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Bioorganic & Medicinal Chemistry

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ISSN (Print) 0968-0896
Published by Elsevier

[2565 journals]

Synthesis and biological evaluation of 4,5-dihydro-1H-pyrazole derivatives as potential nNOS/iNOS selective inhibitors. Part 2: Influence of diverse substituents in both the phenyl moiety and the acyl group
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): M. Dora Carrión , Mariem Chayah , Antonio Entrena , Ana López , Miguel A. Gallo , Darío Acuña-Castroviejo , M. Encarnación Camacho
  In a preliminary article, we reported a series of 4,5-dihydro-1H-pyrazole derivatives as neuronal nitric oxide synthase (nNOS) inhibitors. Here we present the data about the inhibition of inducible nitric oxide synthase (iNOS) of these compounds. In general, we can confirm that these pyrazoles are nNOS selective inhibitors. In addition, taking these compounds as a reference, we have designed and synthesized a series of new derivatives by modification of the heterocycle in 1-position, and by introduction of electron-donating or electron-withdrawing substituents in the aromatic ring. These derivatives have been evaluated as nNOS and iNOS inhibitors in order to identify new compounds with improved activity and selectivity. Compound 3r, with three methoxy electron-donating groups in the phenyl moiety, is the most potent nNOS inhibitor, showing good selectivity nNOS/iNOS.
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  PubDate: 2013-06-11T23:04:52Z
Synthesis and biological evaluation of novel tamoxifen analogues
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Michael S. Christodoulou , Nikolas Fokialakis , Daniele Passarella , Aída Nelly García-Argáez , Ornella Maria Gia , Ingemar Pongratz , Lisa Dalla Via , Serkos A. Haroutounian
  A collection of compounds, structurally related to the anticancer drug tamoxifen, used in breast cancer therapy, were designed and synthesized as potential anticancer agents. McMurry coupling reaction was used as the key synthetic step in the preparation of these analogues and the structural assignment of E, Z isomers was determined on the basis of 2D-NOESY experiments. The compounds were evaluated for their antiproliferative activity on breast cancer (MCF-7), cervix adenocarcinoma (HeLa) and biphasic mesothelioma (MSTO-211H) human tumor cell lines. The estrogen like properties of the novel compounds were compared with those of the untreated controls using an estrogen responsive element-based (ERE) luciferase reporter assay and compared to 17β-estradiol (E2). Finally, with the aim to correlate the antiproliferative activity with an intracellular target(s), the effect on relaxation activity of DNA topoisomerases I and II was assayed.
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  PubDate: 2013-06-11T23:04:52Z
Long-chain triazolyl acids as inhibitors of osteoclastogenesis
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Andrew J. Marshall , Jian-Ming Lin , Andrew Grey , Ian R. Reid , Jillian Cornish , William A. Denny
  Saturated fatty acids (e.g., palmitic acid) are known to moderately inhibit the development of osteoclasts in vitro. In pursuit of more effective inhibitors of osteoclastogenesis we explored two new classes of palmitic acid analogues containing either an ether or triazolyl group at various positions along the chain. The compounds were evaluated for their ability to inhibit the formation of osteoclasts in primary mouse bone marrow cultures. The oxyacids were generally prepared by condensation of the appropriate alkyl halides and diols, followed by Jones oxidation. The triazolyl acids were prepared by copper-catalysed click chemistry between alkyl azides and acetylenic acids, or with the appropriately-protected azides and alkynes, followed by deprotection and oxidation. The oxyacids were little more effective than palmitic acid, but the triazolyl analogues were much more effective osteoclastogenesis inhibitors, especially when the triazole was distant from the acid unit.
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  PubDate: 2013-06-11T23:04:52Z
Identification of 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles as new Pim kinase inhibitors
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Virginie Suchaud , Laurent Gavara , Emmanuelle Saugues , Lionel Nauton , Vincent Théry , Fabrice Anizon , Pascale Moreau
  New 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles were prepared and evaluated for their Pim kinase inhibitory potencies as well as their antiproliferative activities toward two prostatic cancer cell lines. Pyrazolocarbazole 15a was found to be a potent Pim kinase modulator with inhibitory potency toward the three isoforms. Compound 6c strongly inhibited Pim-3 with weaker effect toward Pim-1 and Pim-2, and thus could be used as an interesting molecular tool to study Pim-3 biological functions.
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  PubDate: 2013-06-11T23:04:52Z
C3′-endo-puckered pyrrolidine containing PNA has favorable geometry for RNA binding: Novel ethano locked PNA (ethano-PNA)
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Anjan Banerjee , Vaijayanti A. Kumar
  A novel peptide nucleic acid (PNA) analogue is designed with a constraint in the aminoethyl segment of the aegPNA backbone so that the dihedral angle β is restricted within 60–80°, compatible to form PNA:RNA duplexes. The designed monomer is further functionalized with positively charged amino-/guanidino-groups. The appropriately protected monomers were synthesized and incorporated into aegPNA oligomers at predetermined positions and their binding abilities with cDNA and RNA were investigated. A single incorporation of the modified PNA monomer into a 12-mer PNA sequence resulted in stronger binding with complementary RNA over cDNA. No significant changes in the CD signatures of the derived duplexes of modified PNA with complementary RNA were observed.
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  PubDate: 2013-06-11T23:04:52Z
Chromenylchalcones showing cytotoxicity on human colon cancer cell lines and in silico docking with aurora kinases
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Soon Young Shin , Hyuk Yoon , Seunghyun Ahn , Dong-Wook Kim , Sang Ho Kim , Dongsoo Koh , Young Han Lee , Yoongho Lim
  Due to toxicity problems, various plant-derived compounds have been screened to find the chemotherapeutic agents. As anticancer therapeutic agents, chalcones have advantages such as poor interaction with DNA and low risk of mutagenesity. Chromenones show anticancer activities too. Therefore, hybrids of chalcone and chromenone may be potent chemotherapeutic agents. We prepared 16 synthetic chromenylchalcones and applied a clonogenic long-term survival assay method for them on HCT116 human colorectal cancer cell lines. One of chromenylchalcones tested here, chromenylchalcone 11, showed IC50 of 93.1nM which can be competed with the IC50 values of well-known flavonoids such as catechin gallate and epicatechin gallate. Further biological experiments including cell cycle analysis, apoptosis assay, Western blot analysis, and immunofluorescent microscopy were carried out for this compound. In addition, in vitro kinases binding assay performed to explain its molecular mechanism demonstrated the compound inhibited aurora kinases. The binding modes between chromenylchalcone 11 and aurora kinases were elucidated using in silico docking experiments. These findings could be used for designing cancer therapeutic or preventive plant-derived chromenylchalcone agents.
