Bioorganic & Medicinal Chemistry Letters

Editorial board ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14
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Fused bi-heteroaryl substituted hydantoin compounds as TACE inhibitors ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Ling Tong, Seong Heon Kim, Kristin Rosner, Wensheng Yu, Bandarpalle B. Shankar, Lei Chen, Dansu Li, Chaoyang Dai, Vinay Girijavallabhan, Janeta Popovici-Muller, Liping Yang, Guowei Zhou, Aneta Kosinski, M. Arshad Siddiqui, Neng-Yang Shih, Zhuyan Guo, Peter Orth, Shiying Chen, Daniel Lundell, Xiaoda Niu, Shelby Umland, Joseph A. Kozlowski We have identified a series of hydantoin-derived TNF-a converting enzyme (TACE) inhibitors containing a pendant fused bi-heteroaryl group, which demonstrate sub-nanomolar potency (Ki), excellent activity in human whole blood assay, and improved DMPK profiles over prior series. Graphical abstract image
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New merosesquiterpenes from a Vietnamese marine sponge of Spongia sp. and their biological activities ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Hien Minh Nguyen, Takuya Ito, Shin-ichiro Kurimoto, Mika Ogawa, Nwet Nwet Win, Vo Quoc Hung, Hoai Thi Nguyen, Takaaki Kubota, Jun'ichi Kobayashi, Hiroyuki Morita The investigation of the Vietnamese marine sponge Spongia sp. led to the isolation of three new sesquiterpene phenols, langconols A–C (1–3), and one new sesquiterpene hydroxyquinone, langcoquinone C (4), together with two known meroterpenoids (5 and 6). Their structures were determined on the basis of spectroscopic analyses and comparisons with published data. Furthermore, the antibacterial assays of the isolates 1–6 suggested that 4 and 6 had significant antibacterial activities against Bacillus subtilis and Staphylococcus aureus, with MICs ranging from 6.25 to 25.0µM, while 1 and 3 possessed significant antibacterial activities against B. subtilis with MICs of 12.5 and 25.0µM, respectively. In contrast, cytotoxic assays of the isolated compounds 1–6, as well as compounds 7–15 previously isolated from this sponge, indicated that 1 and the previously reported anti-B. subtilis and anti-S. aureus sesquiterpene phenol 9 lacked cytotoxic activities against three human cancer cell lines (A549, lung cancer; MCF7, breast cancer; HeLa, cervix cancer) and a human normal cell line (WI-38 fibroblast). Graphical abstract image
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Design, synthesis of novel furan appended benzothiazepine derivatives and in vitro biological evaluation as potent VRV-PL-8a and H+/K+ ATPase inhibitors ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Devirammanahalli Mahadevaswamy Lokeshwari, Nanjappagowda Dharmappa Rekha, Bharath Srinivasan, Hamse Kameshwar Vivek, Ajay Kumar Kariyappa A series of new of furan derivatised [1,4] benzothiazepine analogues were synthesized starting from 1-(furan-2-yl)ethanone. 1-(Furan-2-yl)ethanone was converted into chalcones by its reaction with various aromatic aldehydes, then were reacted with 2-aminobenzenethiol in acidic conditions to obtain the title compounds in good yields. The synthesized new compounds were characterized by 1H NMR, 13C NMR, Mass spectral studies and elemental analyses. All the new compounds were evaluated for their in vitro VRV-PL-8a and H+/K+ ATPase inhibitor properties. Preliminary studies revealed that, some molecules amongst the designed series showed promising VRV-PL-8a and H+/K+ ATPase inhibitor properties. Further, rigid body docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This finding presents a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorder that can mitigate the ulcer inducing side effect shown by other NSAIDs. Graphical abstract image
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Key analogs of a uniquely potent synthetic vinblastine that contain modifications of the C20′ ethyl substituent ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Oliver Allemann, R. Matthew Cross, Manuela M. Brütsch, Aleksandar Radakovic, Dale L. Boger A key series of vinblastine analogs 7–13, which contain modifications to the C20′ ethyl group, was prepared with use of two distinct synthetic approaches that provide modifications of the C20′ side chain containing linear and cyclized alkyl groups or added functionalized substituents. Their examination revealed the unique nature of the improved properties of the synthetic vinblastine 6, offers insights into the origins of its increased tubulin binding affinity and 10-fold improved cell growth inhibition potency, and served to probe a small hydrophobic pocket anchoring the binding of vinblastine with tubulin. Especially noteworthy were the trends observed with substitution of the terminal carbon of the ethyl group that, with the exception of 9 (R=F vs H, equipotent), led to remarkably substantial reductions in activity (>10-fold): R=F (equipotent with H)>N3, CN (10-fold)>Me (50-fold)>Et (100-fold)>OH (inactive). This is in sharp contrast to the maintained (7) or enhanced activity (6) observed with its incorporation into a cyclic C20′/C15′-fused six-membered ring. Graphical abstract image
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Sialidase inhibitory activity of diarylnonanoid and neolignan compounds extracted from the seeds of Myristica fragrans ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Ji-Young Park, Su Hwan Lim, Bo Ram Kim, Hyung Jae Jeong, Hyung-Jun Kwon, Gyu-Yong Song, Young Bae Ryu, Woo Song Lee Sialidases are key virulence factors that remove sialic acid from host cell surface glycans, thus unmasking receptors to facilitate bacterial adherence and colonization. In this study, we report the isolation and characterization of novel inhibitors of the Streptococcus pneumoniae sialidases NanA, NanB, and NanC from Myristica fragrans seeds. Of the isolated compounds (1–12), malabaricone C showed the most pneumococcal sialidases inhibition (IC50 of 0.3μM for NanA, 3.6μM for NanB, and 2.9μM for NanC). These results suggested that malabaricone C and neolignans could be potential agents for combating S. pneumoniae infection agents. Graphical abstract image
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Minor phenolics from Angelica keiskei and their proliferative effects on Hep3B cells ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Yun-Seo Kil, Jiyoung Park, Mahtab Jafari, Hyun Ae Woo, Eun Kyoung Seo A new coumarin, (−)-cis-(3′R,4′R)-4′-O-angeloylkhellactone-3′-O-β-d-glucopyranoside (1) and two new chalcones, 3′-[(2E)-5-carboxy-3-methyl-2-pentenyl]-4,2′,4′-trihydroxychalcone (4) and (±)-4,2′,4′-trihydroxy-3′-{2-hydroxy-2-[tetrahydro-2-methyl-5-(1-methylethenyl)-2-furanyl]ethyl}chalcone (5) were isolated from the aerial parts of Angelica keiskei (Umbelliferae), together with six known compounds: (R)-O-isobutyroyllomatin (2), 3′-O-methylvaginol (3), (−)-jejuchalcone F (6), isoliquiritigenin (7), davidigenin (8), and (±)-liquiritigenin (9). The structures of the new compounds were determined by interpretation of their spectroscopic data including 1D and 2D NMR data. All known compounds (2, 3, and 6–9) were isolated as constituents of A. keiskei for the first time. To identify novel hepatocyte proliferation inducer for liver regeneration, 1–9 were evaluated for their cell proliferative effects using a Hep3B human hepatoma cell line. All isolates exhibited cell proliferative effects compared to untreated control (DMSO). Cytoprotective effects against oxidative stress induced by glucose oxidase were also examined on Hep3B cells and mouse fibroblast NIH3T3 cells and all compounds showed significant dose-dependent protection against oxidative stress. Graphical abstract image
