Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9
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Graphical contents list ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9
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Synthetic approaches to the 2013 new drugs ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Hong X. Ding , Carolyn A. Leverett , Robert E. Kyne Jr. , Kevin K.-C. Liu , Sarah J. Fink , Andrew C. Flick , Christopher J. O’Donnell New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of twenty-four NCEs that were approved for the first time in 2013 and two 2012 drugs which were not covered during the previous edition of this review. Graphical abstract image
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Design and synthesis of piperazine derivatives as a novel class of γ-secretase modulators that selectively lower Aβ42 production ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Takafumi Takai , Tatsuki Koike , Eiji Honda , Yuichi Kajita , Minoru Nakamura , Sachie Morimoto , Yasutaka Hoashi , Makoto Kamata , Tomomichi Watanabe , Tomoko Igari , Jun Terauchi Novel piperazine derivatives as γ-secretase modulators (GSMs) were prepared and tested for their ability to selectively lower Aβ42 production. Lead compound 3, with selective Aβ42-lowering activity, was modified by replacing its imidazolylphenyl moiety with an oxazolylphenyl moiety. Optimization of the urea group significantly improved mouse microsomal stability, while retaining both activity and selectivity. These efforts led to the successful identification of an orally available and brain-penetrant GSM, 6j, which selectively reduced brain Aβ42 in mice. Graphical abstract image
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Design and synthesis of novel anti-tuberculosis agents from the celecoxib pharmacophore ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Santosh B. Salunke , Abul K. Azad , Naval P. Kapuriya , Joan-Miquel Balada-Llasat , Preeti Pancholi , Larry S. Schlesinger , Ching-Shih Chen The identification of compounds with anti-mycobacterial activity within classes of molecules that have been developed for other purposes is a fruitful approach for the development of anti-tuberculosis (TB) agents. In this study we used the scaffold of celecoxib which exhibits several activities against different pathogens, for the design and focused synthesis of a library of 64 compounds. For the primary screen, we used a bioluminescence-based method by constructing a luciferase-expressing reporter M.tb strain which contains the entire bacterial Lux operon cloned in a mycobacterial integrative expression vector. Through the screening of this library, we identified 6 hit compounds with high in vitro anti-mycobacterial activity (IC50 ∼0.18–0.48μM). In particular, compounds 41, 51 and 53 were capable of inhibiting M.tb as effectively as the anti-TB drug isoniazid (INH) at 5μM over a 72-h period, as analyzed by both bioluminescence- and colony forming unit (CFU)-based assays. All hit compounds also showed anti-M.tb activities against several multi-drug-resistant (MDR) strains. Most of the hit compounds showed no cytotoxicity for human macrophages at concentrations as high as 40μM, setting the stage for further optimization and development of these anti-TB hit compounds both ex vivo and in vivo. Graphical abstract image
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Synthesis, crystal structures, and urease inhibition of an acetohydroxamate-coordinated oxovanadium(V) complex derived from N′-(3-bromo-2-hydroxybenzylidene)-4-methoxybenzohydrazide ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Dan Qu , Fang Niu , Xinlu Zhao , Ke-Xiang Yan , Yu-Ting Ye , Jia Wang , Mei Zhang , Zhonglu You A new benzohydrazone compound N′-(3-bromo-2-hydroxybenzylidene)-4-methoxybenzohydrazide (H2L) was prepared. Reaction of H2L and acetohydroxamic acid (HAHA) with VO(acac)2 in methanol gave the complex [VOL(AHA)]. Both H2L and the oxovanadium complex were characterized by elemental analysis, IR, UV–vis and 1H NMR spectra, and single crystal X-ray diffraction. H2L was also characterized by high-resolution mass spectrum. Thermal analysis of the oxovanadium complex was carried out. The benzohydrazone ligand, in its dianionic form, coordinates to V atom through the phenolate oxygen, imino nitrogen and enolate oxygen. The acetohydroxamic acid coordinates to V atom through the carbonyl oxygen and deprotonated hydroxyl oxygen. The V atom is in octahedral coordination. H2L, HAHA and the oxovanadium complex were tested for their urease inhibitory activities. The percent inhibition at concentration of 100μmol·L−1 on Helicobacter pylori urease is 78% for the oxovanadium complex. The IC50 value for the complex is 36.5μmol·L−1. Molecular docking study was performed to study the inhibition. Graphical abstract image
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Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Lei Wang , Shao Xie , Longjun Ma , Yi Chen , Wei Lu Fifteen novel homocamptothecin derivatives with α-OMe substituted E-rings were designed and synthesized. All of the derivatives exhibited similar or superior cytotoxicities compared with that of SN-38, and they inhibited Topo I activity in a cell-free assay in a manner similar to that of SN-38, confirming that they represent a new class of Topo I inhibitors. Notably, the water soluble compound 36o (1.2mg/mL) exhibited increased lactone stability, and at 0.5mg/kg and 3.0mg/kg, it demonstrated significant antitumor activity in mice bearing a xenograft model using human colon cancer cell line HT-29. On the basis of these positive results, further development of 36o-related compounds as potential anticancer clinical trial candidates is definitely warranted. Graphical abstract image
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Design, synthesis and biological evaluation of tasiamide B derivatives as BACE1 inhibitors ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Jian Liu , Wuyan Chen , Yechun Xu , Sumei Ren , Wei Zhang , Yingxia Li Nineteen new derivatives based on the structure of marine natural product tasiamide B were designed, synthesized, and evaluated for their inhibitory activity against BACE1, a potential therapeutic target for Alzheimer’s disease. The hydrophobic substituents Val at P3 position, Leu at P1′ position, Ala at P2′ position, and Phe at P3′ position were found to significantly affect the inhibition. Free carboxylic acid at C-terminus was also found to be important to the activity. In addition, the structure–activity relationships (SARs) were supported by molecular docking simulation. Graphical abstract image
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Novel arylazopyrazole inhibitors of cyclin-dependent kinases ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Radek Jorda , Eva Schütznerová , Petr Cankař , Veronika Brychtová , Jana Navrátilová , Vladimír Kryštof Here, we describe new 4-arylazo-3,5-diamino-1H-pyrazole derivatives developed from CAN508, one of the first inhibitors to show preference for transcriptional regulator cyclin-dependent kinase 9. By substituting nitrogen in the pyrazole ring and employing a heteroatom in the 4-aryl ring, we obtained more potent derivatives differing in their CDK-selectivity profiles. The antiproliferative and anti-CDK kinase activities of the novel arylazopyrazoles were examined. The cellular effect of compound IVc was studied on MCF-7 cells synchronized by various methods and compared with other selective CDK inhibitors. The results demonstrated that IVc shows a preference for CDK4 and CDK1. In contrast to cytostatic effects induced by IVc in MCF-7 and K562 cells, we observed apoptotic activities in the RPMI-8226 cell line, which were confirmed by detecting active caspases by different biochemical assays. Graphical abstract image