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  PubDate: 2013-06-11T23:04:52Z
Synthesis and biological evaluation of a targeted DNA-binding transcriptional activator with HDAC8 inhibitory activity
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Abhijit Saha , Ganesh N. Pandian , Shinsuke Sato , Junichi Taniguchi , Kaori Hashiya , Toshikazu Bando , Hiroshi Sugiyama
  Development of multifunctional transcriptional activators is of increasing importance as they could trigger complicated gene networks. Recently, we developed a differential gene activating multifunctional small molecule SAHA-PIP (Sδ) by conjugating a histone deacetylase (HDAC) inhibitor, SAHA, to a selective DNA-binding pyrrole-imidazole polyamide (PIP). Epigenetic activity of Sδ was attributed to the active metal-binding (–NHOH) domain of SAHA. We synthesized a derivative of Sδ, called Jδ to evaluate the role of surface recognition domain (–phenyl) of SAHA in Sδ-mediated transcriptional activation. In vitro studies revealed that Jδ displayed potent inhibitory activity against HDAC8. Jδ retained the pluripotency gene-inducing ability of Sδ when used alone and in combination with Sδ; a notable increase in the pluripotency gene expression was observed. Interestingly, Jδ significantly induced the expression of HDAC8-controlled Otx2 and Lhx1. Our results suggest that the epigenetic activity of our multifunctional molecule could be altered to improve its efficiency as a transcriptional activator for intricate gene network(s).
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  PubDate: 2013-06-11T23:04:52Z
Small-molecule modulators of 14-3-3 protein–protein interactions
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Christian Ottmann
  14-3-3 Proteins are eukaryotic adapter proteins that regulate a plethora of physiological processes by binding to several hundred partner proteins. They play a role in biological activities as diverse as signal transduction, cell cycle regulation, apoptosis, host-pathogen interactions and metabolic control. As such, 14-3-3s are implicated in disease areas like cancer, neurodegeneration, diabetes, pulmonary disease, and obesity. Targeted modulation of 14-3-3 protein–protein interactions (PPIs) by small molecules is therefore an attractive concept for disease intervention. In recent years a number of examples of inhibitors and stabilizers of 14-3-3 PPIs have been reported promising a vivid future in chemical biology and drug development for this remarkable class of proteins.
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  PubDate: 2013-06-11T23:04:52Z
Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Mark E. Welker , George Kulik
  This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, that is, inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention.
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  PubDate: 2013-06-11T23:04:52Z
Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Philip C. Simister , James Luccarelli , Sam Thompson , Daniel H. Appella , Stephan M. Feller , Andrew D. Hamilton
  The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 310 helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2–Gab2 interaction in a competition assay, with moderate to low affinities (5: IC50 320μM). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface.
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  PubDate: 2013-06-11T23:04:52Z
Direct targeting of β-catenin: Inhibition of protein–protein interactions for the inactivation of Wnt signaling
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Gernot Hahne , Tom N. Grossmann
  The activation of developmental signaling pathways such as Notch, Hedgehog and Wnt has implications in the onset and progression of numerous types of cancer. Consequently, targeting of such pathways is considered an attractive therapeutic approach. Inhibition of the Wnt signaling cascade proves to be complicated, in part, due to the lack of druggable pathway components. The central hub in Wnt signaling is the protein β-catenin, which is involved in numerous protein–protein interactions. In general, the inhibition of protein–protein interactions is challenging in particular with binding interfaces lacking pronounced hydrophobic pockets. Herein, we give an overview of β-catenin–protein interactions, and we review active agents that were reported to inhibit canonical Wnt signaling via direct targeting of β-catenin.
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  PubDate: 2013-06-11T23:04:52Z
Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Douglas Marcotte , Weike Zeng , Jean-Christophe Hus , Andres McKenzie , Cathy Hession , Ping Jin , Chris Bergeron , Alexey Lugovskoy , Istvan Enyedy , Hernan Cuervo , Deping Wang , Cédric Atmanene , Dominique Roecklin , Malgorzata Vecchi , Valérie Vivat , Joachim Kraemer , Dirk Winkler , Victor Hong , Jianhua Chao , Matvey Lukashev , Laura Silvian
  Keap1 binds to the Nrf2 transcription factor to promote its degradation, resulting in the loss of gene products that protect against oxidative stress. While cell-active small molecules have been identified that modify cysteines in Keap1 and effect the Nrf2 dependent pathway, few act through a non-covalent mechanism. We have identified and characterized several small molecule compounds that specifically bind to the Keap1 Kelch-DC domain as measured by NMR, native mass spectrometry and X-ray crystallography. One compound upregulates Nrf2 response genes measured by a luciferase cell reporter assay. The non-covalent inhibition strategy presents a reasonable course of action to avoid toxic side-effects due to non-specific cysteine modification.
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  PubDate: 2013-06-11T23:04:52Z
Plucking the high hanging fruit: A systematic approach for targeting protein–protein interactions
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Monika Raj , Brooke N. Bullock , Paramjit S. Arora
  Development of specific ligands for protein targets that help decode the complexities of protein–protein interaction networks is a key goal for the field of chemical biology. Despite the emergence of powerful in silico and experimental high-throughput screening strategies, the discovery of synthetic ligands that selectively modulate protein–protein interactions remains a challenge for bioorganic and medicinal chemists. This Perspective discusses emerging principles for the rational design of PPI inhibitors. Fundamentally, the approach seeks to adapt nature’s protein recognition principles for the design of suitable secondary structure mimetics.