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One-pot microwave assisted stereoselective synthesis of novel dihydro-2′H-spiro[indene-2,1′-pyrrolo-[3,4-c]pyrrole]-tetraones and evaluation of their antimycobacterial activity and inhibition of AChE ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Chelliah Bharkavi, Sundaravel Vivek Kumar, Mohamed Ashraf Ali, Hasnah Osman, Shanmugam Muthusubramanian, Subbu Perumal An efficient one-pot microwave assisted stereoselective synthesis of novel dihydro-2′H-spiro[indene-2,1′-pyrrolo[3,4-c]pyrrole]-tetraone derivatives through three-component 1,3-dipolar cycloaddition of azomethine ylides generated in situ from ninhydrin and sarcosine with a series of 1-aryl-1H-pyrrole-2,5-diones is described. The synthesised compounds were screened for their antimycobacterial and AChE inhibition activities. Compound 4b (IC50 1.30µM) has been found to display twelve fold antimycobacterial activity compared to cycloserine and it is thirty seven times more active than pyrimethamine. Compound 4h displays maximum AchE inhibitory activity with IC50 value of 0.78±0.01µmol/L. Graphical abstract image
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Anti-inflammatory effects and corresponding mechanisms of cirsimaritin extracted from Cirsium japonicum var. maackii Maxim ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Myoung-Sook Shin, Jun Yeon Park, Jaemin Lee, Hye Hyun Yoo, Dae-Hyun Hahm, Sang Cheon Lee, Sanghyun Lee, Gwi Seo Hwang, Kiwon Jung, Ki Sung Kang In this study, we investigated the anti-inflammatory effects and mechanisms of cirsimaritin isolated from an ethanol extract of the aerial parts of Cirsium japonicum var. maackii Maxim. using RAW264.7 cells. The extract and its flavonoid cirsimaritin inhibited nitric oxide (NO) production and inducible nitric oxide synthase expression in RAW264.7 cells. Cirsimaritin inhibited interleukin-6, tumor necrosis factor-α, and NO production in a concentration-dependent manner in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. From a western blot study, pretreatment with cirsimaritin inhibited phosphorylation/degradation of IκBα and phosphorylation of Akt in LPS-stimulated RAW264.7 cells. Moreover, cirsimaritin suppressed activation of LPS-induced transcription factors, such as c-fos and signal transducer and activator of transcription 3 (STAT3), in RAW264.7 cells. Collectively, these results show that cirsimaritin possesses anti-inflammatory activity, which is regulated by inhibition of c-fos and STAT3 phosphorylation in RAW264.7 cells. Graphical abstract image
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Evaluation of the antiprotozoan properties of 5′-norcarbocyclic pyrimidine nucleosides ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Khalid J. Alzahrani, Elena S. Matyugina, Anastasia L. Khandazhinskaya, Sergei N. Kochetkov, Katherine L. Seley-Radtke, Harry P. de Koning Carbocyclic nucleoside analogues have a distinguished history as anti-infectious agents, including key antiviral agents. Toxicity was initially a concern but this was reduced by the introduction of 5′-nor variants. Here, we report the result of our preliminary screening of a series of 5′-norcarbocyclic uridine analogues against protozoan parasites, specifically the major pathogens Leishmania mexicana and Trypanosoma brucei. The series displayed antiparasite activity in the low to mid-micromolar range and establishes a preliminary structure-activity relationship, with the 4′,N 3-di-(3,5-dimethylbenzoyl)-substituted analogues showing the most prominent activity. Utilizing an array of specially adapted cell lines, it was established that this series of analogues likely act through a common target. Moreover, the strong correlation between the trypanocidal and anti-leishmanial activities indicates that this mechanism is likely shared between the two species. EC50 values were unaffected by the disabling of pyrimidine biosynthesis in T. brucei, showing that these uridine analogues do not act directly on the enzymes of pyrimidine nucleotide metabolism. The lack of cross-resistance with 5-fluorouracil, also establishes that the carbocyclic analogues are not imported through the known uracil transporters, thus offering forth new insights for this class of nucleosides. The lack of cross-resistance with current trypanocides makes this compound class interesting for further exploration. Graphical abstract image
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Inhibition of phosphatidylinositol-3-kinase by the furanosesquiterpenoid hibiscone C ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Caroline Besley, Dena P. Rhinehart, Taylor Ammons, Brian C. Goess, Jason S. Rawlings The phosphatidylinositol-3-kinase (PI3K) pathway regulates cellular metabolism and is upregulated in many cancers, making it an attractive chemotherapeutic target. Wortmannin is a potent inhibitor of PI3K; however, its potential as a chemotherapeutic is limited due to its instability, lack of selectivity, and lengthy chemical synthesis. In contrast, hibiscone C, a structurally simpler and less studied member of the furanosteroid family, has been expediently prepared by total synthesis. We demonstrate that hibiscone C competitively inhibits PI3K activity in intact cells, slows proliferation, and induces cell death. Hibiscone C may therefore serve as a productive scaffold for the development of therapeutically relevant PI3K inhibitors. Graphical abstract image
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Synthesis and anti-proliferative activity of a small library of 7-substituted 5H-pyrrole [1,2-a][3,1]benzoxazin-5-one derivatives ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Mariateresa Badolato, Gabriele Carullo, Biagio Armentano, Salvatore Panza, Rocco Malivindi, Francesca Aiello In this study, we investigate the anti-proliferative activity of a small library of 7-substituted 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one derivatives, against a panel of human cancer cell lines. We reported the synthesis of these compounds in a previous work. 7-Bromo-5H-benzo[d]pyrrolo[2,1-b][1,3]oxazin-5-one showed a promising anti-proliferative effect. As starting material for Suzuki-Miyaura cross coupling reaction, it was selected for the design and the synthesis of six further derivatives, with the aim to better define structure-activity relationships. The anti-proliferative MTT assay revealed a dose-dependent reduction of cell viability, especially for 7-([1,1′-biphenyl]-4-yl)-5H-benzo[d]pyrrolo[2,1-b][1,3]oxazin-5-one. Cell cycle and western blotting analysis suggested apoptosis as possible mechanism for its anti-proliferative activity. These preliminary results encourage our interest for further optimizations. Graphical abstract image
