Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14
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Structure–activity relationship of lipid core peptide-based Group A Streptococcus vaccine candidates ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Amy Chan, Waleed M. Hussein, Khairunnisa Abdul Ghaffar, Nirmal Marasini, Ahmed Mostafa, Sharareh Eskandari, Michael R. Batzloff, Michael F. Good, Mariusz Skwarczynski, Istvan Toth Infection with Group A Streptococcus (GAS) can result in a range of different illnesses, some of which are fatal. Currently, our efforts to develop a vaccine against GAS focuses on the lipid core peptide (LCP) system, a subunit vaccine containing a lipoamino acid (LAA) moiety which allows the stimulation of systemic antibody activity. In the present study, a peptide (J14) representing the B-cell epitope from the GAS M protein was incorporated alongside a universal T-helper epitope (P25) in four LCP constructs of different spatial orientation or LAA lengths. Through structure–activity studies, it was discovered that while the alteration of the LCP orientation had a weaker effect on immunostimulation, increasing the LAA side chain length within the construct increased antibody responses in murine models. Furthermore, the mice immunised with the lead LCP construct were also able to maintain antibody activity throughout the course of five months. These findings highlight the importance of LAA moieties in the development of intranasal peptide vaccines and confirmed that its side chain length has an effect on the immunogenicity of the structure. Graphical abstract image
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Discovery and preliminary structure–activity relationship studies on tecomaquinone I and tectol as novel farnesyltransferase and plasmodial inhibitors ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Melissa M. Cadelis, Marie-Lise Bourguet-Kondracki, Joëlle Dubois, Alexis Valentin, David Barker, Brent R. Copp Biological screening of a library of synthesized benzo[c]chromene-7,10-dione natural products against human farnesyltransferase (FTase) has identified tecomaquinone I (IC50 of 0.065±0.004μM) as being one of the more potent natural product inhibitors identified to date. Anti-plasmodial screening of the same library against a drug-resistant strain of Plasmodium falciparum identified the structurally-related dichromenol tectol as a moderately active growth inhibitor with an IC50 3.44±0.20μM. Two novel series of analogues, based on the benzo[c]chromene-7,10-dione scaffold, were subsequently synthesized, with one analogue exhibiting farnesyltransferase inhibitory activity in the low micromolar range. A preliminary structure–activity relationship (SAR) study has identified different structural requirements for anti-malarial activity in comparison to FTase activities for these classes of natural products. Our results identify tecomaquinone I as a novel scaffold from which more potent inhibitors of human and parasitic FTase could be developed. Graphical abstract image
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Synthesis and evaluation of biphenyl derivatives as potential downregulators of VEGF protein secretion and telomerase-related gene expressions ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): María Sánchez-Peris, Eva Falomir, Juan Murga, Miguel Carda, J. Alberto Marco A group of 47 biphenyl functionalized compounds, prepared by means of Suzuki couplings, has been investigated for their cytotoxicity on two tumoral cell lines (HT-29 and MCF-7) and one non tumoral cell line (HEK-293). 29 selected compounds have been investigated for their ability to inhibit the production of the vascular endothelial growth factor (VEGF). Subsequently, the capacity of the compounds to downregulate the expression of the VEGF, h-TERT and c-Myc genes, the two latter involved in the control of the activation of telomerase, has also been determined. Graphical abstract image
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Synthesis and biological activity of pyrazole analogues of the staurosporine aglycon K252c ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Yannick J. Esvan, Francis Giraud, Elisabeth Pereira, Virginie Suchaud, Lionel Nauton, Vincent Théry, Lyubov G. Dezhenkova, Dmitry N. Kaluzhny, Vsevolod N. Mazov, Alexander A. Shtil, Fabrice Anizon, Pascale Moreau A derivative of the staurosporine aglycon (K252c), in which the lactam ring was replaced by a pyrazole moiety, was synthesized. The resulting indolopyrazolocarbazole (3) inhibited Pim isoforms 1–3 whereas it did not impair the activity of two known targets of K252c, protein kinase C isoforms α and γ. Compound 3 exhibited moderate cytotoxic activity toward human leukemia and colon carcinoma cell lines (K562 and HCT116), strongly suggesting that this new scaffold deserves further investigations for treatment of malignancies associated with Pim activity. Graphical abstract image