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  PubDate: 2013-06-11T23:04:52Z
Design, synthesis and biological evaluation of enzymatically cleavable NSAIDs prodrugs derived from self-immolative dendritic scaffolds for the treatment of inflammatory diseases
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Jinbao Wei , Jianyou Shi , Jing Zhang , Gu He , Junzhu Pan , Jun He , Rui Zhou , Li Guo , Liang Ouyang
  It has been reported that delivery systems based on dendritic prodrugs of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) improved the properties of drug molecules and reduced the side effects and irritation on the gastric mucosa. To find a more effective way in NSAIDs dendritic prodrugs, in this paper, three different dendritic scaffolds of enzymatically cleavable naproxen conjugates have been synthesized in a convergent approach and well characterized by NMR and MS techniques. These self-immolative dendritic NISADs prodrugs programmed to release multiple molecules of the potent naproxen after a single enzymatic activation step, and in 50% human plasma, the drug released from the compound T3 reaching 47.3% after 24h in vitro assay. Moreover, all prodrugs were also found to maintain more significant anti-inflammatory activity, no significant cytotoxicity against HEK293 cells and less degree of ulcerogenic potential in vivo than their monomeric counterpart naproxen. These results provided an effective entry to the development of new dendritic NSAIDs prodrugs.
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  PubDate: 2013-06-11T23:04:52Z
Large conductance Ca2+-activated K+ channel (BKCa) activating properties of a series of novel N-arylbenzamides: Channel subunit dependent effects
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): R.W. Kirby , A. Martelli , V. Calderone , N.G. McKay , K. Lawson
  Large conductance calcium activated potassium channels (BKCa) are fundamental in the control of cellular excitability. Thus, compounds that activate BKCa channels could provide potential therapies in the treatment of pathologies of the cardiovascular and central nervous system. A series of novel N-arylbenzamide compounds, and the reference compound NS1619, were evaluated for BKCa channel opener properties in Human Embryonic Kidney (HEK293) cells expressing the human BKCa channel α-subunit alone or α+β1-subunit complex. Channel activity was determined using a non-radioactive Rb+ efflux assay to construct concentration effect curves for each compound. All N-arylbenzamide compounds and NS1619 evoked significant (p <0.05) concentration related increases in Rb+ efflux both in cells expressing α-subunit alone or α+β1-subunits. Co-expression of the β1-subunit modified the Rb+ efflux responses, relative to that obtained in cells expressing the α-subunit alone, for most of the N-arylbenzamide compounds, in contrast to NS1619. The EC40 values of NS1619, BKMe1 and BKOEt1 were not significantly affected by the co-expression of the BKCa channel α+β1-subunits. In contrast, 5 other N-arylbenzamides (BKPr2, BKPr3, BKPr4, BKH1 and BKVV) showed a significant (p <0.05) 2- to 10-fold increase in EC40 values when tested on the BKCa α+β1-subunit expressing cells compared to BKCa α-subunit expressing cells. Further, the E max values for BKPr4, BKVV and BKH1 were lower in the BKCa channel α+β1-subunit expressing cells. In conclusion, the N-arylbenzamides studied, like NS1619, were able to activate BKCa channels formed of the α-subunit only. The co-expression of the β1-subunit, however, modified the ability of certain compounds to active the channel leading to differentiated pharmacodynamic profiles.
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  PubDate: 2013-06-11T23:04:52Z
Design, synthesis and biological activity evaluation of desloratadine analogues as H1 receptor antagonists
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Yan Lin , Yue Wang , Li-Feng Sima , Dong-Hua Wang , Xiao-Hui Cao , Li-Gong Chen , Bo Chen
  A series of N-substituted desloratadine analogues were designed and synthesized. They were tested for H1 antihistamine activity by inhibiting histamine-induced contraction of isolated ileum muscles of guinea-pigs in vitro and inhibiting histamine-induced asthmatic reaction in guinea-pigs in vivo. All the evaluated compounds exhibited significant antihistamine activity compared with desloratadine. Five active compounds induced no sedative effects on mouse and four of them exhibited lower anticholinergic side effects than desloratadine. Among these analogues, compound 10, (1S,4S)-4-chlorocyclohexyl desloratadine displayed the highest activity and best safety profile. And it was believed to be a potential candidate as the 3rd generation antihistamine.
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  PubDate: 2013-06-11T23:04:52Z
Novel synthetic acridine derivatives as potent DNA-binding and apoptosis-inducing antitumor agents
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Xuliang Lang , Lulu Li , Yuzong Chen , Qinsheng Sun , Qin Wu , Feng Liu , Chunyan Tan , Hongxia Liu , Chunmei Gao , Yuyang Jiang
  Acridine derivatives have been explored as DNA-binding anticancer agents. Some derivatives show undesired pharmacokinetic properties and new derivatives need to be explored. In this work, a series of novel acridine analogues were synthesized by modifying previously unexplored linkers between the acridine and benzene groups and their antiproliferative activity and the DNA-binding ability were evaluated. Among these derivatives, compound 5c demonstrated DNA-binding capability and topoisomerase I inhibitory activity. In K562 cell lines, 5c induced apoptosis through mitochondria-dependent intrinsic pathways. These data suggested that compound 5c and other acridine derivatives with modified linkers between the acridine and benzene groups might be potent DNA-binding agents.
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  PubDate: 2013-06-11T23:04:52Z
Synthesis and bioactive evaluation of novel hybrids of metronidazole and berberine as new type of antimicrobial agents and their transportation behavior by human serum albumin
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Ling Zhang , Juan-Juan Chang , Shao-Lin Zhang , Guri L.V. Damu , Rong-Xia Geng , Cheng-He Zhou
  A series of novel hybrids of metronidazole and berberine as new type of antimicrobial agents were synthesized and characterized by 1H NMR, 13C NMR, IR, MS and HRMS spectra. Bioactive assay manifested that most of the prepared compounds exhibited effective antibacterial and antifungal activities and some showed comparable or superior potency against Methicillin-resistant Staphylococcus aureus to reference drugs Norfloxacin, Chloromycin and Berberine. The transportation behavior of human serum albumin (HSA) to the highly active compound 5g was evaluated and revealed that the association of imidazole derivative 5g with HSA was spontaneous and the electrostatic interactions played important roles in the transportation of HSA to 5g. The calculated parameters indicated that compound 5g could be effectively stored and carried by HSA.
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  PubDate: 2013-06-11T23:04:52Z
Synthesis and preliminary biological evaluation of a compound library of triazolylcyclitols
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Gonzalo Carrau , Carine C. Drewes , Ana Lúcia B. Shimada , Ana Bertucci , Sandra H.P. Farsky , Helio A. Stefani , David Gonzalez
  A small library of compounds was prepared by a combination of toluene dioxygenase (TDO)-catalyzed enzymatic dihydroxylation and copper(I)-catalyzed Hüisgen cycloaddition. Some compounds were obtained by coupling an alkyne and a conduritol derivative, while more complex structures were obtained by a double Hüisgen reaction of a dialkyne and two molecules of the cyclitol. The compounds were fully characterized and subjected to preliminary biological screening.