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Quinazolinone derivatives as inhibitors of homologous recombinase RAD51 ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Ambber Ward, Lilong Dong, Jonathan M. Harris, Kum Kum Khanna, Fares Al-Ejeh, David P. Fairlie, Adrian P. Wiegmans, Ligong Liu RAD51 is a vital component of the homologous recombination DNA repair pathway and is overexpressed in drug-resistant cancers, including aggressive triple negative breast cancer (TNBC). A proposed strategy for improving therapeutic outcomes for patients is through small molecule inhibition of RAD51, thereby sensitizing tumor cells to DNA damaging irradiation and/or chemotherapy. Here we report structure-activity relationships for a library of quinazolinone derivatives. A novel RAD51 inhibitor (17) displays up to 15-fold enhanced inhibition of cell growth in a panel of TNBC cell lines compared to compound B02, and approximately 2-fold increased inhibition of irradiation-induced RAD51 foci formation. Additionally, compound 17 significantly inhibits TNBC cell sensitivity to DNA damage, implying a potentially targeted therapy for cancer treatment. Graphical abstract image
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Discovery of potent and efficacious pyrrolopyridazines as dual JAK1/3 inhibitors ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): John Hynes, Hong Wu, James Kempson, James J.-W. Duan, Zhonghui Lu, Bin Jiang, Sylwia Stachura, John S. Tokarski, John S. Sack, Javed A. Khan, Jonathan S. Lippy, Rosemary F. Zhang, Sidney Pitt, Guoxiang Shen, Kate Gillooly, Kim McIntyre, Percy H. Carter, Joel C. Barrish, Steven G. Nadler, Luisa M. Salter-Cid, Aberra Fura, Gary L. Schieven, William J. Pitts, Stephen T. Wrobleski A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described. Graphical abstract image
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Design, synthesis and evaluation of antitumor acylated monoaminopyrroloquinazolines ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Bo Chao, Bingbing X. Li, Xiangshu Xiao Pyrroloquinazoline is a privileged chemical scaffold with diverse biological activities. We recently described a series of N-3 acylated 1,3-diaminopyrroloquinazolines with potent anticancer activities. The N-1 primary amino group in 1,3-diaminopyrroloquinazoline is critical for its inhibitory activity against dihydrofolate reductase (DHFR). In order to design out this unnecessary DHFR inhibition activity and further expand the chemical space associated with pyrroloquinazoline, we removed the N-1 primary amino group. In this report, we describe our design and synthesis of a series of N-3 acylated monoaminopyrroloquinazolines. Biological evaluation of these compounds identified a naphthamide 4a as a potent anticancer agent (GI50 =88–200nM), suggesting that removing the N-1 primary amino group in 1,3-diaminopyrroloquinazoline is a useful chemical modification that can be introduced to improve the anticancer activity. Graphical abstract image
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Optimization of the process of inverted peptides (PIPEPLUS) to screen PDZ domain ligands ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Quentin Seisel, Marisa Rädisch, Nicholas P. Gill, Dean R. Madden, Prisca Boisguerin PDZ domains play crucial roles in cell signaling processes and are therefore attractive targets for the development of therapeutic inhibitors. In many cases, C-terminal peptides are the physiological binding partners of PDZ domains. To identify both native ligands and potential inhibitors we have screened arrays synthesized by the process of inverted peptides (PIPE), a variant of SPOT synthesis that generates peptides with free C-termini. Here, we present the development of a new functionalized cellulose membrane as solid support along with the optimized PIPEPLUS technology. Improved resolution and accuracy of the synthesis were shown with peptide arrays containing both natural and non-natural amino acids. These new screening possibilities will advance the development of active, selective and metabolically stable PDZ interactors. Graphical abstract image
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Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Aisha A.K. Al-Ashmawy, Fatma A. Ragab, Khaled M. Elokely, Manal M. Anwar, Oscar Perez-Leal, Mario C. Rico, John Gordon, Eugeney Bichenkov, George Mateo, Emad M.M. Kassem, Gehan H. Hegazy, Magid Abou-Gharbia, Wayne Childers PI3Kα/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2-d]pyrimidine and pyrido[2,3-d]pyrimidine analogs were designed and synthesized as PI3Kα/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC50 values ranging from single to double digit nM. Unlike many PI3Kα/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kα. Based on its potent enzyme inhibitory activity, selectivity for PI3Kα and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC50 against MCF7 breast cancer cells as well as for docking studies with both enzymes. Graphical abstract image
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Lodopyridones B and C from a marine sediment-derived bacterium Saccharomonospora sp. ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Tu Cam Le, Chae-Yoon Yim, Songhee Park, Nikita Katila, Inho Yang, Myoung Chong Song, Yeo Joon Yoon, Dong-Young Choi, Hyukjae Choi, Sang-Jip Nam, William Fenical HPLC-UV guided isolation of the culture broth of a marine bacterium Saccharomonospora sp. CNQ-490 has led to the isolation of two new natural products, lodopyridones B and C (1 and 2) along with the previously reported lodopyridone A (3). Their chemical structures were established from the interpretation of 2D NMR spectroscopic data and the comparison of NMR data with the lodopyridone A (3). Lodopyridones B and C (1 and 2) possess the thiazole, and chloroquinoline groups which are characteristic features of these molecules. Lodopyridones A–C show weak inhibitory activities on the β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Graphical abstract image
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Ratiometric fluorescence imaging of nuclear pH in living cells using Hoechst-tagged fluorescein ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Akinobu Nakamura, Shinya Tsukiji Small-molecule fluorescent sensors that allow specific measurement of nuclear pH in living cells will be valuable for biological research. Here we report that Hoechst-tagged fluorescein (hoeFL), which we previously developed as a green fluorescent DNA-staining probe, can be used for this purpose. Upon excitation at 405nm, the hoeFL–DNA complex displayed two fluorescence bands around 460nm and 520nm corresponding to the Hoechst and fluorescein fluorescence, respectively. When pH was changed from 8.3 to 5.5, the fluorescence intensity ratio (F 520/F 460) significantly decreased, which allowed reliable pH measurement. Moreover, because hoeFL binds specifically to the genomic DNA in cells, it was applicable to visualize the intranuclear pH of nigericin-treated and intact living human cells by ratiometric fluorescence imaging. Graphical abstract image