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Synthesis and structure–activity relationships of boswellic acid derivatives as potent VEGFR-2 inhibitors ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Sida Shen , Xingyu Xu , Zhulong Liu , Junhua Liu , Lihong Hu A series of AKBA derivatives were synthesized, and evaluated as potent VEGFR-2 inhibitors. The initial biological evaluation indicated that the introduction of C-24 amide group or a heterocycle at C-2,3 position effectively improved the potency. Further structure–activity relationship analysis showed that amide (7, 23, 25, and 26) and heterocycle (19, 34, and 36) substituted AKBA derivatives displayed more potential anti-proliferation activities than AKBA (1) on HUVECs that express high levels of VEGFR-2. Among all tested compounds, compounds 7 and 19 exhibited the best potency (IC50: 2.36 and 2.13μM) and obvious inhibitory activities with VEGFR-2 inhibition rates of 96% and 94% at 50μM, respectively. Graphical abstract image
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Design, synthesis and preliminary bioactivity studies of 2-thioxo-4-thiazolidinone derivatives as Bcl-2 inhibitors ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Yichao Wan , Shaolei Wu , Guizhi Xiao , Tingting Liu , Xuben Hou , Chen Chen , Peng Guan , Xinying Yang , Hao Fang The B-cell lymphoma-2 (Bcl-2) protein is a promising target for cancer therapy. In the present study, a series of 2-thioxo-4-thiazolidinone derivatives were designed and synthesized as Bcl-2 inhibitors. Most of them possessed decent inhibitory activity for anti-apoptotic Bcl-2 proteins. Among them, compound 31 has similar growth inhibition towards K562 compared to (R)-Gossypol. In addition, it inhibits the myeloid cell leukemia sequence 1 (Mcl-1) protein with a K i value of 74nM. Graphical abstract image
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The CERT antagonist HPA-12: First practical synthesis and individual binding evaluation of the four stereoisomers ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Cécile Santos , Laurence Fleury , Frédéric Rodriguez , Jozef Markus , Dušan Berkeš , Adam Daïch , Frédéric Ausseil , Cécile Baudoin-Dehoux , Stéphanie Ballereau , Yves Génisson The first unified synthetic route to the four enantiopure HPA-12 stereoisomers in multi-gram scale is reported based on Crystallization-Induced Asymmetric Transformation (CIAT) technology. This preparative stereoselective synthesis allowed the unprecedented comparative evaluation of HPA-12 stereoisomers regarding their interaction with the CERT START domain. In vitro binding assay coupled to in silico docking approach indicate a possible interaction for the four derivatives. The first TR-FRET homogeneous-phase assay was developed to quantify their binding to the START domain, allowing complete determination of HPA-12 EC50. Results indicate that not only the (1R,3S) lead to the strongest binding, but that both 1R and 3S stereocenters similarly contribute to extent of recognition This automated homogenous assay further opens up promising prospect for the identification of novel potential CERT antagonist by means of high throughput screening. Graphical abstract image
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Synthesis and ABCG2 inhibitory evaluation of 5-N-acetylardeemin derivatives ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Daigo Hayashi , Naoki Tsukioka , Yutaka Inoue , Yoshiki Matsubayashi , Toshimasa Iizuka , Kazuhiro Higuchi , Yoji Ikegami , Tomomi Kawasaki An efficient and versatile synthesis of 5-N-acetylardeemin (1a) and sixteen 2-, 3- and 13-substituted derivatives 1b–q was achieved through Ugi three-component reaction of 3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole and cyclization/epimerization. Their inhibitory activity on the drug efflux of breast cancer resistance protein (ABCG2) was evaluated by flow cytometric analysis of accumulation of Hoechst 33342 stain in Flp-In-293/ABCG2 cells. Most of the derivatives exhibited a stronger ABCG2 inhibitory effect compared with natural product 1a. The derivative 1m with a 4-tolyl substituent at the C-13 position exhibited the most potent ABCG2 inhibition. This preliminary structure–activity relationship study indicates that an electron-rich aryl moiety as the 13-substituent is key to increasing the inhibitory activity. Graphical abstract image
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Structure–activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Son T. Nguyen , Steven M. Kwasny , Xiaoyuan Ding , Steven C. Cardinale , Courtney T. McCarthy , Hong-Suk Kim , Hiroshi Nikaido , Norton P. Peet , John D. Williams , Terry L. Bowlin , Timothy J. Opperman Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-β-naphthylamide (PAβN), D13-9001, and the pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d–f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli. Graphical abstract image
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Synthesis and antimycobacterial properties of ring-substituted 6-hydroxynaphthalene-2-carboxanilides ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Jiri Kos , Eoghan Nevin , Michal Soral , Ivan Kushkevych , Tomas Gonec , Pavel Bobal , Peter Kollar , Aidan Coffey , Jim O’Mahony , Tibor Liptaj , Katarina Kralova , Josef Jampilek In this study, a series of twenty-two ring-substituted 6-hydroxynaphthalene-2-carboxanilides was prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Mycobacterium tuberculosis H37Ra, Mycobacterium avium complex and M. avium subsp. paratuberculosis. Derivatives substituted by trifluoromethyl, bromo, methyl and methoxy moieties in C′(3) and C′(4) positions of the anilide ring showed 2-fold higher activity against M. tuberculosis than isoniazid and 4.5-fold higher activity against M. avium subsp. paratuberculosis than rifampicin. 6-Hydroxy-N-(2-methylphenyl)naphthalene-2-carboxamide had MIC=29μM against M. avium complex. A significant decrease of mycobacterial cell metabolism (viability of M. tuberculosis H37Ra) was observed using MTT assay. Screening of the cytotoxicity of the most effective antimycobacterial compounds was performed using the THP-1 cells, and no significant lethal effect was observed. The structure–activity relationships are discussed. Graphical abstract image
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Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Alexandra Zakharenko , Tatyana Khomenko , Svetlana Zhukova , Olga Koval , Olga Zakharova , Rashid Anarbaev , Natalya Lebedeva , Dina Korchagina , Nina Komarova , Vladimir Vasiliev , Jóhannes Reynisson , Konstantin Volcho , Nariman Salakhutdinov , Olga Lavrik Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a promising target for antitumor therapy based on Top1 poison-mediated DNA damage. Several novel benzopentathiepines were synthesized and tested as inhibitors of TDP1 using a new oligonucleotide-based fluorescence assay. The benzopentathiepines have IC50 values in the range of 0.2–6.0μM. According to the molecular modeling, the conformational flexibility of the dibutylamine group of the most effective inhibitor (3d) allows it to occupy an advantageous position for effective binding compared to its cyclic counterparts. The study of cytotoxicity of these compounds revealed that all compounds cause an apoptotic cell death in MCF-7 and Hep G2 cells. Therefore the new class of very effective inhibitors of TDP1 was elaborated. Graphical abstract image