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  PubDate: 2013-06-11T23:04:52Z
Discovery of novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones as human chymase inhibitors using structure-based drug design
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Taisaku Tanaka , Hajime Sugawara , Hiroshi Maruoka , Seiichi Imajo , Tsuyoshi Muto
  A novel series of 6-benzyl substituted 4-aminocarbonyl-1,4-diazepane-2,5-diones were explored as human chymase inhibitors using structure-based drug design according to the X-ray cocrystal structure of chymase and compound 1. The optimization focused on the prime site led to the attainment of compounds that showed potent inhibitory activity, and among them, 18R shows a novel interaction mode.
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  PubDate: 2013-06-11T23:04:52Z
Synthesis and anti-HCMV activity of 1-[ω-(phenoxy)alkyl]uracil derivatives and analogues thereof
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Mikhail S. Novikov , Denis A. Babkov , Maria P. Paramonova , Anastasia L. Khandazhinskaya , Alexander A. Ozerov , Alexander O. Chizhov , Graciela Andrei , Robert Snoeck , Jan Balzarini , Katherine L. Seley-Radtke
  HCMV infection represents a life-threatening condition for immunocompromised patients and newborn infants and novel anti-HCMV agents are clearly needed. In this regard, a series of 1-[ω-(phenoxy)alkyl]uracil derivatives were synthesized and examined for antiviral properties. Compounds 17, 20, 24 and 28 were found to exhibit highly specific and promising inhibitory activity against HCMV replication in HEL cell cultures with EC50 values within 5.5–12μM range. Further studies should be undertaken to elucidate the mechanism of action of these compounds and the structure–activity relationship for the linker region.
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  PubDate: 2013-06-11T23:04:52Z
1-substituted apomorphines as potent dopamine agonists
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Reet Reinart-Okugbeni , Argo Vonk , Ain Uustare , Zsuzsanna Gyulai , Attila Sipos , Ago Rinken
  A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5β-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands.
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  PubDate: 2013-06-11T23:04:52Z
Peptidomimetic modification improves cell permeation of bivalent farnesyltransferase inhibitors
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Shinnosuke Machida , Mai Tsubamoto , Nobuo Kato , Kazuo Harada , Junko Ohkanda
  Bivalent enzyme inhibitors, in which a surface binding module is linked to an active site binding module through a spacer, are a robust approach for site-selectively delivering a minimally-sized agent to a protein surface to regulate its functions, such as protein–protein interactions (PPIs). Previous research revealed that these agents effectively disrupt the interaction between farnesyltransferase (FTase) and the C-terminal region of K-Ras4B protein. However, the whole cell activity of these peptide-based agents is limited due to their low membrane permeability. In this study, we tested a peptidomimetic modification of these bivalent agents using a previously developed inhibitor, FTI-249, and evaluated their cell permeability and biological activity in cells. Confocal cell imaging using fluorescently-labeled agents showed that the peptidomimetic 3-BODIPY penetrated cells, while the peptide-based 1-BODIPY did not. Cell-based evaluation demonstrated that peptidomimetic 3 at a concentration of 100μM inhibited HDJ-2 processing in cells, indicating that this peptidomimetic modification improves cell permeability, thus leading to enhanced whole cell activity of the bivalent compounds.
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  PubDate: 2013-06-11T23:04:52Z
Effects on polo-like kinase 1 polo-box domain binding affinities of peptides incurred by structural variation at the phosphoamino acid position
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Wenjian Qian , Jung-Eun Park , Fa Liu , Kyung S. Lee , Terrence R. Burke Jr.
  Protein–protein interactions (PPIs) mediated by the polo-box domain (PBD) of polo-like kinase 1 (Plk1) serve important roles in cell proliferation. Critical elements in the high affinity recognition of peptides and proteins by PBD are derived from pThr/pSer-residues in the binding ligands. However, there has been little examination of pThr/pSer mimetics within a PBD context. Our current paper compares the abilities of a variety of amino acid residues and derivatives to serve as pThr/pSer replacements by exploring the role of methyl functionality at the pThr β-position and by replacing the phosphoryl group by phosphonic acid, sulfonic acid and carboxylic acids. This work sheds new light on structure activity relationships for PBD recognition of phosphoamino acid mimetics.
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  PubDate: 2013-06-11T23:04:52Z
Benzimidazole-2-one: A novel anchoring principle for antagonizing p53-Mdm2
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Wei Wang , Haiping Cao , Siglinde Wolf , Miguel S. Camacho-Horvitz , Tad A. Holak , Alexander Dömling
  Herein we propose the benzimidazole-2-one substructure as a suitable tryptophan mimic and thus a reasonable starting point for the design of p53 Mdm2 antagonists. We devise a short multicomponent reaction route to hitherto unknown 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamides by reacting mono N-carbamate protected phenylenediamine in a Ugi-3CR followed by base induced cyclisation. Our preliminary synthesis and screening results are presented here. The finding of the benzimidazolone moiety as a tryptophan replacement in mdm2 is significant as it offers access to novel scaffolds with potentially higher selectivity and potency and improved biological activities. Observing low μM affinities to mdm2 by NMR and fluorescence polarization we conclude that the 2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetamide scaffold might be a good starting point to further optimize the affinities to Mdm2.
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  PubDate: 2013-06-11T23:04:52Z
Synthesis, biological evaluation and molecular modeling of substituted 2-aminobenzimidazoles as novel inhibitors of acetylcholinesterase and butyrylcholinesterase
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Jinmei Zhu , Chun-Feng Wu , Xiaobing Li , Gui-Sheng Wu , Shan Xie , Qian-Nan Hu , Zixin Deng , Michael X. Zhu , Huai-Rong Luo , Xuechuan Hong
  A series of novel 2-aminobenzimidazole derivatives were synthesized under microwave irradiation. Their biological activities were evaluated on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A number of the 2-aminobenzimidazole derivatives showed good inhibitory activities to AChE and BuChE. Among them, compounds 9, 12 and 13 were found to be >25-fold more selective for BuChE than AChE. No evidence of cytotoxicity was observed by MTT assay in PC12 cells or HepG2 cells exposed to 100μM of the compounds. Molecular modeling studies indicate that the benzimidazole moiety of compounds 9, 12 and 13 forms a face-to-face π–π stacking interaction in a ‘sandwich’ form with the indole ring of Trp82 (4.09Å) in the active gorge, and compounds 12 and 13 form a hydrogen bond with His438 at the catalytic site of BuChE. In addition, compounds 12 and 13 fit well into the hydrophobic pocket formed by Ala328, Trp430 and Tyr332 of BuChE. Our data suggest the 2-aminobenzimidazole drugs as promising new selective inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.