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Switching subtype-selectivity: Fragment replacement strategy affords novel class of peroxisome proliferator-activated receptor α/δ (PPARα/δ) dual agonists ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Ryuta Shioi, Shogo Okazaki, Tomomi Noguchi-Yachide, Minoru Ishikawa, Makoto Makishima, Yuichi Hashimoto, Takao Yamaguchi Peroxisome proliferator-activated receptors (PPARs) are important drug targets for treatment of dyslipidemia, type 2 diabetes, cardiovascular disease, nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and great efforts have been made to develop novel PPAR ligands. However, most existing PPAR ligands contain a carboxylic acid (CA) or thiazolidinedione (TZD) structure (acidic head group) that is essential for activity. We recently discovered non-CA/TZD class PPARα/δ partial agonists, which contain an acetamide moiety and adjacent methyl group, linked to a 1,2,4-oxadiazole ring (“fragment a”). We hypothesized that the acetamide structure might interact with the CA/TZD-binding pocket. To test this idea, we firstly replaced fragment a in one of our compounds with the α-alkoxy-CA structure often found in PPAR agonists. Secondly, we replaced the α-alkoxy-CA head group of several reported PPAR agonists with our acetamide-based fragment a. The agonistic activities of the synthesized hybrid compounds toward PPARs (PPARα, PPARγ and PPARδ) were evaluated by means of cell-based reporter gene assays. All the hybrid molecules showed PPAR-agonistic activities, but replacement of the α-alkoxy-CA head group altered the maximum efficacy and the subtype-specificity. The acetamide-based hybrid molecules showed partial agonism toward PPARα and PPARδ, whereas the α-alkoxy-CA-based molecules were generally selective for PPARα and PPARγ, with relatively high activation efficacies. Thus, the fragment replacement strategy appears promising for the development of novel acetamide-based PPARα/δ dual agonists. Graphical abstract image
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Syntheses of prodrug-type phosphotriester oligonucleotides responsive to intracellular reducing environment for improvement of cell membrane permeability and nuclease resistance ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Junsuke Hayashi, Yusuke Samezawa, Yosuke Ochi, Shun-ichi Wada, Hidehito Urata We synthesized prodrug-type phosphotriester (PTE) oligonucleotides containing the six-membered cyclic disulfide moiety by using phosphoramidite chemistry. Prodrug-type oligonucleotides named “Reducing-Environment-Dependent Uncatalyzed Chemical Transforming (REDUCT) PTE oligonucleotides” were converted into natural oligonucleotides under cytosol-mimetic reductive condition. Furthermore, the REDUCT PTE oligonucleotides were robust to nuclease digestion and exhibited good cell membrane permeability. Graphical abstract image
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Synthesis and in vitro evaluation of three novel radiotracers for imaging of metabotropic glutamate receptor subtype 2 in rat brain ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Katsushi Kumata, Tomoteru Yamasaki, Akiko Hatori, Yiding Zhang, Wakana Mori, Masayuki Fujinaga, Lin Xie, Takayuki Okubo, Nobuki Nengaki, Ming-Rong Zhang The purpose of this study was to develop three new radiotracers, 1-(cyclopropylmethyl)-4-([11C/18F]substituted-phenyl)piperidin-1-yl-2-oxo-1,2-dihydropyridine-3-carbonitrile ([11C]1, [11C]2, and [18F]4), and to examine their specific bindings with metabotropic glutamate receptor subtype 2 (mGluR2) in rat brain sections by using in vitro autoradiography. These compounds were found to possess potent in vitro binding affinities (K i: 8.0–34.1nM) for mGluR2 in rat brain homogenate. [11C]1, [11C]2, and [18F]4 were synthesized by [11C/18F]alkylation of the corresponding phenol precursors with [11C]methyl iodide or [18F]fluoroethyl bromide with >98% radiochemical purity and 80–130GBq/μmol specific activity at the end of synthesis. In vitro autoradiography indicated that these radiotracers showed heterogeneous specific bindings in mGluR2-rich brain regions, such as the cerebral cortex, striatum, hippocampus, and granular layer of the cerebellum. Graphical abstract image
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Cytotoxic pterosins from Pteris multifida roots against HCT116 human colon cancer cells ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Jung Wha Kim, Hong Pyo Kim, Sang Hyun Sung Two new pterosin glycosides, (2S,3S)-pterosin C 3-O-β-d-(4′-(E)-caffeoyl)-glucopyranoside (1) and (2S,3S)-pterosin C 3-O-β-d-(6′-(E)-p-coumaroyl)-glucopyranoside (2), were isolated from Pteris multifida (Pteridaceae) roots along with ten known pterosin compounds (3–12). The chemical structures of the isolated compounds were elucidated by extensive analysis of the 1D, 2D NMR, HRESIMS, and CD spectroscopic data. The cytotoxicities of 1–12 against HCT116 human colorectal cancer cell line were evaluated. Among the isolates, compound 1 showed moderate antiproliferative activity in HCT116 cells with an IC50 value of 8.0±1.7μM. Additionally, 1 induced the upregulation of the caspase-9 and procaspase-9 levels in Western blots and increased the annexin V/propidium iodide (PI)-positive cell population in flow cytometry. Graphical abstract image
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Synthesis, SAR and molecular docking studies of benzo[d]thiazole-hydrazones as potential antibacterial and antifungal agents ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Gao-Feng Zha, Jing Leng, N. Darshini, T. Shubhavathi, H.K. Vivek, Abdullah M. Asiri, Hadi M. Marwani, K.P. Rakesh, N. Mallesha, Hua-Li Qin A series of new benzo[d]thiazole-hydrazones analogues were synthesized and screened for their in vitro antibacterial and antifungal activities. The results revealed that compounds 13, 14, 15, 19, 20, 28 and 30 exhibited superior antibacterial potency compared to the reference drug chloramphenicol and rifampicin. Compounds 5, 9, 10, 11, 12, 28 and 30 were found to be good antifungal activity compared to the standard drug ketoconazole. A preliminary study of the structure-activity relationship (SAR) revealed that the antimicrobial activity depended on the effect of different substituents on the phenyl ring. The electron donating (OH and OCH3) groups presented in the analogues, increase the antibacterial activity (except compound 12), interestingly, while the electron withdrawing (Cl, NO2, F and Br) groups increase the antifungal activity (except compound 19 and 20). In addition, analogues containing thiophene (28) and indole (30) showed good antimicrobial activities. Whereas, aliphatic analogues (24–26) shown no activities in both bacterial and fungal stains even in high concentrations (100µg/mL). Molecular docking studies were performed for all the synthesized compounds of which compounds 11, 19 and 20 showed the highest glide G-score. Graphical abstract image