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Synthesis of N-methylarylnitrones derived from alkyloxybenzaldehydes and antineoplastic effect on human cancer cell lines ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Débora S.S. Costa , Thiago Martino , Fernanda C. Magalhães , Graça Justo , Marsen G.P. Coelho , Julio C.F. Barcellos , Victor B. Moura , Paulo R.R. Costa , Kátia C.C. Sabino , Ayres G. Dias New O-isoprenylated-N-methylarylnitrones derived from isomeric o, m and p-hydroxybenzaldehydes have been prepared and the antineoplastic effects on human cancer cell lines were evaluated. The O-geranylated nitrone LQB-278 (1b) and its isomers 2b and 3b inhibited the NO production, but the anti-leukemic activity was drastically dependent on nitrone isomer, with the 1b being the most effective one (IC50 of 6.7μM) on Jurkat leukemia cell, by MTT assay. In addition, 1b up-regulated p21CIP1/WAF1/Sdi1 protein expression (flow cytometry), a cell cycle inhibitor, reduced cell growth, and induced DNA fragmentation (increased sub-G1 phase cells) and phosphatidylserine externalization in plasmatic membrane (increased annexin V positive cells). Finally, the 1b up-regulation of p21 expression and apoptosis induction seem to be the mechanisms by which it promotes its anti-leukemic effects, making this new molecular architecture a promising prototype for leukemia intervention. Graphical abstract image
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Design and synthesis of novel quinoline–aminopiperidine hybrid analogues as Mycobacterium tuberculosis DNA gyraseB inhibitors ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Brahmam Medapi , Janupally Renuka , Shalini Saxena , Jonnalagadda Padma Sridevi , Raghavender Medishetti , Pushkar Kulkarni , Perumal Yogeeswari , Dharmarajan Sriram Antibiotics with good therapeutic value and novel mechanism of action are becoming increasingly important in today’s battle against bacterial resistance. One of the popular targets being DNA gyrase, is currently becoming well-established and clinically validated for the development of novel antibacterials. In the present work, a series of forty eight quinoline–aminopiperidine based urea and thiourea derivatives were synthesized as pharmacophoric hybrids and evaluated for their biological activity. Compound, 1-(4-chlorophenyl)-3-(1-(6-methoxy-2-methylquinolin-4-yl)piperidin-4-yl)thiourea (45) was found to exhibit promising in vitro Mycobacterium smegmatis GyrB IC50 of 0.95±0.12μM and a well correlated Mycobacterium tuberculosis (MTB) DNA gyrase supercoiling IC50 of 0.62±0.16μM. Further, compound 45 also exhibited commendable MTB MIC, safe eukaryotic cytotoxic profile with no signs of cardiotoxicity in zebrafish ether-a-go-go-related gene (zERG). Graphical abstract image
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Discovery of a potent, orally available dual CysLT1 and CysLT2 antagonist with dicarboxylic acid ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Satoshi Itadani , Shinya Takahashi , Masaki Ima , Tetsuya Sekiguchi , Yoshiyuki Aratani , Hiromu Egashira , Naoya Matsumura , Atsuto Inoue , Yasuo Yonetomi , Manabu Fujita , Yoshisuke Nakayama , Jun Takeuchi A potent, orally available dual CysLT1 and CysLT2 receptor antagonist with a dicarboxylic acid is described. 4-(3-(Carboxymethyl)-4-{(E)-2-[4-(4-phenoxybutoxy)phenyl]vinyl}-1H-indol-1-yl)butanoic acid (15: ONO-4310321, IC50: CysLT1 =13nM, CysLT2 =25nM) showed excellent pharmacokinetic profiles (%F rat =100) compared with our previously reported compound 1 (%F rat =1.5). In addition, we describe a new rule for dicarboxylic acid derivatives to show good oral bioavailability (%F rat ⩾40) in rats (HBDs: ⩽2, C log P: >6.5 and TPSA: <100). Especially, reduction of only one hydrogen-bond donor (HBDs) showed dramatically improved oral bioavailability. This small change of HBDs in dicarboxylic acid derivatives is generally a very effective modification. Graphical abstract image
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Cell-based biological evaluations of 5-(3-bromo-4-phenethoxybenzylidene)thiazolidine-2,4-dione as promising wound healing agent ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Yu Lan Piao , A Ram Song , Hoon Cho Recent studies have focused on prostaglandin E2 (PGE2) because PGE2 regulates vertebrate hematopoietic stem cell induction and engraftment. PGE2 acts through EP2 and EP4 receptors to mediate regeneration and hematopoietic stem cell (HSC) development via the Wnt signaling pathway. Previously we reported that inhibitors of 15-PGDH can control the intracellular levels of PGE2. Therefore, we developed new potent 15-PGDH inhibitor, 5-(3-bromo-4-phenethoxybenzylidene)thiazolidine-2,4-dione (TD191), with an IC50 of 4nM and tested cell-based wound healing effects. This compound significantly increased the level of PGE2 (451pg/mL) in A549 cells, which was about 7-fold higher than that of control. HaCaT cells exposed to TD191 showed significantly improved wound healing after 48h in scratch wound healing test, whereas treatment of TD191 to the fibroblast Hs27 cells slightly decreased cell growth compared with control. SCL is a basic helix-loop-helix transcription factor that is an essential for HSC development. By qPCR, SCL expression in HaCaT cells was 2-fold enhanced after addition of TD191, while treatment of TD191 into fibroblast Hs27 cells was not significantly changed the expression levels of the gene. This data provides in vitro evidence that TD191 may have utility for the therapeutic management of wound healing without scar formation. Graphical abstract image
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α-Adrenoceptor antagonistic and hypotensive properties of novel arylpiperazine derivatives of pyrrolidin-2-one ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Paula Zaręba , Magdalena Dudek , Klaudia Lustyk , Agata Siwek , Gabriela Starowicz , Marek Bednarski , Leszek Nowiński , Katarzyna Raźny , Jacek Sapa , Barbara Malawska , Katarzyna Kulig This study focused on a series of pyrrolidin-2-one derivatives connected via two or four methylene units to arylpiperazine fragment. The compounds obtained for α1- and α2-adrenoceptors were assessed. The compound with highest affinity for the α1-adrenoceptors was 1-{4-[4-(2-chloro-phenyl)-piperazin-1-yl]-butyl}-pyrrolidin-2-one (10h) with pK i =7.30. Compound with pK i (α1) ⩾6.44 were evaluated in functional bioassays for intrinsic activity at α1A- and α1B-adrenoceptors. All compounds tested were antagonists of the α1B-adrenoceptors. Additionally, compounds 10e and 10h were α1A-adrenoceptors antagonist. The dual α1A-/α1B-adrenoceptors antagonists, compounds 10e and 10h were also tested in vivo for their hypotensive activity in rats. These compounds, when dosed of 1.0mg/kg iv in normotensive, anesthetized rats, significantly decreased systolic and diastolic pressure and their hypotensive effects lasted for longer than one hour. Graphical abstract image
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Novel 2-(2-phenalkyl)-1H-benzo[d]imidazoles as antitubercular agents. Synthesis, biological evaluation and structure–activity relationship ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Katarzyna Gobis , Henryk Foks , Karolina Suchan , Ewa Augustynowicz-Kopeć , Agnieszka Napiórkowska , Krzysztof Bojanowski A series of novel 2-(2-phenalkyl)-1H-benzo[d]imidazole derivatives and analogues (2a–3l) have been synthesized and evaluated for tuberculostatic activity. Benzimidazoles substituted at the C-2 position with phenethyl, styryl and 3,5-dichlorophenethyl moiety were obtained. Compounds 2g, 2h and 2i bearing methyl groups at the benzimidazole system and phenalkyl substituent at the C-2 position showed high tuberculostatic activity against Mycobacterium tuberculosis strains with MIC values ranging from 0.8 to 6.2μg/mL (2.5–25μM). More importantly, derivatives 2g (5,6-dimethyl-2-phenethyl-1H-benzo[d]imidazole) and 2i (2-(3,5-dichlorophenethyl)-5,6-dimethyl-1H-benzo[d]imidazole) appeared selective for M. tuberculosis as compared with eukaryotic cells: non-malignant (neonatal human dermal fibroblasts) and malignant (mouse melanoma B16-F10 cell line). These compounds may thus represent a novel, selective class of anti-tubercular agents. SAR studies resulted in interesting conclusions on structural factors affecting tuberculostatic activity. Graphical abstract image