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Identification, characterization, kinetics, and molecular docking of flavonoid constituents from Archidendron clypearia (Jack.) Nielsen leaves and twigs ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Nguyen Phuong Thao, Bui Thi Thuy Luyen, Jang Hoon Kim, Ah Reum Jo, Nguyen Tien Dat, Phan Van Kiem, Chau Van Minh, Young Ho Kim In our search for natural soluble epoxide hydrolase (sEH) inhibitors from plants, we found that the methanolic extract of the leaves and twigs of Archidendron clypearia (Jack.) Nielsen (Fabaceae) significantly inhibits sEH in vitro. In a phytochemical investigation of the water layer of A. clypearia, we isolated two new chalcones, clypesides A–B (1–2), 13 flavonoid derivatives (3–15) and established their structures based on an extensive 1D and 2D NMR, CD data, and MS analysis. All of the flavonoid derivatives inhibited sEH enzymatic activity in a dose-dependent manner, with IC50 values ranging from 10.0±0.4 to 30.1±2.1μM. A kinetic analysis of compounds 4, 8–10, 12, 13, and 15 revealed that the compounds 8–10 were non-competitive, 4, 13, and 15 were mixed-type, and 12 was competitive inhibitors. Additionally, molecular docking increased our understanding of their receptor-ligand binding. These results demonstrated that flavonoid derivatives from A. clypearia are potential sEH inhibitors. Graphical abstract image
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2-Aryl-8-aza-3-deazaadenosine analogues of 5′-O-[N-(salicyl)sulfamoyl]adenosine: Nucleoside antibiotics that block siderophore biosynthesis in Mycobacterium tuberculosis ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Anna Krajczyk, Joanna Zeidler, Piotr Januszczyk, Surendra Dawadi, Helena I. Boshoff, Clifton E. Barry, Tomasz Ostrowski, Courtney C. Aldrich A series of 5′-O-[N-(salicyl)sulfamoyl]-2-aryl-8-aza-3-deazaadenosines were designed to block mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) through inhibition of the essential adenylating enzyme MbtA. The synthesis of the 2-aryl-8-aza-3-deazaadenosine nucleosides featured sequential copper-free palladium-catalyzed Sonogashira coupling of a precursor 4-cyano-5-iodo-1,2,3-triazolonucleoside with terminal alkynes and a Minakawa–Matsuda annulation reaction. These modified nucleosides were shown to inhibit MbtA with apparent K i values ranging from 6.1 to 25nM and to inhibit Mtb growth under iron-deficient conditions with minimum inhibitory concentrations ranging from 12.5 to >50μM. Graphical abstract image
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Efficient protein knockdown of HaloTag-fused proteins using hybrid molecules consisting of IAP antagonist and HaloTag ligand ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Shusuke Tomoshige, Yuichi Hashimoto, Minoru Ishikawa We previously reported a protein knockdown system for HaloTag-fused proteins using hybrid small molecules consisting of alkyl chloride, which binds covalently to HaloTag, linked to BE04 (2), a bestatin (3) derivative with an affinity for cellular inhibitor of apoptosis protein 1 (cIAP1, a kind of ubiquitin ligase). This system addressed several limitations of prior protein knockdown technology, and was applied to degrade two HaloTag-fused proteins. However, the degradation activity of these hybrid small molecules was not potent. Therefore, we set out to improve this system. We report here the design, synthesis and biological evaluation of novel hybrid compounds 4a and 4b consisting of alkyl chloride linked to IAP antagonist MV1 (5). Compounds 4a and 4b were confirmed to reduce the levels of HaloTag-fused tumor necrosis factor α (HaloTag-TNFα), HaloTag-fused cell division control protein 42 (HaloTag-Cdc42), and unfused HaloTag protein in living cells more potently than did BE04-linked compound 1b. Analysis of the mode of action revealed that the reduction of HaloTag-TNFα is proteasome-dependent, and is also dependent on the linker structure between MV1 (5) and alkyl chloride. These compounds appear to induce ubiquitination at the HaloTag moiety of HaloTag-fused proteins. Our results indicate that these newly synthesized MV1-type hybrid compounds, 4a and 4b, are efficient tools for protein knockdown for HaloTag-fused proteins. Graphical abstract image