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Evaluation of guggulsterone derivatives as novel kidney cell protective agents against cisplatin-induced nephrotoxicity ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Dahae Lee, Taejung Kim, Ki Hyun Kim, Jungyeob Ham, Tae Su Jang, Ki Sung Kang, Jae Wook Lee Guggulsterone derivatives were prepared using [3+2] click chemistry with aryl and alkyl acetylene. The series of derivatives were evaluated for their cellular protective effects on cisplatin-treated cultured LLC-PK1 kidney epithelial cells. Among the guggulsterone-triazole derivatives, compound 6g, which contains a hydroxyl methyl group, was the most active of all the derivatives. In an additional study, we determined that inhibition of the mitogen-activated protein kinase/caspase-3 signaling cascade by 6g mediates its protective effects against cytotoxicity in cultured LLC-PK1 cells. Graphical abstract image
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Design, synthesis and biological evaluation of 4-piperazinyl-containing Chidamide derivatives as HDACs inhibitors ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Qingwei Zhang, Bingliu Lu, Jianqi Li The synthesis and biological evaluation of a variety of 4-piperazinyl-containing Chidamide derivatives is described. Some of these compounds were shown to inhibit HDAC1 with IC50 values below micromolar range, and inhibited proliferation of several human cancer cells, not possessing toxicity to human normal cells and hERG K+ ion channels. Compound 9g, proved to be the most potent and efficacious derivative in this series, was orally active in an HCT116 xenograft model in vivo. Graphical abstract image
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Synthesis of resveratrol derivatives as new analgesic drugs through desensitization of the TRPA1 receptor ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Syuhei Nakao, Miyuki Mabuchi, Shenglan Wang, Yoko Kogure, Tadashi Shimizu, Koichi Noguchi, Akito Tanaka, Yi Dai A series of 31 resveratrol derivatives was designed, synthesized and evaluated for activation and inhibition of the TRPA1 channel. Most acted as activators and desensitizers of TRPA1 channels like resveratrol or allyl isothiocyanate (AITC). Compound 4z (HUHS029) exhibited higher inhibitory activity than resveratrol with an IC50 value of 16.1μM. The activity of 4z on TRPA1 was confirmed in TRPA1-expressing HEK293 cells, as well as in rat dorsal root ganglia neurons by a whole cell patch clamp recording. Furthermore, pretreatment with 4z exhibited an analgesic effect on AITC-evoked TRPA1-related pain behavior in vivo. Graphical abstract image
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Oligodeoxynucleotides containing 2′-amino-LNA nucleotides as constrained morpholino phosphoramidate and phosphorodiamidate monomers ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Kim Vejlegaard, Sibasish Paul, Tamer Kosbar, Jesper Wengel, Marvin H. Caruthers Incorporation in a 2′→5′ direction of a phosphorodiamidite 2′-amino-LNA-T nucleotide as the morpholino phosphoramidate and N,N-dimethylamino phosphorodiamidate monomers into six oligonucleotides is reported. Thermal denaturation studies showed that the novel 2′-amino-LNA-based morpholino monomers exert a destabilizing effects on duplexes formed with complementary DNA and RNA. Graphical abstract image
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Structure-based identification of inhibitors targeting obstruction of the HIVgp41 N-heptad repeat trimer ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): T. Dwight McGee, Hyun Ah Yi, William J. Allen, Amy Jacobs, Robert C. Rizzo The viral protein HIVgp41 is an attractive and validated drug target that proceeds through a sequence of conformational changes crucial for membrane fusion, which facilitates viral entry. Prior work has identified inhibitors that interfere with the formation of a required six-helix bundle, composed of trimeric C-heptad (CHR) and N-heptad (NHR) repeat elements, through blocking association of an outer CHR helix or obstructing formation of the inner NHR trimer itself. In this work, we employed similarity-based scoring to identify and experimentally characterize 113 compounds, related to 2 small-molecule inhibitors recently reported by Allen et al. (Bioorg. Med. Chem Lett. 2015, 25 2853–59), proposed to act via the NHR trimer obstruction mechanism. The compounds were first tested in an HIV cell-cell fusion assay with the most promising evaluated in a second, more biologically relevant viral entry assay. Of the candidates, compound #11 emerged as the most promising hit (IC50 =37.81µM), as a result of exhibiting activity in both assays with low cytotoxicity, as was similarly seen with the known control peptide inhibitor C34. The compound also showed no inhibition of VSV-G pseudotyped HIV entry compared to a control inhibitor suggesting it was specific for HIVgp41. Molecular dynamics simulations showed the predicted DOCK pose of #11 interacts with HIVgp41 in an energetic fashion (per-residue footprints) similar to the four native NHR residues (IQLT) which candidate inhibitors were intended to mimic. Graphical abstract image
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The design, synthesis, and anti-inflammatory evaluation of a drug-like library based on the natural product valerenic acid ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Folake A. Egbewande, Niclas Nilsson, Jonathan M. White, Mark J. Coster, Rohan A. Davis The plant natural product, valerenic acid (1) was chosen as a desirable scaffold for the generation of a novel screening library due to its drug-like physicochemical parameters (such as LogP, hydrogen bond donor/acceptor counts, and molecular weight). An 11-membered amide library (2–12) was subsequently generated using parallel solution-phase synthesis and Ghosez’s reagent. The chemical structures of all semi-synthetic analogues (2–12) were elucidated following analysis of the NMR, MS, UV and IR data. The structures of compounds 8 and 11 were also confirmed by X-ray crystallographic analysis. All library members were evaluated for their ability to inhibit the release of IL-8 and TNF-α. Six analogues showed moderate activity in the IL-8 assay with IC50 values of 2.8–8.3μM, while none of the tested compounds showed any significant effect on inhibiting TNF-α release. Graphical abstract image
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Development of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1 ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Daniel P. Mould, Ulf Bremberg, Allan M. Jordan, Matthis Geitmann, Alba Maiques-Diaz, Alison E. McGonagle, Helen F. Small, Tim C.P. Somervaille, Donald Ogilvie A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23µM. Optimisation of this compound by rational design afforded compounds with K d values of <10nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound. Graphical abstract image