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Discovery of novel pyrazolopyrimidinone analogs as potent inhibitors of phosphodiesterase type-5 ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Sanghapal D. Sawant , G. Lakshma Reddy , Mohd Ishaq Dar , M. Srinivas , Gourav Gupta , Promod Kumar Sahu , Priya Mahajan , Amit Nargotra , Surjeet Singh , Subhash C. Sharma , Manoj Tikoo , Gurdarshan Singh , Ram A. Vishwakarma , Sajad Hussain Syed Cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type-5 (PDE5), a clinically proven target to treat erectile dysfunction and diseases associated with lower cGMP levels in humans, is present in corpus cavernosum, heart, lung, platelets, prostate, urethra, bladder, liver, brain, and stomach. Sildenafil, vardenafil, tadalafil and avanafil are FDA approved drugs in market as PDE5 inhibitors for treating erectile dysfunction. In the present study a lead molecule 4-ethoxy-N-(6-hydroxyhexyl)-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzenesulfonamide, that is, compound-4a, an analog of pyrazolopyrimidinone scaffold has been identified as selective PDE5 inhibitor. A series of compounds was synthesized by replacing N-methylpiperazine moiety (ring-C) of sildenafil structure with different N-substitutions towards sulfonamide end. Compound-4a showed lower IC50 value (1.5nM) against PDE5 than parent sildenafil (5.6nM) in in vitro enzyme assay. The isoform selectivity of the compound-4a against other PDE isoforms was similar to that of the Sildenafil. In corroboration with the in vitro data, this molecule showed better efficacy in in vivo studies using the conscious rabbit model. Also compound-4a exhibited good physicochemical properties like solubility, caco-2 permeability, c Log P along with optimal PK profile having no significant CYP enzyme inhibitory liabilities. Discovery of these novel bioactive compounds may open a new alternative for developing novel preclinical candidates based on this drugable scaffold. Graphical abstract image
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Synthesis and fungicidal activity of N-thiazol-4-yl-salicylamides, a new family of anti-oomycete compounds ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Sarah Sulzer-Mosse , Fredrik Cederbaum , Clemens Lamberth , Guillaume Berthon , Jayant Umarye , Valeria Grasso , Alexandra Schlereth , Mathias Blum , Rita Waldmeier A novel class of experimental fungicides has been discovered, which consists of special N-thiazol-4-yl-salicylamides. They originated from amide reversion of lead structures from the patent literature and are highly active against important phytopathogens, such as Phytophthora infestans (potato and tomato late blight), Plasmopara viticola (grapevine downy mildew) and Pythium ultimum (damping-off disease). Structure–activity relationship studies revealed the importance of a phenolic or enolic hydroxy function in the β-position of a carboxamide. An efficient synthesis route has been worked out, which for the first time employs the carbonyldiimidazole-mediated Lossen rearrangement in the field of thiazole carboxylic acids. Graphical abstract image
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Nucleobase modified neamines with a lysine as a linker, their inhibition specificity for TAR-Tat derived from HIV-1 ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Ryo Inoue , Kentarou Watanabe , Toyofusa Katou , Yasunori Ikezawa , Keita Hamasaki Nucleobase modified neamines with a lysine as the linker (NbK-neamines) were synthesized and their binding toward hairpin RNAs derived from HIV-1 activator region were studied. NbK-neamines were bind those RNAs with micro molar level of binding affinities and compete with corresponding activator peptide for TAR RNA, but not for RRE RNA. GbK-neamine denotes the highest binding affinity with TAR RNA, three to five times higher than other three NbK-neamines. GbK-neamine could be a candidate of potential inhibitor for TAR-Tat. Graphical abstract image
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Design, synthesis and in vitro cell-based evaluation of the anti-cancer activities of hispolon analogs ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Neduri V. Balaji , Modukuri V. Ramani , Arabela G. Viana , Leticia P. Sanglard , Jason White , Vanisree Mulabagal , Crystal Lee , Theophilus J. Gana , Nosa O. Egiebor , Gottumukkala V. Subbaraju , Amit K. Tiwari Phytochemicals play an important role in cancer therapy. Hispolon and 26 of its analogs (9 known and 17 new) were synthesized and evaluated for their antiproliferative activities in a panel of six independent human cancer cell lines using the in vitro cell-based MTT assay. Among the hispolon analogs tested, compound VA-2, the most potent overall, produced its most significant effect in the colon cancer cell lines HCT-116 (IC50 1.4±1.3μM) and S1 (IC50 1.8±0.9μM) compared to its activity in the normal HEK293/pcDNA3.1 cell line (IC50 15.8±3.7μM; p <0.01 for each comparison). Based on our results, VA-2 was about 9- to 11-times more potent in colon cancer cells and 2- to 3-times more potent in prostate cancer cells compared to HEK293/pcDNA3.1 cells. Morphological analysis of VA-2 showed significant reduction of cell number, while the cells’ sizes were also markedly increased and were obvious at 68h of treatment with 1μM in HCT-116 (colon) and PC-3 (prostate) cancer cells. A known analog, compound VA-4, prepared by simple modifications on the aromatic functional groups of hispolon, inhibited prostate and colon cancer cell lines with IC50 values <10μM. In addition, hispolon isoxazole and pyrazole analogs, VA-7 and VA-15 (known), respectively, have shown significant activity with the mean IC50 values in the range 3.3–10.7μM in all the cancer cell lines tested. Activity varied among the analogs in which aromatic functional groups and β-diketone functional groups are modified. But the activity of analogs VA-16 to VA-27 was completely lost when the side chain double-bond was hydrogenated indicating the crucial role of this functionality for anticancer activity. Furthermore, many of the compounds synthesized were not substrates for the ABCB1-transporter, the most common cause of multidrug resistance in anti-cancer drugs, suggesting they may be more effective anticancer agents. Graphical abstract image
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Development of a clickable activity-based protein profiling (ABPP) probe for agmatine deiminases ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Mikhail Marchenko , Andrew Thomson , Terri N. Ellis , Bryan Knuckley , Corey P. Causey Agmatine deiminases (AgDs) catalyze the hydrolytic conversion of agmatine (decarboxylated arginine) to N-carbamoylputrescine with concomitant release of ammonia. These enzymes, which are encoded by some pathogenic bacterial species, confer a competitive survival advantage by virtue of energy production and acid tolerance through agmatine catabolism. Herein we report the development of a clickable activity-based protein profiling (ABPP) probe that targets the AgD encoded by Streptococcus mutans with high selectivity and sensitivity. Graphical abstract image