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New bifunctional antioxidant/σ1 agonist ligands: Preliminary chemico-physical and biological evaluation ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Emanuela Arena, Ivana Cacciatore, Laura S. Cerasa, Hasan Turkez, Valeria Pittalà, Lorella Pasquinucci, Agostino Marrazzo, Carmela Parenti, Antonio Di Stefano, Orazio Prezzavento We previously reported bifunctional sigma-1 (σ1) ligands endowed with antioxidant activity (1 and 2). In the present paper, pure enantiomers (R)-1 and (R)-2 along with the corresponding p-methoxy (6, 11), p-fluoro derivatives (7, 12) were synthesized. σ1 and σ2 affinities, antioxidant properties, and chemico-physical profiles were evaluated. Para derivatives, while maintaining strong σ1 affinity, displayed improved σ1 selectivity compared to the parent compounds 1 and 2. In vivo evaluation of compounds 1, 2, (R)-1, 7, and 12 showed σ1 agonist pharmacological profile. Chemico-physical studies revealed that amides 2, 11 and 12 were more stable than corresponding esters 1, 6 and 7 under our experimental conditions. Antioxidant properties were exhibited by fluoro derivatives 7 and 12 being able to increase total antioxidant capacity (TAC). Our results underline that p-substituents have an important role on σ1 selectivity, TAC, chemical and enzymatic stabilities. In particular, our data suggest that new very selective compounds 7 and 12 could be promising tools to investigate the disorders in which σ1 receptor dysfunction and oxidative stress are contemporarily involved. Graphical abstract image
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Thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives: Structure–activity relationships of selective nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) inhibitors ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Sang-Yong Lee, Arianna Perotti, Steven De Jonghe, Piet Herdewijn, Theodor Hanck, Christa E. Müller Ecto-nucleotide pyrophosphatase/phosphodiesterase1 (NPP1) is the most important member of the NPP family, which consists of seven closely related proteins (NPP1–NPP7). This glycoprotein is a membrane-associated or secreted enzyme, which catalyzes the hydrolysis of a wide range of phosphodiester bonds, e.g., in nucleoside triphosphates, dinucleotides and nucleotide sugars. NPP1 plays a crucial role in various physiological functions including bone mineralization, soft-tissue calcification, and insulin receptor signaling. Recently, an upregulated expression of NPP1 has been observed in astrocytic brain cancers. Therefore, NPP1 has been proposed as a novel drug target for the treatment of glioblastoma. Despite their therapeutic potential, only few NPP1 inhibitors have been reported to date, which are in most cases non- or only moderately selective. The best investigated NPP1 inhibitors so far are nucleotide derivatives and analogs, however they are not orally bioavailable due to their high polarity. We identified thiazolo[3,2-a]benzimidazol-3(2H)-one derivatives as a new class of NPP1 inhibitors with drug-like properties. Among the 25 derivatives investigated in the present study, 2-[(5-iodo-2-furanyl)methylene]thiazolo[3,2-a]benzimidazol-3(2H)-one (17) was found to be the most potent NPP1 inhibitor with a K i value of 467nM versus ATP as a substrate and an un-competitive mechanism of inhibition. Compound 17 did not inhibit other human ecto-nucleotidases, including NTPDase1 (CD39), NTPDases2-3, NPP2, NPP3, tissue-nonspecific alkaline phosphatase (TNAP), and ecto-5′-nucleotidase (eN, CD73), and is thus highly selective for NPP1. Graphical abstract image
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The influence of halogen substituents on the biological properties of sulfur-containing flavonoids ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Lucian Gabriel Bahrin, Laura Gabriela Sarbu, Henning Hopf, Peter G. Jones, Cornelia Babii, Marius Stefan, Mihail Lucian Birsa A series of halogen-substituted tricyclic flavonoids containing a 1,3-dithiol-2-ylium moiety has been synthesized from the corresponding 3-dithiocarbamic flavanones. The influence of halogen substituents on the antibacterial properties of the tricyclic flavonoids has been investigated against Staphylococcus aureus and Escherichia coli. On going from fluorine to iodine, these compounds exhibit good to excellent inhibitory properties against both Gram-positive and Gram-negative pathogens. These results suggest that size is the main factor for the change in potency rather than polarity/electronics. Graphical abstract image
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A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Jelica Vucicevic, Tatjana Srdic-Rajic, Marco Pieroni, Jonne M.M. Laurila, Vladimir Perovic, Sabrina Tassini, Elisa Azzali, Gabriele Costantino, Sanja Glisic, Danica Agbaba, Mika Scheinin, Katarina Nikolic, Marco Radi, Nevena Veljkovic The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers. Graphical abstract image