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  PubDate: 2013-06-11T23:04:52Z
Graphical contents list
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  
  PubDate: 2013-06-11T23:04:52Z
Inhibition and stabilization of protein–protein interactions
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Christian Ottmann , John Robinson
  
  PubDate: 2013-06-11T23:04:52Z
Pt(II) complexes with (N,N′) or (C,N,E)− (E=N,S) ligands: Cytotoxic studies, effect on DNA tertiary structure and structure–activity relationships
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Joan Albert , Ramon Bosque , Margarita Crespo , Jaume Granell , Concepción López , Roldán Cortés , Asensio Gonzalez , Josefina Quirante , Carme Calvis , Ramon Messeguer , Laura Baldomà , Josefa Badia , Marta Cascante
  The cytotoxic activity of two series of platinum(II) complexes containing the polyfunctional imines R1–CHN–R2 [R1 =phenyl or ferrocenyl unit and R2 =(CH2) n –CH2–NMe2 where n =1 or 2) (1 and 2) or C6H4-2-SMe (3)] acting as a bidentate (N,N′) (4–7) or terdentate [C(phenyl or ferrocenyl),N,N′]− (8–10) or [C(ferrocenyl),N,S]− ligand (11) in front of A549 lung, MDA-MB231 breast and HCT116 colon human adenocarcinoma cell lines is reported. The results reveal that most of the platinum(II) complexes are active against the three assayed lines and compounds 6, 7 and the platinacycles 10 and 11 exhibit a remarkable antiproliferative activity, even greater than cisplatin itself, in the cisplatin resistant HCT116 human cancer cell line. Electrophoretic DNA migration studies showed that most of them modify the DNA tertiary structure in a similar way as the reference cisplatin. Solution studies of a selection of the most relevant complexes have also been performed in order to test: (a) their stability in the aqueous biological medium and/or the formation of biologically active species and (b) their proclivity to react with 9-methylguanine (9-MeG), as a model nucleobase. Computational studies at DFT level have also been performed in order to explain the different solution behaviour of the complexes and their proclivity to react with the nucleobase.
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  PubDate: 2013-06-11T23:04:52Z
Editorial board
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  
  PubDate: 2013-06-11T23:04:52Z
Microwave assisted solid phase synthesis of highly functionalized N-alkylated oligobenzamide α-helix mimetics
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Kérya Long , Thomas A. Edwards , Andrew J. Wilson
  Protein–protein interactions (PPIs) mediate cellular pathways and are implicated in numerous aberrant conditions. α-Helix mimetics—small molecules that reproduce the spatial projection of key residues from an α-helix involved in a PPI—are attractive generic templates for development of screening libraries, however library syntheses of α-helix mimetics with diverse functionality are less established. This manuscript describes the automated, microwave assisted solid phase synthesis based on one such scaffold; an N-alkylated oligobenzamide.
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  PubDate: 2013-06-11T23:04:52Z
Inhibition of HIV-1 integrase dimerization and activity with crosslinked interfacial peptides
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Lei Zhao , Jean Chmielewski
  Alternative modes of inhibition for the design of anti-HIV therapies are sought due to the resistance of HIV to a number of the currently approved drugs. A non-active site strategy for generating potent inhibitors of HIV-1 integrase is described based on blocking protein association. Peptides α5 and α6 derived from the HIV-1 integrase dimeric interface have previously demonstrated efficacious dimerization inhibition of HIV-1 integrase. Due to the proximity of the termini of these peptides within the integrase structure, a focused library of tethered agents was designed based on crosslinking the peptides α5 and α6 to mimic a larger interfacial region. The best crosslinked inhibitors are approximately five-fold more potent against HIV-1 integrase than the individual peptides alone or in combination. The most active agents have an inhibitory constant in the mid-nM range and function via a dissociative mechanism of inhibition.
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  PubDate: 2013-06-11T23:04:52Z
Functional consequences of retro-inverso isomerization of a miniature protein inhibitor of the p53–MDM2 interaction
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Chong Li , Changyou Zhan , Le Zhao , Xishan Chen , Wei-Yue Lu , Wuyuan Lu
  Peptide retro-inverso isomerization is thought to be functionally neutral and has been widely used as a tool for designing proteolytically stable d-isomers to recapitulate biological activities of their parent l-peptides. Despite success in a wide range of applications, exceptions amply exist that clearly defy this rule of thumb when parent l-peptides adopt an α-helical conformation in their bound state. The detrimental energetic effect of retro-inverso isomerization of an α-helical l-peptide on its target protein binding has been estimated to be 3.0–3.4kcal/mol. To better understand how the retro-inverso isomer of a structured protein works at the molecular level, we chemically synthesized and functionally characterized the retro-inverso isomer of a rationally designed miniature protein termed stingin of 18 amino acid residues, which adopts an N-terminal loop and a C-terminal α-helix stabilized by two intra-molecular disulfide bridges. Stingin emulated the transactivation peptide of the p53 tumor suppressor protein and bound with high affinity and via its C-terminal α-helix to MDM2 and MDMX—the two negative regulators of p53. We also prepared the retro isomer and d-enantiomer of stingin for comparative functional studies using fluorescence polarization and surface plasmon resonance techniques. We found that retro-inverso isomerization of l-stingin weakened its MDM2 binding by 720 fold (3.9kcal/mol); while enantiomerization of l-stingin drastically reduced its binding to MDM2 by three orders of magnitude, sequence reversal completely abolished it. Our findings demonstrate the limitation of peptide retro-inverso isomerization in molecular mimicry and reinforce the notion that the strategy works poorly with biologically active α-helical peptides due to inherent differences at the secondary and tertiary structural levels between an l-peptide and its retro-inverso isomer despite their similar side chain topologies at the primary structural level. 1
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  PubDate: 2013-06-11T23:04:52Z
Synthesis and in vitro evaluation of glycosyl derivatives of luteinizing hormone-releasing hormone (LHRH)
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Shayli Varasteh Moradi , Friederike M. Mansfeld , Istvan Toth
  Luteinizing hormone-releasing hormone (LHRH) analogues are used extensively for the treatment of various hormone-dependent diseases. However, none of the currently marketed derivatives can be administered orally. Modification of peptide sequences by attachment of carbohydrate moieties is a promising strategy that may increase the metabolic stability of the target peptide and enhance its transport across cell membranes, subsequently improving peptide bioavailability. In this study, either the N- or C-terminus of the LHRH peptide was altered by attachment of carbohydrate moieties. Caco-2 cells were chosen as an in vitro model to investigate both the permeability and stability of the new LHRH analogues. Our findings show that conjugating sugar moieties to the N-terminus of the LHRH peptide significantly increased both permeability and metabolic stability of most of the modified LHRH derivatives.