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SiO2 nanoparticles as platform for delivery of 3′-triazole analogues of AZT-triphosphate into cells ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Svetlana V. Vasilyeva , Asya S. Levina , Nikolai S. Li-Zhulanov , Natalia V. Shatskaya , Sergei I. Baiborodin , Marina N. Repkova , Valentina F. Zarytova , Natalia A. Mazurkova , Vladimir N. Silnikov A system for delivery of analogues of AZT-triphosphates (AZT*TP) based on SiO2 nanoparticles was proposed. For this purpose, a simple and versatile method was developed for the preparation of SiO2∼dNTP conjugates using the ‘click’-reaction between AZTTP and premodified nanoparticles containing the alkyne groups. The substrate properties of SiO2∼AZT*TP were tested using Klenow fragment and HIV reverse transcriptase. The 3′-triazole derivatives of thymidine triphosphate being a part of the SiO2∼AZT*TP nanocomposites were shown to be incorporated into the growing DNA chain. It was shown by confocal microscopy that the proposed SiO2∼AZT*TP nanocomposites penetrate into cells. These nanocomposites were shown to inhibit the reproduction of POX and Herpes viruses at nontoxic concentrations. Graphical abstract image
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Investigation into novel thiophene- and furan-based 4-amino-7-chloroquinolines afforded antimalarials that cure mice ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Igor M. Opsenica , Tatjana Ž. Verbić , Mikloš Tot , Richard J. Sciotti , Brandon S. Pybus , Olgica Djurković-Djaković , Ksenija Slavić , Bogdan A. Šolaja We herein report the design and synthesis of a novel series of thiophene- and furan-based aminoquinoline derivatives which were found to be potent antimalarials and inhibitors of β-hematin polymerization. Tested compounds were 3–71 times more potent in vitro than CQ against chloroquine-resistant (CQR) W2 strain with benzonitrile 30 being as active as mefloquine (MFQ), and almost all synthesized aminoquinolines (22/27) were more potent than MFQ against multidrug-resistant (MDR) strain C235. In vivo experiments revealed that compound 28 showed clearance with recrudescence at 40mg/kg/day, while 5/5 mice survived in Thompson test at 160mg/kg/day. Graphical abstract image
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Design, synthesis and biological evaluation of a highly-potent and cancer cell selective folate–taxoid conjugate ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Joshua D. Seitz , Jacob G. Vineberg , Evan Herlihy , Bora Park , Eduard Melief , Iwao Ojima The folate receptor (FR) has been widely recognized as an excellent target for the tumor-selective delivery of cytotoxic agents, and four folate–drug conjugates have entered clinical evaluations for the treatment of solid tumors to date. However, most of these conjugates required structural modification of the cytotoxic warheads in order to achieve efficient drug release from the linkers. We designed and constructed a novel folate conjugate of a highly-potent next-generation taxoid, SB-T-1214, by exploiting bioorthogonal Cu-free ‘click’ chemistry. The synthesis was highly convergent and required no HPLC purification to obtain the final folate–taxoid conjugate 1. Conjugate 1 demonstrated highly FR-specific potency (IC50 2.1–3.5nM) against a panel of cancer cell lines, with a >1000-fold decrease in cytotoxicity against normal human cells (IC50 >5000nM). The remarkable potency and selectivity of conjugate 1 can be attributed to highly FR-specific receptor-mediated endocytosis as well as efficient release of the unmodified cytotoxic warhead using a mechanism-based self-immolative linker. Graphical abstract image
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Structure–activity relationships of substituted 1H-indole-2-carboxamides as CB1 receptor allosteric modulators ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Thuy Nguyen , Nadezhda German , Ann M. Decker , Jun-Xu Li , Jenny L. Wiley , Brian F. Thomas , Terry P. Kenakin , Yanan Zhang A series of substituted 1H-indole-2-carboxamides structurally related to compounds Org27569 (1), Org29647 (2) and Org27759 (3) were synthesized and evaluated for CB1 allosteric modulating activity in calcium mobilization assays. Structure–activity relationship studies showed that the modulation potency of this series at the CB1 receptor was enhanced by the presence of a diethylamino group at the 4-position of the phenyl ring, a chloro or fluoro group at the C5 position and short alkyl groups at the C3 position on the indole ring. The most potent compound (45) had an IC50 value of 79nM which is ∼2.5 and 10 fold more potent than the parent compounds 3 and 1, respectively. These compounds appeared to be negative allosteric modulators at the CB1 receptor and dose-dependently reduced the E max of agonist CP55,940. These analogs may provide the basis for further optimization and use of CB1 allosteric modulators. Graphical abstract image
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Synthesis of nitro(benzo)thiazole acetamides and in vitro antiprotozoal effect against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Gabriel Navarrete-Vázquez , Fabiola Chávez-Silva , Blanca Colín-Lozano , Samuel Estrada-Soto , Sergio Hidalgo-Figueroa , Jorge Guerrero-Álvarez , Sara T. Méndez , Horacio Reyes-Vivas , Jesús Oria-Hernández , Jaqueline Canul-Canché , Rolffy Ortiz-Andrade , Rosa Moo-Puc We synthesized four 5-nitrothiazole (1–4) and four 6-nitrobenzothiazole acetamides (5–8) using an easy two step synthetic route. All compounds were tested in vitro against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis, showing excellent antiprotozoal effects. IC50’s of the most potent compounds range from nanomolar to low micromolar order, being more active than their drugs of choice. Compound 1 (IC50 =122nM), was 44-times more active than Metronidazole, and 10-fold more effective than Nitazoxanide against G. intestinalis and showed good trichomonicidal activity (IC50 =2.24μM). This compound did not display in vitro cytotoxicity against VERO cells. The in vitro inhibitory effect of compounds 1–8 and Nitazoxanide against G. intestinalis fructose-1,6-biphosphate aldolase (GiFBPA) was evaluated as potential drug target, showing a clear inhibitory effect over the enzyme activity. Molecular docking of compounds 1, 4 and Nitazoxanide into the ligand binding pocket of GiFBPA, revealed contacts with the active site residues of the enzyme. Ligand efficiency metrics of 1 revealed optimal combinations of physicochemical and antiprotozoal properties, better than Nitazoxanide. Graphical abstract image
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Acyl-2-aminobenzimidazoles: A novel class of neuroprotective agents targeting mGluR5 ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Xinhua He , Sirish K. Lakkaraju , Marie Hanscom , Zaorui Zhao , Junfang Wu , Bogdan Stoica , Alexander D. MacKerell Jr. , Alan I. Faden , Fengtian Xue Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 5 (mGluR5) are promising therapeutic agents for treating traumatic brain injury (TBI). Using computational and medicinal methods, the structure–activity relationship of a class of acyl-2-aminobenzimidazoles (1–26) is reported. The new compounds are designed based on the chemical structure of 3,3′-difluorobenzaldazine (DFB), a known mGluR5 PAM. Ligand design and prediction of binding affinities of the new compounds have been performed using the site identification by ligand competitive saturation (SILCS) method. Binding affinities of the compounds to the transmembrane domain of mGluR5 have been evaluated using nitric oxide (NO) production assay, while the safety of the compounds is tested. One new compound found in this study, compound 22, showed promising activity with an IC50 value of 6.4μM, which is ∼20 fold more potent than that of DFB. Compound 22 represents a new lead for possible development as a treatment for TBI and related neurodegenerative conditions. Graphical abstract image