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Structure–activity relationships of dibenzoylhydrazines for the inhibition of P-glycoprotein-mediated quinidine transport ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Ken-ichi Miyata, Yoshiaki Nakagawa, Yasuhisa Kimura, Kazumitsu Ueda, Miki Akamatsu We previously demonstrated that dibenzoylhydrazines (DBHs) are not only P-glycoprotein (P-gp) substrates, but also inhibitors. In the present study, we evaluated the inhibition of P-gp-mediated quinidine transport by two series of DBHs and performed a classical QSAR analysis and docking simulation in order to investigate the mechanisms underlying P-gp substrate/inhibitor recognition. The results of the QSAR analysis identified the hydrophobic factor as the most important for inhibitory activities, while electronic and steric effects also influenced the activities. The different substituent effects observed in each series suggested the different binding modes of each series of DBHs, which was supported by the results of the docking simulation. Graphical abstract image
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Discovery of novel 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives as γ-secretase modulators (Part 2) ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Takafumi Takai, Tatsuki Koike, Minoru Nakamura, Yuichi Kajita, Toshiro Yamashita, Naohiro Taya, Tetsuya Tsukamoto, Tomomichi Watanabe, Koji Murakami, Tomoko Igari, Makoto Kamata γ-Secretase modulators (GSMs), which lower pathogenic amyloid beta (Aβ) without affecting the production of total Aβ or Notch signal, have emerged as a potential therapeutic agent for Alzheimer’s disease (AD). A novel series of 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine derivatives was discovered and characterized as GSMs. Optimization of substituents at the 8-position of the core scaffold using ligand-lipophilicity efficiency (LLE) as a drug-likeness guideline led to identification of various types of high-LLE GSMs. Phenoxy compound (R)-17 exhibited especially high LLE as well as potent in vivo Aβ42-lowering effect by single administration. Furthermore, multiple oral administration of (R)-17 significantly reduced soluble and insoluble brain Aβ42, and ameliorated cognitive deficit in novel object recognition test (NORT) using Tg2576 mice as an AD model. Graphical abstract image
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Design, synthesis, and biological evaluation of a novel series of peripheral-selective noradrenaline reuptake inhibitors—Part 2 ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Tomoya Yukawa, Ikuo Fujimori, Taku Kamei, Yoshihisa Nakada, Nobuki Sakauchi, Masami Yamada, Yusuke Ohba, Hiroyuki Ueno, Maiko Takiguchi, Masako Kuno, Izumi Kamo, Hideyuki Nakagawa, Yasushi Fujioka, Tomoko Igari, Yuji Ishichi, Tetsuya Tsukamoto Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood–brain barrier. We observed that steric shielding of the hydrogen-bond acceptors and donors (HBA and HBD) of compound 1 reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound 6, a methoxyacetamide derivative, was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism of the CYPs. Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led to compound 13, which was mainly metabolized by CYP3A4. To our knowledge, this study represents the first report of the effect of deuterium replacement for a major metabolic enzyme. The compound 13, N-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-[(2H 3)methyloxy]acetamide hydrochloride, which exhibited peripheral NET selective inhibition at tested doses in rats, increased urethral resistance in a dose-dependent manner. Graphical abstract image
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Development of hydroxy-based sphingosine kinase inhibitors and anti-inflammation in dextran sodium sulfate induced colitis in mice ()
Publication date: 15 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 14 Author(s): Meiyang Xi, Jun Ge, Xiaojian Wang, Chenbin Sun, Tianqi Liu, Liang Fang, Qiong Xiao, Dali Yin Sphingosine kinase (SphK)-catalyzed production of sphingosine-1-phosphate (S1P) regulates cell growth, survival and proliferation as well as inflammatory status in animals. In recent study we reported the N′-(3-(benzyloxy)benzylidene)-3,4,5-trihydroxybenzohydrazide scaffold as a potent SphK inhibitor. As a continuation of these efforts, 51 derivatives were synthesized and evaluated by SphK1/2 inhibitory activities for structure–activity relationship (SAR) study. Among them, 33 was identified as the most potent SphK inhibitor. Potency of 33 was also observed to efficiently decrease SphK1/2 expression in human colorectal cancer cells (HCT116) and significantly inhibit dextran sodium sulfate (DSS)-induced colitis as well as the decreased expression of interleukin (IL)-6 and cyclooxygenase-2 (COX-2) in mouse models. Collectively, 33 was validated as an effective SphK inhibitor, which can be served as anti-inflammatory agent to probably treat inflammatory bowel diseases in human. Graphical abstract image