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Pyrazolo[3,4-d]pyrimidines-loaded human serum albumin (HSA) nanoparticles: Preparation, characterization and cytotoxicity evaluation against neuroblastoma cell line ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Anna Lucia Fallacara, Arianna Mancini, Claudio Zamperini, Elena Dreassi, Stefano Marianelli, Mario Chiariello, Gianni Pozzi, Francesco Santoro, Maurizio Botta, Silvia Schenone Pyrazolo[3,4-d]pyrimidine derivatives 1–5, active as c-Src inhibitors, have been selected to be formulated as drug-loaded human serum albumin (HSA) nanoparticles, with the aim of improving their solubility and pharmacokinetic properties. The present study includes the optimization of a desolvation method-based procedure for preparing HSA nanoparticles. First, characterization by HPLC-MS and Dynamic Light Scattering (DLS) showed a good entrapment efficacy, a controllable particle size (between 100 and 200nm) and an optimal stability over time, confirmed by an in vitro drug release assay. Then, 1–4 and the corresponding NPs were tested for their antiproliferative activity against neuroblastoma SH-SY5Y cell line. Notably, 3-NPs and 4-NPs were identified as the most promising formulation showing a profitable balance of stability, small size and a similar activity compared to the free drugs in cell-based assays. In addition, albumin formulations increase the solubility of pyrazolo[3,4-d]pyrimidine avoiding the use of DMSO as solubilizing agent. Graphical abstract image
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Discovery of pyrazolo[1,5-a]pyrimidine-3-carbonitrile derivatives as a new class of histone lysine demethylase 4D (KDM4D) inhibitors ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Zhen Fang, Tian-qi Wang, Hui Li, Guo Zhang, Xiao-ai Wu, Li Yang, Yu-lan Peng, Jun Zou, Lin-li Li, Rong Xiang, Sheng-yong Yang Herein we report the discovery of a series of new small molecule inhibitors of histone lysine demethylase 4D (KDM4D). Molecular docking was first performed to screen for new KDM4D inhibitors from various chemical databases. Two hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the more selective one, compound 2, which led to the discovery of several new KDM4D inhibitors. Among them, compound 10r is the most potent one with an IC50 value of 0.41±0.03μM against KDM4D. Overall, compound 10r could be taken as a good lead compound for further studies. Graphical abstract image
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Corrigendum to “Discovery of substituted 6-pheny-3H-pyridazin-3-one derivatives as novel c-Met kinase inhibitors” [Bioorg. Med. Chem. Lett. 24 (2014) 5093–5097] ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 14 Author(s): Seung-Tae Kang, Eun-Young Kim, Raghavendra Achary, Heejung Jung, Chi Hoon Park, Chang-Soo Yun, Jong Yeon Hwang, Sang Un Choi, Chonghak Chae, Chong Ock Lee, Hyoung Rae Kim, Jae Du Ha, Dohyun Ryu, Sung Yun Cho
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Editorial board ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13
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Conformational control in structure-based drug design ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Yajun Zheng, Colin M. Tice, Suresh B. Singh In structure-based drug design, the basic goal is to design molecules that fit complementarily to a given binding pocket. Since such computationally modeled molecules may not adopt the intended bound conformation outside the binding pocket, one challenge is to ensure that the designed ligands adopt similar low energy conformations both inside and outside of the binding pocket. Computational chemistry methods and conformational preferences of small molecules from PDB and Cambridge Structural Database (CSD) can be used to predict the bound structures of the designed molecules. Herein, we review applications of conformational control in structure-based drug design using selected examples from the recent medicinal chemistry literature. The main purpose is to highlight some intriguing conformational features that can be applied to other drug discovery programs. Graphical abstract image
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Recent progress towards clinically relevant ATP-competitive Akt inhibitors ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Bayard R. Huck, Igor Mochalkin The frequency of PI3K/Akt/mTOR (PAM) Pathway mutations in human cancers sparked interest to determine if the pathway is druggable. The modest clinical benefit observed with mTOR rapalogs (temsirolimus and everolimus) provided further motivation to identify additional nodes of pathway inhibition that lead to improved clinical benefit. Akt is a central signaling node of the PAM pathway and could be an ideal target for improved pathway inhibition. Furthermore, inhibitors of Akt may be especially beneficial in tumors with Akt1 mutations. Recently, multiple ATP-competitive Akt inhibitors have been identified and are currently in clinical development. This review details the medicinal chemistry efforts towards identification of these molecules, highlights relevant preclinical data supporting clinical evaluation, and summarizes current clinical development plans. Graphical abstract image
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Identification of highly potent and selective PI3Kδ inhibitors ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): David Marcoux, Lan-Ying Qin, Zheming Ruan, Qing Shi, Qian Ruan, Carolyn Weigelt, Hongchen Qiu, Gary Schieven, John Hynes, Rajeev Bhide, Michael Poss, Joseph Tino Selective PI3Kδ inhibitors have recently been hypothesized to be appropriate immunosuppressive agents for the treatment of immunological disorders such as rheumatoid arthritis. However, few reports have highlighted molecules that are highly selective for PI3Kδ over the other PI3K isoforms. In this letter, isoform and kinome selective PI3Kδ inhibitors are presented. The Structural Activity Relationship leading to such molecules is outlined. Graphical abstract image
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Synthesis and biological evaluation of new C-12(α/β)-(N-) sulfamoyl-phenylamino-14-deoxy-andrographolide derivatives as potent anti-cancer agents ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Sai Giridhar Sarma Kandanur, Srinivas Nanduri, Nageswara Rao Golakoti Andrographolide, the major diterpenoidal constituent of Andrographis paniculata (Acanthaceae) and its derivatives have been reported to possess plethora of biological properties including potent anti-cancer activity. In this work, synthesis and in-vitro anti-cancer evaluation of new C-12-substituted aryl amino 14-deoxy-andrographolide derivatives (III a–f) are reported. The substitutions include various sulfonamide moieties –SO2-NH-R1. The new derivatives (III a–e) exhibited improved cytotoxicity (GI50, TGI and LC50) compared to andrographolide (I) and the corresponding 3,14,19-O-triacetyl andrographolide (II) when evaluated against 60 NCI cell line panel. Compounds III c and III e are found to be non-toxic to normal human dermal fibroblasts (NHDF) cells compared to reference drug THZ-1. Graphical abstract image