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Identification of novel class of falcipain-2 inhibitors as potential antimalarial agents ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Sai Kumar Chakka , Mohammad Kalamuddin , Srividhya Sundararaman , Lianhu Wei , Sourabh Mundra , Radhakrishnan Mahesh , Pawan Malhotra , Asif Mohmmed , Lakshmi P. Kotra Falcipain-2 is a papain family cysteine protease and an emerging antimalarial drug target. A pseudo-tripeptide scaffold I was designed using in silico screening tools and the three dimensional structures of falcipain-2, falcipain-3, and papain. This scaffold was investigated at four positions, T1, T2, T3, and T3′, with various targeted substitutions to understand the structure–activity relationships. Inhibitor synthesis was accomplished by first obtaining the appropriate dipeptide precursors with common structural components. The pyrrolidine moiety introduced interesting rotamers in a number of synthesized molecules, which was confirmed using high-temperature 1H NMR spectroscopy. Among the synthesized compounds, 61, 62, and 66 inhibited falcipain-2 activity with inhibition constants (K i) of 1.8±1.1, 0.2±0.1 and 7.0±2.3μM, respectively. A group of molecules with a pyrrolidine moiety at the T2 position (68, 70, 71, 72, and 73) also potently inhibited falcipain-2 activity (K i =0.4±0.1, 2.5±0.5, 3.3±1.1, 7.5±1.9, and 4.6±0.7μM, respectively). Overall, compound 74 exhibited potent anti-parasitic activity (IC50 =0.9±0.1μM), corresponding with its inhibitory activity against falcipain-2, with a K i of 1.1±0.1μM. Compounds 62 and 67 inhibited the growth of the drug resistant parasite Dd2 with better efficacy, and compound 74 exhibited a 7- to 12-fold higher potency against Dd2 and MCamp isolates, than the laboratory strain (3D7). These data suggest that this novel series of compounds should be further investigated as potential antimalarial agents. Graphical abstract image
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Structure–activity relationships of benzhydrol derivatives based on 1′-acetoxychavicol acetate (ACA) and their inhibitory activities on multiple myeloma cell growth via inactivation of the NF-κB pathway ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Takashi Misawa , Kosuke Dodo , Minoru Ishikawa , Yuichi Hashimoto , Morihiko Sagawa , Masahiro Kizaki , Hiroshi Aoyama 1′-Acetoxychavicol acetate (ACA), which was isolated from the rhizomes of Zingiberaceae, exhibits various biological actions, including anti-inflammatory, anti-human immunodeficiency virus (HIV), and anti-cancer activities. ACA represents an attractive candidate for the treatment of many cancers. We herein examined the structure–activity relationships of ACA derivatives based on the benzhydrol skeleton in human leukemia cells (HL-60). Our results revealed that the ACA derivatives synthesized (ACA, 1, and 18) had inhibitory effects on the growth of multiple myeloma cells (IM-9 cells) by inactivating the NF-κB pathway. Graphical abstract image
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A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Ken-ichi Kusakabe , Nobuyuki Ide , Yataro Daigo , Takeshi Itoh , Takahiko Yamamoto , Eiichi Kojima , Yasunori Mitsuoka , Genta Tadano , Sachie Tagashira , Kenichi Higashino , Yousuke Okano , Yuji Sato , Makiko Inoue , Motofumi Iguchi , Takayuki Kanazawa , Yukichi Ishioka , Keiji Dohi , Yasuto Kido , Shingo Sakamoto , Shigeru Ando , Masahiro Maeda , Masayo Higaki , Hidenori Yoshizawa , Hitoshi Murai , Yusuke Nakamura Mps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics. Starting from an aminopyridine-based lead 3a that binds to a flipped-peptide conformation at the hinge region in Mps1, elaboration of the aminopyridine scaffold at the 2- and 6-positions led to the discovery of 19c that exhibited no significant inhibition for 287 kinases as well as improved cellular Mps1 and antiproliferative activities in A549 lung carcinoma cells (cellular Mps1 IC50 =5.3nM, A549 IC50 =26nM). A clear correlation between cellular Mps1 and antiproliferative IC50 values indicated that the antiproliferative activity observed in A549 cells would be responsible for the cellular inhibition of Mps1. The X-ray structure of 19c in complex with Mps1 revealed that this compound retains the ability to bind to the peptide flip conformation. Finally, comparative analysis of the X-ray structures of 19c, a deamino analogue 33, and a known Mps1 inhibitor bound to Mps1 provided insights into the unique binding mode at the hinge region. Graphical abstract image
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Synthesis and evaluation of 123/131I-Iochlonicotinamide as a novel SPECT probe for malignant melanoma ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Chih-Chao Chang , Chih-Hsien Chang , Chih-Chieh Shen , Chuan-Lin Chen , Ren-Shyan Liu , Ming-Hsien Lin , Hsin-Ell Wang Malignant melanoma expresses a highly aggressive metastasis. Early diagnosis of malignant melanoma is important for patient survival. Radiolabeled benzamides and nicotinamides have been reported to be attractive candidates for malignant melanoma diagnosis as they bind to melanin, a characteristic substance that displays in malignant melanoma, and show high tumor accumulation and retention. Herein, we designed and synthesized a novel 123 / 131I-labeled nicotinamide derivative that specifically binds to melanin. 123 / 131I-Iochlonicotinamide was prepared with good radiochemical yield (50–70%, decay corrected) and high specific radioactivity (50–80GBq/μmol). 131I-Iochlonicotinamide exhibited good in vitro stability (radiochemical purity >95% after a 24-h incubation) in human serum. High uptake of 123 / 131I-Iochlonicotinamide in B16F0 melanoma cells compared to that in A375 amelanotic cells demonstrated its selective binding to melanin. Intravenous administration of 123 / 131I-Iochlonicotinamide in a melanoma-bearing mouse model revealed high uptake in melanotic melanoma and high tumor-to-muscle ratio. MicroSPECT scan of 123 / 131I-Iochlonicotinamide injected mice also displayed high contrast tumor imaging as compared with normal organs. The radiation-absorbed dose projection for the administration of 131I-Iochlonicotinamide to human was based on the results of biodistribution study. The effective dose appears to be approximately 0.44mSv/MBq−1. The specific binding of 123 / 131I-Iochlonicotinamide to melanin along with a prolonged tumor retention and acceptable projected human dosimetry suggest that it may be a promising theranostic agent for treating malignant melanoma. Graphical abstract image
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Synthesis of novel 24-amino-25,26,27-trinorlanost-8-enes: Cytotoxic and apoptotic potential in U937 cells ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Roisin O’Keeffe , Olivia Kenny , Nigel P. Brunton , Mohammad B. Hossain , Dilip K. Rai , Peter W. Jones , Nora O’Brien , Anita R. Maguire , Stuart G. Collins In the present study, the synthesis of a range of novel 24-amino-25,26,27-trinorlanost-8-ene derivatives including 24-piperadino-trinorlanost-8-enes, 24-piperazino-trinorlanost-8-enes, 24-morpholino-trinorlanost-8-enes, and 24-diethylamino-trinorlanost-8-enes is reported and their cytotoxic and apoptotic potential evaluated in U937 cell lines. Excellent IC50 results for piperidine and 1-(2-hydroxyethyl)piperazine derivatives have been observed (IC50 values of 1.9μM and 2.7μM in U937 cells, respectively). Graphical abstract image