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  PubDate: 2013-06-11T23:04:52Z
Development of time resolved fluorescence resonance energy transfer-based assay for FXR antagonist discovery
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Donna D. Yu , Wenwei Lin , Taosheng Chen , Barry M. Forman
  FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism. FXR ligands have been investigated in preclinical studies for targeted therapy against metabolic diseases, but have shown limitations. Therefore, there is a need for new agonist or antagonist ligands of FXR, both for potential clinical applications, as well as to further elucidate its biological functions. Here we describe the use of the X-ray crystal structure of FXR complexed with the potent small molecule agonist GW4064 to design and synthesize a novel fluorescent, high-affinity probe (DY246) for time resolved fluorescence resonance energy transfer (TR-FRET) assays. We then used the TR-FRET assay for high throughput screening of a library of over 5000 bioactive compounds. From this library, we identified 13 compounds that act as putative FXR transcriptional antagonists.
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  PubDate: 2013-06-11T23:04:52Z
20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Junhua Liu , Xu Wang , Peng Liu , Rongxin Deng , Min Lei , Wantao Chen , Lihong Hu
  Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure–activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3–2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.
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  PubDate: 2013-06-11T23:04:52Z
1,4-Diaryl-substituted triazoles as cyclooxygenase-2 inhibitors: Synthesis, biological evaluation and molecular modeling studies
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Jatinder Kaur , Atul Bhardwaj , Sai Kiran Sharma , Frank Wuest
  A novel group of 1,4-diaryl-substituted triazoles was designed and synthesized by introducing the cyclooxygenase-2 (COX-2) pharmacophore SO2NH2 attached to one aryl ring and various substituents (H, F, Cl, CH3 or OCH3) attached to the other aryl ring. The effects of size and flexibility of the compounds upon COX-1/COX-2 inhibitory potency and selectivity was studied by increasing the size of an alkyl linker chain [(–CH2) n , where n =0, 1, 2]. In vitro COX-1/COX-2 inhibition studies showed that all compounds (14–18, 21–25 and 28–32) are more potent inhibitors of COX-2 isozyme (IC50 =0.17–28.0μM range) compared to COX-1 isozyme (IC50 =21.0 to >100μM range). Within the group of 1,4 diaryl-substituted triazoles, 4-{2-[4-(4-chloro-phenyl)-[1,2,3]triazol-1-yl]-ethyl}-benzenesulfonamide (compound 30) displayed highest COX-2 inhibitory potency and selectivity (COX-1: IC50 =>100μM, COX-2: IC50 =0.17μM, SI >588). Molecular docking studies using the catalytic site of COX-1 and COX-2, respectively, provided complementary theoretical support for the obtained experimental biological structure–activity relationship data. Results of molecular docking studies revealed that COX-2 pharmacophore SO2NH2 in compound 30 is positioned in the secondary pocket of COX-2 active site; with the nitrogen atom of the SO2NH2 group being hydrogen bonded to Q192 (N⋯OC=2.85Å), and one of the oxygen atoms of SO2NH2 group forming a hydrogen bond to H90 (SO⋯N=2.38Å).
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  PubDate: 2013-06-11T23:04:52Z
Synthesis and functional analysis of deferriferrichrysin derivatives: Application to colorimetric pH indicators
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Yuka Kobayashi , Shinya Oishi , Kazuya Kobayashi , Hiroaki Ohno , Hiroko Tsutsumi , Yoji Hata , Nobutaka Fujii
  Deferriferrichrysin belongs to the siderophore peptide family which are Fe(III)-coordinating cyclic peptides. The common structure of this family is three consecutive hydroxamate moieties, such as N δ-acetyl-N δ-hydroxy-l-ornithine (Aho). We have designed two deferriferrichrysin derivatives where three Aho residues were arranged as: cyclo(-Aho-Gly-Aho-Gly-Aho-Gly-) and cyclo(-Aho-Ser-Aho-Ser-Aho-Ser-). Comparative evaluation of the physicochemical properties of their Fe(III) complexes revealed that naturally occurring deferriferrichrysin formed a more stable Fe(III) complex when compared with the two derivatives. This result shows that three consecutive Aho residues are indispensable for high affinity Fe(III) binding by deferriferrichrysin. Of note, the observed pH-dependent chromogenic response of the Fe(III) complexes of the derivatives suggests that these two derivatives should function as sensitive pH indicators in acidic environments.
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  PubDate: 2013-06-11T23:04:52Z
Synthesis of organic nitrates of luteolin as a novel class of potent aldose reductase inhibitors
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Qi-Qin Wang , Ning Cheng , Xiao-Wei Zheng , Sheng-Ming Peng , Xiao-Qing Zou
  Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099±0.008) μM to (2.833±0.102) μM. O7-Nitrooxyethyl-O3′,O4′-ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50 =(0.099±0.008) μM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure–activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications.