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Isocostunolide inhibited glioma stem cell by suppression proliferation and inducing caspase dependent apoptosis ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Zhi Dai, Shi-Rong Li, Pei-Feng Zhu, Lu Liu, Bei Wang, Ya-Ping Liu, Xiao-Dong Luo, Xu-Dong Zhao Glioblastoma multiform (GBM) is a highly aggressive brain tumor with poor life expectancy, and glioma stem cells (GSCs) are a small population of tumor cells existed in GBM, in which GSCs response to drive GBM recurrence, invasion and contribute to the anti-cancer resistance. GSCs have been identified and developed as a therapeutic target for GBM and can be used in drugs screening. Isocostunolide is a natural sesquiterpenoid and contained abundant resource in medicinal plants, but the anti-cancer efficacies of it against GSCs are still unexplored. In this investigation, the anti-tumor activity of isocostunolide against GSCs was investigated and the result demonstrated that it inhibited the growth of GSCs (GSC-3#, GSC-12#, GSC-18#) significantly with an IC50 value of 2.80μg/ml, 2.61μg/ml, 1.07μg/ml, respectively. In further mechanism study, isocostunolide inhibited GSCs cell proliferation, induced GSCs apoptosis significantly, as well as increased the proportion of the cleavage of caspase-3. The result suggested that isocostunolide induced GSCs apoptosis via the caspase dependent apoptotic pathway. Moreover, isocostunolide damaged GSCs colony formation capacity significantly and exhibited the anti-cancer efficacy against GSCs in vitro. Graphical abstract image
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Structural insight into the active site of mushroom tyrosinase using phenylbenzoic acid derivatives ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Takahiro Oyama, Atsushi Yoshimori, Satoshi Takahashi, Tetsuya Yamamoto, Akira Sato, Takanori Kamiya, Hideaki Abe, Takehiko Abe, Sei-ichi Tanuma So far, many inhibitors of tyrosinase have been discovered for cosmetic and clinical agents. However, the molecular mechanisms underlying the inhibition in the active site of tyrosinase have not been well understood. To explore this problem, we examined here the inhibitory effects of 4′-hydroxylation and methoxylation of phenylbenzoic acid (PBA) isomers, which have a unique scaffold to inhibit mushroom tyrosinase. The inhibitory effect of 3-PBA, which has the most potent inhibitory activity among the isomers, was slightly decreased by 4′-hydroxylation and further decreased by 4′-methoxylation against mushroom tyrosinase. Surprisingly, 4′-hydroxylation but not methoxylation of 2-PBA appeared inhibitory activity. On the other hand, both 4′-hydroxylation and methoxylation of 4-PBA increased the inhibitory activity against mushroom tyrosinase. In silico docking analyses using the crystallographic structure of mushroom tyrosinase indicated that the carboxylic acid or 4′-hydroxyl group of PBA derivatives could chelate with cupric ions in the active site of mushroom tyrosinase, and that the interactions of Asn260 and Phe264 in the active site with the adequate-angled biphenyl group are involved in the inhibitory activities of the modified PBAs, by parallel and T-shaped π-π interactions, respectively. Furthermore, Arg268 could fix the angle of the aromatic ring of Phe264, and Val248 is supposed to interact with the inhibitors as a hydrophobic manner. These results may enhance the structural insight into mushroom tyrosinase for the creation of novel tyrosinase inhibitors. Graphical abstract image
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Diversity-oriented sustainable synthesis of antimicrobial spiropyrrolidine/thiapyrrolizidine oxindole derivatives: New ligands for a metallo-β-lactamase from Klebsiella pneumonia ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Anshu Dandia, Shahnawaz Khan, Pragya Soni, Aayushi Indora, Dinesh Kumar Mahawar, Prateek Pandya, Chetan Singh Chauhan A simple, environmentally benign and highly proficient microwave assisted one-pot approach for the synthesis of antimicrobial spiropyrrolidine/thiapyrrolizidine oxindole derivatives is reported assembling two pharmacophoric moieties (1,3-indanedione and pyrrolidine/thiapyrrolizidine) in a single molecular framework via three-component 1,3-dipolar cycloaddition reaction of substituted isatin, sarcosine/1,3-thiazoles-4-carboxylic acid and Knoevenagel adduct (2-Cyano-3-phenyl-acrylic acid ethyl ester or 2-Benzylidene-malononitrile) in 2,2,2-trifluoroethanol as a reusable green solvent. Good functional group tolerance and broad scope of usable substrates are other prominent features of the present methodology with high degree of chemo-, regio- and stereoselectivity. The stereochemistry of synthesized compounds was confirmed by single crystal X-ray analysis. All the synthetic compounds were examined for their antimicrobial potential. The synthesized compounds having pyrrolothiazole moiety showed excellent activity against K. pneumoniae as compared to others and even more inhibitory activity than the mentioned drugs, i.e. compounds 6a (MIC=0.09μg/mL), 6b (MIC=0.045μg/mL), 6c (MIC=0.005μg/mL), 6d (MIC=0.19μg/mL). Additionally, compound 6c has shown better binding affinity against New Delhi Metallo-beta-Lactamase-1 (NDM-1) protein in computational docking studies. Graphical abstract image
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Protective effect of lanostane triterpenoids from the sclerotia of Poria cocos Wolf against cisplatin-induced apoptosis in LLC-PK1 cells ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Dahae Lee, Seulah Lee, Sang Hee Shim, Hae-Jeung Lee, Youkyung Choi, Tae Su Jang, Ki Hyun Kim, Ki Sung Kang Cisplatin-induced nephrotoxicity is a serious adverse effect that limits the use of cisplatin in cancer patients. In the present study, we investigated the protective effect of lanostane triterpenoids (1–10) isolated from the ethanolic extract of Poria cocos Wolf against cisplatin-induced cell death in LLC-PK1 kidney tubular epithelial cells. Treatment of cisplatin induced significant cell death, which was suppressed by treatment with dehydroeburicoic acid monoacetate (1) and 3β-acetoxylanosta-7,9(11),24-trien-21-oic acid (9). Compound 1 exhibited the highest efficacy among the tested compounds and was thus subjected to further mechanistic studies. The increase in the percentage of apoptotic cells induced by cisplatin reduced by 4.3% after co-treatment of cells with compound 1 (50 and 100μM). Furthermore, phosphorylation of the mitogen-activated protein kinases JNK, ERK, and p38, and caspase-3, which characterize oxidative stress-mediated apoptosis, increased significantly after treatment with cisplatin, and decreased after treatment with compound 1. These results indicate that the renoprotective effects of compound 1 may be mediated by its anti-apoptotic activity. Graphical abstract image
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A minimalistic tetrapeptide amphiphile scaffold for transmembrane pores with a preference for sodium ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Debajyoti Basak, Sucheta Sridhar, Amal K. Bera, Nandita Madhavan Synthetic channels or pores that are easy to synthesize, stable and cation-selective are extremely attractive for the development of therapeutics and materials. Herein, we report a pore developed from a small tetrapeptide scaffold that shows a preference for sodium over lithium/potassium. The sodium selectivity is attributed to the appended oligoether tail at the C-terminus. A peptide dimer is proposed as the predominant cation-transporting pore. Such pyridine containing stable pores can be potentially utilized for the pH modulated ion transport. Graphical abstract image