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Effect of arginine methylation on the RNA recognition and cellular uptake of Tat-derived peptides ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): Jhe-Hao Li , Wen-Chieh Chiu , Yun-Chiao Yao , Richard P. Cheng Arginine (Arg) methylation is a common post-translational modification that regulates gene expression and viral infection. The HIV-1 Tat protein is an essential regulatory protein for HIV proliferation, and is methylated in the cell. The basic region (residues 47–57) of the Tat protein contains six Arg residues, and is responsible for two biological functions: RNA recognition and cellular uptake. In this study, we explore the effect of three different methylation states at each Arg residue in Tat-derived peptides on the two biological functions. The Tat-derived peptides were synthesized by solid phase peptide synthesis. TAR RNA binding of the peptides was assessed by electrophoresis mobility shift assays. The cellular uptake of the peptides into Jurkat cells was determined by flow cytometry. Our results showed that RNA recognition was affected by both methylation state and position. In particular, asymmetric dimethylation at position 53 decreased TAR RNA binding affinity significantly, but unexpectedly less so upon asymmetric dimethylation at position 52. The RNA binding affinity even slightly increased upon methylation at some of the flanking Arg residues. Upon Arg methylation, the cellular uptake of Tat-derived peptides mostly decreased. Interestingly, cellular uptake of Tat-derived peptides with a single asymmetrically dimethylated Arg residue was similar to the native all Arg peptide (at 120μM). Based on our results, TAR RNA binding apparently required both guanidinium terminal NH groups on Arg53, whereas cellular uptake apparently required guanidinium terminal NH2 groups instead. These results should provide insight into how nature uses arginine methylation to regulate different biological functions, and should be useful for the development of functional molecules with methylated arginines Graphical abstract image
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Design, synthesis and biological evaluation of N-phenylthieno[2,3-d]pyrimidin-4-amines as inhibitors of FGFR1 ()
Publication date: 1 May 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 9 Author(s): A.A. Gryshchenko , V.G. Bdzhola , A.O. Balanda , N.V. Briukhovetska , I.M. Kotey , A.G. Golub , T.P. Ruban , L.L. Lukash , S.M. Yarmoluk Fibroblast grow factor receptor 1 (FGFR1) is an important anti-cancer target that plays crucial role in oncogenesis and oncogenic angiogenesis. The structure–activity relationship (SAR) of N-phenylthieno[2,3-d]pyrimidin-4-amines was investigated. Binding of active compounds with FGFR1 kinase was analyzed by molecular modeling studies. Selected active thieno[2,3-d]pyrimidines were tested for selectivity and antiproliferative activity. The most active compounds, 3-({6-phenylthieno[2,3-d]pyrimidin-4-yl}amino)phenol and 3-({5-phenylthieno[2,3-d]pyrimidin-4-yl}amino)phenol have IC50 0.16 and 0.18μM, respectively. The results presented here may help to identify new thienopyrimidines with optimized cell growth inhibitory activity which may be further used as anticancer agents. Graphical abstract image
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Editorial board ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8
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Graphical contents list ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8
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β-Sheet interfering molecules acting against β-amyloid aggregation and fibrillogenesis ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Antonio Francioso , Pasqualina Punzi , Alberto Boffi , Clorinda Lori , Sara Martire , Cesare Giordano , Maria D’Erme , Luciana Mosca β-Sheet aggregates and amyloid fibrils rising from conformational changes of proteins are observed in several pathological human conditions. These structures are organized in β-strands that can reciprocally interact by hydrophobic and π–π interactions. The amyloid aggregates can give rise to pathological conditions through complex biochemical mechanisms whose physico-chemical nature has been understood in recent times. This review focuses on the various classes of natural and synthetic small molecules able to act against β-amyloid fibrillogenesis and toxicity that may represent new pharmacological tools in Alzheimer’s diseases. Some peptides, named ‘β-sheet breaker peptides’, are able to hamper amyloid aggregation and fibrillogenesis by interfering with and destabilizing the non native β-sheet structures. Other natural compounds, like polyphenols or indolic molecules such as melatonin, can interfere with β-amyloid peptide pathogenicity by inhibiting aggregation and counteracting oxidative stress that is a key hallmark in Alzheimer’s disease. Graphical abstract image
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Synthesis, optical properties and preliminary in vitro photodynamic effect of pyridyl and quinoxalyl substituted chlorins ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Jiazhu Li , Xin Zhang , Yang Liu , Il Yoon , Dong-Kyoo Kim , Jun-Gang Yin , Jin-Jun Wang , Young Key Shim A series of chlorophyll a-based chlorins conjugated with pyridyl or quinoxalyl group at different positions were synthesized, characterized and evaluated for their photodynamic effect in vitro. It was found that all the pyridyl and quinoxalyl chlorins showed promising photocytotoxicities but nontoxic without irradiation in HeLa cells, and the substituted types and positions had a significant influence on the photocytotoxicities of the chlorophyll a-based chlorins. All the chlorins with a pyridyl group at the C–D ring end exhibited relatively high photocytotoxicity as compared to those with 32-pyridyl. Among them, compound 12 conjugated with a pyridyl group at its C12 position showed the best photodynamic effect in HeLa cells with an IC50 value of 0.033μM. These facts, associated with the relative high long wavelength absorptions of those chlorins may provide valuable ways to design and prepare promising photosensitizers for application in photodynamic therapy. Graphical abstract image
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Triazine–benzimidazole hybrids: Anticancer activity, DNA interaction and dihydrofolate reductase inhibitors ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Prinka Singla , Vijay Luxami , Kamaldeep Paul A new series of triazine–benzimidazole hybrids has been synthesized with different substitution of primary and secondary amines at one of the position of triazine in moderate to good yields. These compounds were evaluated for their inhibitory activities over 60 human tumor cell lines at one dose and five dose concentrations. Compounds 6b, 8 and 9 showed broad spectrum of antitumor activities with GI50 values of 9.79, 2.58 and 3.81μM, respectively. DNA binding studies also indicated strong interaction properties of these compounds. These synthesized compounds also showed inhibition of mammalian dihydrofolate reductase (DHFR). Compound 6b was depicted as the most active member of DHFR inhibitor with IC50 value of 1.05μM. Molecular modelling studies were used to identify the stabilized interactions of Compound 6b within the active site of enzyme for DHFR. Graphical abstract image
