , Sovy Chao , Leyre Brizuela , Emmanuel Pfund , Olivier Cuvillier , Ludovic Jean , Pierre-Yves Renard , Thierry Lequeux The bioactive metabolite sphingosine-1-phosphate (S1P), a product of sphingosine kinases (SphKs), mediates diverse biological processes such as cell differentiation, proliferation, survival and angiogenesis. A fluorinated analogue of S1P receptor agonist has been synthesized by utilizing a ring opening reaction of oxacycles by a lithiated difluoromethylphosphonate anion as the key reaction. In vitro activity of this S1P analogue is also reported. Graphical abstract image
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Design of granulatimide and isogranulatimide analogues as potential Chk1 inhibitors: Study of amino-platforms for their synthesis ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Hubert Lavrard , Frédéric Rodriguez , Evelyne Delfourne The two marine alkaloids granulatimide and isogranulatimide have been shown to inhibit the checkpoint kinase 1 (Chk1), a promising target for cancer treatment. A molecular docking study allowing the design of new potential Chk1 inhibitors based on the natural products skeleton and the synthetic work to an amino-target platform to prepare them are described. Graphical abstract image
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Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Radoslaw Laufer , Grace Ng , Yong Liu , Narendra Kumar B. Patel , Louise G. Edwards , Yunhui Lang , Sze-Wan Li , Miklos Feher , Don E. Awrey , Genie Leung , Irina Beletskaya , Olga Plotnikova , Jacqueline M. Mason , Richard Hodgson , Xin Wei , Guodong Mao , Xunyi Luo , Ping Huang , Erin Green , Reza Kiarash , Dan Chi-Chia Lin , Marees Harris-Brandts , Fuqiang Ban , Vincent Nadeem , Tak W. Mak , Guohua J. Pan , Wei Qiu , Nickolay Y. Chirgadze , Henry W. Pauls TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50 =3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described. Graphical abstract image
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Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors ()
Publication date: 1 September 2014 Source:Bioorganic & Medicinal Chemistry, Volume 22, Issue 17 Author(s): Maria Gabriella Brasca , Marcella Nesi , Nilla Avanzi , Dario Ballinari , Tiziano Bandiera , Jay Bertrand , Simona Bindi , Giulia Canevari , Davide Carenzi , Daniele Casero , Lucio Ceriani , Marina Ciomei , Alessandra Cirla , Maristella Colombo , Sabrina Cribioli , Cinzia Cristiani , Franco Della Vedova , Gabriele Fachin , Marina Fasolini , Eduard R. Felder , Arturo Galvani , Antonella Isacchi , Danilo Mirizzi , Ilaria Motto , Achille Panzeri , Enrico Pesenti , Paola Vianello , Paola Gnocchi , Daniele Donati We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile. Graphical abstract image
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