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One-pot synthesis and biological evaluation of N-(aminosulfonyl)-4-podophyllotoxin carbamates as potential anticancer agents ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Xiao-Hui Xu, Xiao-Wen Guan, Shi-Liang Feng, You-Zhen Ma, Shi-Wu Chen, Ling Hui A series of N-(aminosulfonyl)-4-podophyllotoxin carbamates were synthesized via the Burgess-type intermediate, and their antiproliferative activities were evaluated. Most of them possessed more potent cytotoxic effects against four human tumor cell lines (HeLa, A-549, HCT-8 and HepG2) and less toxic to normal human fetal lung fibroblast WI-38 cells than etoposide. In particular, N-(morpholinosulfonyl)-4-podophyllotoxin carbamate (9) exhibited the most potent activity towards these four tumor cells with IC50 values in the range of 0.5–16.5μM. Furthermore, immunofluorescence analysis revealed that 9 induced cell apoptosis by up-regulating the expression of p53 and ROS. Meanwhile, 9 effectively inhibited tubulin polymerization and microtubule assembly at cellular levels in HeLa cells. In addition, 9 could induce cell cycle arrest in the G2/M phase in HeLa cells by up-regulating levels of cyclinB1 and cdc2 and decreasing the expression of p-cdc2. These results indicated that 9 had potential for further development as anticancer agents. Graphical abstract image
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Radiosynthesis and evaluation of IGF1R PET ligand [11C]GSK1838705A ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Kiran Kumar Solingapuram Sai, Jaya Prabhakaran, Anirudh Sattiraju, J. John Mann, Akiva Mintz, J.S. Dileep Kumar Radiosynthesis and evaluation of [11C]GSK1838705A in mice using microPET and determination of specificity in human GBM UG87MR cells are described herein. The radioligand was synthesized by reacting desmethyl-GSK1838705A with [11C]CH3I using GE FX2MeI module in ∼5% yield (EOS), >95% radiochemical purity and a specific activity of 2.5±0.5Ci/μmol. MicroPET imaging in mice indicated that [11C]GSK1838705A penetrated blood brain barrier (BBB) and showed retention of radiotracer in brain. The radioligand exhibited high uptake in U87MG cells with >70% specific binding to IGF1R. Our experiments suggest that [11C]GSK-1838705A can be a potential PET radiotracer for the in vivo quantification of IGF1R expression in GBM and other brain tumors. Graphical abstract image
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Gemcitabine anti-proliferative activity significantly enhanced upon conjugation with cell-penetrating peptides ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Nuno Vale, Abigail Ferreira, Iva Fernandes, Cláudia Alves, Maria João Araújo, Nuno Mateus, Paula Gomes Gemcitabine proven efficiency against a wide range of solid tumors and undergoes deamination to its inactive uridine metabolite, which underlies its low bioavailability, and tumour resistance was also associated with nucleoside transporter alterations. Hence, we have conjugated gemcitabine to cell-penetrating peptides (CPP), in an effort to both mask its aniline moiety and facilitate its delivery into cancer cells. Two CPP-drug conjugates have been synthesized and studied regarding both the time-dependent kinetics of gemcitabine release and their anti-proliferative activity on three different human cancer cell lines. Results obtained reveal a dramatic increase in the anti-proliferative activity of gemcitabine in vitro, upon conjugation with the CPPs. As such, CPP-gemcitabine conjugates emerge as promising leads for cancer therapy. Graphical abstract image
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Phytochemical and cytotoxic studies on the leaves of Calotropis gigantea ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Khang D.H. Nguyen, Phu H. Dang, Hai X. Nguyen, Mai T.T. Nguyen, Suresh Awale, Nhan T. Nguyen A new lignan, 9′-methoxypinoresinol (1), and two new glycosylated 5-hydroxymethylfurfurals, calofurfuralside A (2), and calofurfuralside B (3), together with nine known compounds (4–12) have been isolated from the active fractions, CHCl3 (IC50, 0.32μgmL−1) and EtOAc (IC50, 0.55μgmL−1) fractions of the leaves of Calotropis gigantea. Their structures were elucidated based on NMR and MS data. Among the isolated compounds, compounds 1 and 9 exhibited potent cytotoxicity against PANC-1 human pancreatic cancer cell line under the normoglycemic condition with IC50 values of 3.7 and 3.3μM, respectively. 9′-Methoxypinoresinol (1) significantly inhibited the colony formation of PANC-1 cells in a concentration-dependent manner. Graphical abstract image
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Design and synthesis of potent inhibitors of the mono(ADP-ribosyl)transferase, PARP14 ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Kristen Upton, Matthew Meyers, Ann-Gerd Thorsell, Tobias Karlberg, Jacob Holechek, Robert Lease, Garrett Schey, Emily Wolf, Adrianna Lucente, Herwig Schüler, Dana Ferraris A series of (Z)-4-(3-carbamoylphenylamino)-4-oxobut-2-enyl amides were synthesized and tested for their ability to inhibit the mono-(ADP-ribosyl)transferase, PARP14 (a.k.a. BAL-2; ARTD-8). Two synthetic routes were established for this series and several compounds were identified as sub-micromolar inhibitors of PARP14, the most potent of which was compound 4t, IC50 =160nM. Furthermore, profiling other members of this series identified compounds with >20-fold selectivity over PARP5a/TNKS1, and modest selectivity over PARP10, a closely related mono-(ADP-ribosyl)transferase. Graphical abstract image
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Reevaluation of fenpropimorph as a σ receptor ligand: Structure-affinity relationship studies at human σ1 receptors ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 13 Author(s): Elena Sguazzini, Hayden R. Schmidt, Kavita A. Iyer, Andrew C. Kruse, Małgorzata Dukat Fenpropimorph (1) is considered a “super high-affinity” σ1 receptor ligand (K i =0.005nM for guinea pig σ1 receptors). Here, we examine the binding of 1 and several of its deconstructed analogs at human σ1 (hσ1) receptors. We monitored their subtype selectivity by determining the binding affinity at σ2 receptors. In addition, we validated an existing pharmacophore model at the molecular level by conducting 3D molecular modeling studies, using the crystal structure of hσ1 receptors, and Hydrophatic INTeractions (HINT) analysis. Our structure affinity relationship studies showed that 1 binds with lower affinity at hσ1 receptors (K i =17.3nM) compared to guinea pig; moreover, we found that none of the fenpropimorph methyl groups is important for its binding at hσ1 receptors, nor is stereochemistry. For example, removal of all methyl groups as seen in 4 resulted in an almost 5-fold higher affinity at hσ1 receptors compared to 1 and 350-fold selectivity versus σ2 receptors. In addition, although the O atom of the morpholine ring does not contribute to affinity at hσ1 receptors (and might even detract from it), it plays role in subtype (σ1 versus σ2 receptor) selectivity. Graphical abstract image
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