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Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Yunyun Yuan , Saheem A. Zaidi , David L. Stevens , Krista L. Scoggins , Philip D. Mosier , Glen E. Kellogg , William L. Dewey , Dana E. Selley , Yan Zhang A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure–activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1′- and/or 4′-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6′- and/or 7′-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6′-nitro group varied significantly in the different ‘address’ domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands. Graphical abstract image
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In vitro radical scavenging and cytotoxic activities of novel hybrid selenocarbamates ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Beatriz Romano , Daniel Plano , Ignacio Encío , Juan Antonio Palop , Carmen Sanmartín Novel selenocyanate and diselenide derivatives containing a carbamate moiety were synthesised and evaluated in vitro to determine their cytotoxic and radical scavenging properties. Cytotoxic activity was tested against a panel of human cell lines including CCRF-CEM (lymphoblastic leukaemia), HT-29 (colon carcinoma), HTB-54 (lung carcinoma), PC-3 (prostate carcinoma), MCF-7 (breast adenocarcinoma), 184B5 (non-malignant, mammary gland derived) and BEAS-2B (non-malignant, derived from bronchial epithelium). Most of the compounds displayed high antiproliferative activity with GI50 values below 10μM in MCF-7, CCRF-CEM and PC-3 cells. Radical scavenging properties of the new selenocompounds were confirmed testing their ability to scavenge DPPH and ABTS radicals. Based on the activity of selenium-based glutathione peroxidases (GPxs), compounds 1a, 2e and 2h were further screened for their capacity to reduce hydrogen peroxide under thiol presence. Results suggest that compound 1a mimics GPxs activity. Cytotoxic parameters, radical scavenging activity and ADME profile point to 1a as promising drug candidate. Graphical abstract image
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Sulfonamide inhibition studies of the γ-carbonic anhydrase from the Antarctic cyanobacterium Nostoc commune ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Daniela Vullo , Viviana De Luca , Sonia Del Prete , Vincenzo Carginale , Andrea Scozzafava , Clemente Capasso , Claudiu T. Supuran A carbonic anhydrase (CA, EC 4.2.1.1) belonging to the γ-class has been cloned, purified and characterized from the Antarctic cyanobacterium Nostoc commune. The enzyme showed a good catalytic activity for the physiologic reaction (hydration of carbon dioxide to bicarbonate and a proton) with the following kinetic parameters, k cat of 9.5×105 s−1 and k cat/K M of 8.3×107 M−1 s−1, being the γ-CA with the highest catalytic activity described so far. A range of aromatic/heterocyclic sulfonamides and one sulfamate were investigated as inhibitors of the new enzyme, denominated here NcoCA. The best NcoCA inhibitors were some sulfonylated sulfanilamide derivatives possessing elongated molecules, aminobenzolamide, acetazolamide, benzolamide, dorzolamide, brinzolamide and topiramate, which showed inhibition constants in the range of 40.3–92.3nM. As 1,5-bisphosphate carboxylase/oxygenase (RubisCO) and γ-CAs are closely associated in carboxysomes of cyanobacteria for enhancing the affinity of RubisCO for CO2 and the efficiency of photosynthesis, investigation of this new enzyme and its affinity for modulators of its activity may bring new insights in these crucial processes. Graphical abstract image
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Design and synthesis of new potassium channel activators derived from the ring opening of diazoxide: Study of their vasodilatory effect, stimulation of elastin synthesis and inhibitory effect on insulin release ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Nafila Bouider , Wassim Fhayli , Zeinab Ghandour , Marjorie Boyer , Kamel Harrouche , Xavier Florence , Bernard Pirotte , Philippe Lebrun , Gilles Faury , Smail Khelili Benzenesulfonylureas and benzenesulfonylthioureas, as well as benzenecarbonylureas and benzenecarbonylthioureas, were prepared and evaluated as myorelaxants on 30mMKCl-precontracted rat aortic rings. The most active compounds were further examined as stimulators of elastin synthesis by vascular smooth muscle cells and as inhibitors of insulin release from pancreaticβ-cells. The drugs were also characterized for their effects on glycaemia in rats. Benzenesulfonylureas and benzenesulfonylthioureas did not display any myorelaxant activity on precontracted rat aortic rings. Such an effect could be attributed to their ionization at physiological pH. By contrast, almost all benzenecarbonylureas and benzenecarbonylthioureas displayed a myorelaxant activity, in particular the benzenecarbonylureas with an oxybenzyl group linked to the ortho position of the phenyl ring. The vasodilatory activity of the most active compounds was reduced when measured in the presence of 80mMKCl or in the presence of 30mM KCl and 10μM glibenclamide. Such results suggested the involvement, at least in part, of KATP channels. Preservation of a vasodilatory activity in rat aortic rings without endothelium indicated that the site of action of such molecules was located on the vascular smooth muscle cells and not on the endothelial cells. Some of the most active compounds also stimulated elastin synthesis by vascular smooth muscle cells. Lastly, most of the active vasorelaxant drugs, except 15k and 15t at high concentrations, did not exhibit marked inhibitory effects on the insulin releasing process and on glycaemia, suggesting a relative tissue selectivity of some of these compounds for the vascular smooth muscle. Graphical abstract image
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A combination of in silico and SAR studies to identify binding hot spots of Bcl-xL inhibitors ()
Publication date: 15 April 2015 Source:Bioorganic & Medicinal Chemistry, Volume 23, Issue 8 Author(s): Nicolas Levoin , Duc Duy Vo , Fabien Gautier , Sophie Barillé-Nion , Philippe Juin , Olivier Tasseau , René Grée Inhibition of Bcl-2 family protein–protein interactions (PPI) is a very promising direction in cancer chemotherapy. Hence over the last decade, many medicinal chemistry studies endeavoured to discover drug candidates, and a wealth of chemical scaffolds with striking chemical diversity was reported as Bcl-xL inhibitors. This raises the question of whether all these molecules could occupy a unique binding site, or rather discrete pockets of the protein surface. To test if small and chemically diverse Bcl-xL inhibitors are likely to bind a single pocket, and to identify which pocket, we used a battery of computational and modeling approaches. We first checked that the large dataset of Bcl-xL inhibitors we built can actually fit to a universal pharmacophore. Then we defined the probable binding hot spots of interaction through comparison of crystal structures, as well as virtual fragment screening. Finally, new analogues of small polyphenol derivatives were synthesized to precisely probe a hydrogen bond suggested by docking experiments. Bcl-xL inhibition potency of these products confirmed the predicted binding mode. This combination of X-ray structure exploration, molecular modeling studies and medicinal chemistry supports that all these small Bcl-xL inhibitors occupy the same hot spot of interaction. The identification of this binding site should help the design and optimization of small PPI Bcl-xL inhibitors. Graphical abstract image
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