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  PubDate: 2013-06-11T23:04:52Z
Nucleic acid changes during photodynamic inactivation of bacteria by cationic porphyrins
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Eliana Alves , Maria A.F. Faustino , João P.C. Tomé , Maria G.P.M.S. Neves , Augusto C. Tomé , José A.S. Cavaleiro , Ângela Cunha , Newton C.M. Gomes , Adelaide Almeida
  Light activation of photosensitizing dyes in presence of molecular oxygen generates highly cytotoxic reactive oxygen species leading to cell inactivation. Nucleic acids are molecular targets of this photodynamic action but not considered the main cause of cell death. The in vivo effect of the photodynamic process on the intracellular nucleic acid content of Escherichia coli and Staphylococcus warneri was evaluated herein. Two cationic porphyrins (Tetra-Py+-Me and Tri-Py+-Me-PF) were used to photoinactivate E. coli (5.0μM; 108 cellsmL−1) and S. warneri (0.5μM; 108 cellsmL−1) upon white light irradiation at 4.0mWcm−2 for 270min and 40min, respectively. Total nucleic acids were extracted from photosensitized bacteria after different times of irradiation and analyzed by agarose gel electrophoresis. The double-stranded DNA was quantified by fluorimetry and the porphyrin binding to bacteria was determined by spectrofluorimetry. E. coli was completely photoinactivated with both porphyrins (5.0μM), whereas S. warneri was only completely inactivated by Tri-Py+-Me-PF (0.5μM). The hierarchy of nucleic acid changes in E. coli was in the order: 23S rRNA>16S rRNA>genomic DNA. The nucleic acids of S. warneri were extensively reduced after 5min with Tri-Py+-Me-PF but almost unchanged with Tetra-Py+-Me after 40min of irradiation. The amount of Tri-Py+-Me-PF bound to E. coli after washing the cells is higher than Tetra-Py+-Me and the opposite was observed for S. warneri. The binding capacity of the photosensitizers is not directly related to the PDI efficiency or nucleic acid reduction and this reduction occurs in parallel with the decrease of surviving cells.
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  PubDate: 2013-06-11T23:04:52Z
Synthesis and evaluation of novel orally active p53–MDM2 interaction inhibitors
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Masaki Miyazaki , Hiroyuki Naito , Yuuichi Sugimoto , Keisuke Yoshida , Haruko Kawato , Tooru Okayama , Hironari Shimizu , Masaya Miyazaki , Mayumi Kitagawa , Takahiko Seki , Setsuko Fukutake , Yoshinobu Shiose , Masashi Aonuma , Tsunehiko Soga
  We have discovered and reported potent p53–MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53.
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  PubDate: 2013-06-11T23:04:52Z
Exploring DOXP-reductoisomerase binding limits using phosphonated N-aryl and N-heteroarylcarboxamides as DXR inhibitors
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Taryn Bodill , Anne C. Conibear , Marius K.M. Mutorwa , Jessica L. Goble , Gregory L. Blatch , Kevin A. Lobb , Rosalyn Klein , Perry T. Kaye
  DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand–receptor interactions.
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  PubDate: 2013-06-11T23:04:52Z
Design, synthesis and evaluation of retinoids with novel bulky hydrophobic partial structures
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Yohei Amano , Masayuki Noguchi , Madoka Nakagomi , Hideaki Muratake , Hiroshi Fukasawa , Koichi Shudo
  Many synthetic retinoids contain an aromatic structure with a bulky hydrophobic fragment. In order to obtain retinoids with therapeutic potential that do not bind to or activate retinoic acid X receptors (RXRs), we focused on the introduction of novel hydrophobic moieties, that is, metacyclophane, phenalene and benzoheptalene derivatives. The designed compounds were synthesized and their agonistic activities towards RARs and RXRs were evaluated. Most of the active compounds showed selectivity for RARα and RARβ over RARγ, and higher RARβ transactivating activity seemed to correlate with higher cell differentiation-inducing activity towards promyelocytic leukemia cell line HL-60. These compounds showed no agonistic activity towards RXRs.
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  PubDate: 2013-06-11T23:04:52Z
Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Oleg Sadovski , Justin W. Hicks , Jun Parkes , Roger Raymond , José Nobrega , Sylvain Houle , Mariateresa Cipriano , Christopher J. Fowler , Neil Vasdev , Alan A. Wilson
  Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an 18F-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [18F]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17–22% (from [18F]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82nM after a preincubation of 60min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [18F]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [18F]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [18F]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.
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  PubDate: 2013-06-11T23:04:52Z
(+)-Altholactone exhibits broad spectrum immune modulating activity by inhibiting the activation of pro-inflammatory cytokines in RAW 264.7 cell lines
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Tyler A. Johnson , Johann Sohn , Aidan E. Ward , Tanya L. Cohen , Nicholas D. Lorig-Roach , Haixia Chen , Ronaldo A. Pilli , Elizabeth A. Widjaja , Muhammad Hanafi , Leonardus B.S. Kardono , Puspa D. Lotulung , Kyria Boundy-Mills , Leonard F. Bjeldanes
  An evaluation of Indonesian plants to identify compounds with immune modulating activity revealed that the methanolic extract of an Alphonsea javanica Scheff specimen possessed selective anti-inflammatory activity in a nuclear factor-kappa B (NF-κB) luciferase and MTT assay using transfected macrophage immune (Raw264.7) cells. A high-throughput LC/MS-ELSD based library approach of the extract in combination with the NF-κB and MTT assays revealed the styryl lactone (+)-altholactone (2) was responsible for the activity. Compound 2, its acetylated derivate (+)-3-O-acetylaltholactone (3), and the major compound of this class, (+)-goniothalmin (1), were further evaluated to determine their anti-inflammatory potential in the NF-κB assay. Concentration–response studies of 1–3 indicated that only 2 possessed NF-κB based anti-inflammatory activity. Compound 2 reduced the LPS-induced NO production, phosphorylation of IκBα, and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) using Western blot analysis. Further studies using qPCR indicated 2 reduced the expression of eight pro-inflammatory cytokines/enzymes (0.8–5.0μM) which included: COX-2, iNOS, IP-10, IL-1β, MCP-1, GCS-F, IL-6 and IFN-β. These results indicated that 2 displays broad spectrum immune modulating activity by functioning as an anti-inflammatory agent against LPS-induced NF-κB signaling. Conversely the selective cytotoxicity and in vivo anti-tumor and anti-inflammatory activity previously reported for 1 do not appear to arise from a mechanism that is linked to the NF-κB immune mediated pathway.
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  PubDate: 2013-06-11T23:04:52Z
Antagonism of L-type Ca2+ channels CaV1.3 and CaV1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Soosung Kang , Garry Cooper , Sara Fernandez Dunne , Chi-Hao Luan , D. James Surmeier , Richard B. Silverman
  The L-type calcium channel (LTCC) CaV1.3 is regarded as a new potential therapeutic target for Parkinson’s disease. Calcium influx through CaV1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a CaV1.3 antagonist selective over CaV1.2 is essential because CaV1.2 pore-forming subunits are the predominant form of LTCCs and are abundant in the central nervous and cardiovascular systems. We have explored 1,4-dihydropyrimidines and 4H-pyrans to identify potent and selective antagonists of CaV1.3 relative to CaV1.2 LTCCs. A library of 36 dihydropyridine (DHP)-mimic 1,4-dihydropyrimidines and 4H-pyrans was synthesized, and promising chiral compounds were resolved. The antagonism studies of CaV1.3 and CaV1.2 LTCCs using DHP mimic compounds showed that dihydropyrimidines and 4H-pyrans are effective antagonists of DHPs for CaV1.3 LTCCs. Some 1,4-dihydropyrimidines are more selective than isradipine for CaV1.3 over CaV1.2, shown here by both calcium flux and patch-clamp electrophysiology experiments, where the ratio of antagonism is around 2–3. These results support the hypothesis that the modified hydrogen bonding donor/acceptors in DHP-mimic dihydropyrimidines and 4H-pyrans can interact differently with DHP binding sites, but, in addition, the data suggest that the binding sites of DHP in CaV1.3 and CaV1.2 LTCCs are very similar.
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  PubDate: 2013-06-11T23:04:52Z
6′-Methyl-5′-homoaristeromycin: A structural variation of the anti-orthopox virus candidate 5′-homoaristeromycin
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Minmin Yang , Wei Ye , Stewart W. Schneller
  The synthesis of 6′-methyl-5′-homoaristeromycin is described from a known 6′-ethyl ester. Antiviral analysis showed the (S)-6′ stereoisomer retained the vaccinia activity of the parent 5′-homoaristeromycin (1) while the (R)-6′ isomer was less active. Both were weaker than 1 towards cowpox. The diastereomers were equally active versus Epstein Barr virus while (S)-6′ was three times more active toward vesicular stomatitis virus than (R)-6′. The diastereomers were inactive towards numerous other viruses. The CC50 for both diastereomers was >300μM.
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  PubDate: 2013-06-11T23:04:52Z
The synthesis of neurotensin antagonist SR 48692 for prostate cancer research
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): I.R. Baxendale , S. Cheung , M.O. Kitching , S.V. Ley , J.W. Shearman
  An improved synthesis of the molecule SR 48692 is presented and its use as a neurotensin antagonist biological probe for use in cancer research is described. The preparation includes an number of enhanced chemical conversions and strategies to overcome some of the limiting synthetic transformations in the original chemical route.
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  PubDate: 2013-06-11T23:04:52Z
Synthesis and antibacterial activity of novel phosphonium salts on the basis of pyridoxine
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Mikhail V. Pugachev , Nikita V. Shtyrlin , Lubov P. Sysoeva , Elena V. Nikitina , Timur I. Abdullin , Alfiya G. Iksanova , Alina A. Ilaeva , Rashid Z. Musin , Eugeny A. Berdnikov , Yurii G. Shtyrlin
  A series of 13 phosphonium salts on the basis of pyridoxine derivatives were synthesized and their antibacterial activity against clinically relevant strains was tested in vitro. All compounds were almost inactive against gram-negative bacteria and exhibited structure-dependent activity against gram-positive bacteria. A crucial role of ketal protection group in phosphonium salts for their antibacterial properties was demonstrated. Among synthesized compounds 5,6-bis[triphenylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (compound 20) was found to be the most effective towards Staphylococcus aureus and Staphylococcus epidermidis strains (MIC 5μg/ml). The mechanism of antibacterial activity of this compound probably involves cell penetration and interaction with genomic and plasmid DNA.
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  PubDate: 2013-06-11T23:04:52Z
Potent suppression of c-di-GMP synthesis via I-site allosteric inhibition of diguanylate cyclases with 2′-F-c-di-GMP
- Abstract: Publication date: 15 July 2013
  Source:Bioorganic & Medicinal Chemistry, Volume 21, Issue 14
  Author(s): Jie Zhou , Sarah Watt , Jingxin Wang , Shizuka Nakayama , David A. Sayre , Yiu-fai Lam , Vincent T. Lee , Herman O. Sintim
  Cyclic-di-GMP (c-di-GMP) is a central regulator of bacterial behavior. Various studies have implicated c-di-GMP in biofilm formation and virulence factor production in multitudes of bacteria. Hence it is expected that the disruption of c-di-GMP signaling could provide an effective means to disrupt biofilm and/or virulence factor formation in several bacteria of clinical relevance. C-di-GMP achieves the regulation of bacterial phenotype via binding to several effector molecules including transcription factors, enzymes and riboswitches. Crystal structure analyses of c-di-GMP effector molecules, in complex with the ligand, reveal that various classes of c-di-GMP receptors recognize this dinucleotide using different sets of recognition elements. Therefore, it is plausible that different analogues of c-di-GMP could be used to selectively modulate a specific class of c-di-GMP binding receptors, and hence modulate the bacterial phenotype. Thus far only a detailed study of the differential binding of c-di-GMP analogues to riboswitches, but not proteins, has been reported. In this report, we prepared various 2′-modified analogues of c-di-GMP and studied both polymorphisms of these analogues using DOSY NMR and the binding to several effector proteins, such as PilZ-containing proteins, diguanylate cyclases (DGC) containing I-sites, and phoshphodiesterases (PDE). 2′-Modification of c-di-GMP did not adversely affect the propensity to form higher aggregates, such as octameric forms, in the presence of potassium salts. Interestingly, we find that the selective binding to different classes of c-di-GMP binding proteins could be achieved with the 2′-modified analogues and that 2′-F analogue of c-di-GMP binds to the I-site of DGCs better (four times) than the native dinucleotide, c-di-GMP, whereas c-di-GMP binds to PDEs better (10 times) than 2′-F-c-di-GMP. 2′-F-c-di-GMP potently inhibits c-di-GMP synthesis by DGCs and hence raises the potential that cell permeable analogues of 2′-F-c-di-GMP could be used to disrupt c-di-GMP signaling in bacteria.
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  PubDate: 2013-06-11T23:04:52Z