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Editorial board ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13
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Discovery of new [1,4]dioxino[2,3-f]quinazoline-based inhibitors of EGFR including the T790M/L858R mutant ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Xuemei Qin, Zhipeng Li, Leifu Yang, Peng Liu, Liming Hu, Chengchu Zeng, Zhiyong Pan A novel series of 2,3-dihydro-[1,4]dioxino[2,3-f]quinazoline derivatives were designed, synthesized and evaluated as reversible and noncovalent epidermal growth factor receptor (EGFR) inhibitors. Most of the compounds exhibited good potency against EGFRwt and some showed moderate to excellent potency against EGFRT790M/L858R mutant. The half-maximal inhibitory concentration (IC50) values of twenty-one compounds against EGFRwt were less than 50nM, and those of six compounds were less than 10nM. The IC50 values of eleven compounds against EGFRT790M/L858R were less than 100nM. Among these, compound b1 displayed the most potent inhibitory activity against EGFRwt (IC50 =2.0nM) and EGFRT790M/L858R (IC50 =6.9nM). Compounds with excellent inhibitory activities against EGFRwt and EGFRT790M/L858R kinase inhibitory activities showed good antiproliferative activities against H358 and A549 cells. Docking study was performed to position compound b1 into the EGFR active pocket to determine the probable binding conformation. Graphical abstract image
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Novel sulfonamide bearing coumarin scaffolds as selective inhibitors of tumor associated carbonic anhydrase isoforms IX and XII ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Navneet Chandak, Mariangela Ceruso, Claudiu T. Supuran, Pawan K. Sharma Four novel scaffolds consisting of total 24 compounds (1a–1o, 2a–2c, 3a–3c and 4a–4c) bearing aromatic sulfonamide and coumarin moieties connected through various linkers were synthesized in order to synergize the inhibition potential of both the moieties against four selected human carbonic anhydrase isoforms (hCA I, II, IX & XII). All compounds were found to be potent inhibitors of tumor associated hCA IX & XII while at the same time required large amounts to inhibit off-targeted housekeeping hCA I & II. Selectivity was more pronounced against hCA II over I, and hCA XII over IX. Results were compared with antitumor drug acetazolamide. One derivative 2b of series 2 was found to be a better selective inhibitor of hCA IX and XII. Graphical abstract image
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Dihydrochelerythrine and its derivatives: Synthesis and their application as potential G-quadruplex DNA stabilizing agents ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Rajesh Malhotra, Chhanda Rarhi, K.V. Diveshkumar, Rajib Barik, Ruhee D’cunha, Pranab Dhar, Mrinalkanti Kundu, Subrata Chattopadhyay, Subho Roy, Sourav Basu, P.I. Pradeepkumar, Saumen Hajra A convenient route was envisaged toward the synthesis of dihydrochelerythrine (DHCHL), 4 by intramolecular Suzuki coupling of 2-bromo-N-(2-bromobenzyl)-naphthalen-1-amine derivative 5 via in situ generated arylborane. This compound was converted to (±)-6-acetonyldihydrochelerythrine (ADC), 3 which was then resolved by chiral prep-HPLC. Efficiency of DHCHL for the stabilization of promoter quadruplex DNA structures and a comparison study with the parent natural alkaloid chelerythrine (CHL), 1 was performed. A thorough investigation was carried out to assess the quadruplex binding affinity by using various biophysical and biochemical studies and the binding mode was explained by using molecular modeling and dynamics studies. Results clearly indicate that DHCHL is a strong G-quadruplex stabilizer with affinity similar to that of the parent alkaloid CHL. Compounds ADC and DHCHL were also screened against different human cancer cell lines. Among the cancer cells, (±)-ADC and its enantiomers showed varied (15–48%) inhibition against human colorectal cell line HCT116 and breast cancer cell line MDA-MB-231 albeit low enantio-specificity in the inhibitory effect; whereas DHCHL showed 30% inhibition against A431 cell line only, suggesting the compounds are indeed cancer tissue specific. Graphical abstract image
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Optimization of the phenylurea moiety in a phosphoinositide 3-kinase (PI3K) inhibitor to improve water solubility and the PK profile by introducing a solubilizing group and ortho substituents ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Hatsuo Kawada, Hirosato Ebiike, Masao Tsukazaki, Shun Yamamoto, Kohei Koyama, Mitsuaki Nakamura, Kenji Morikami, Kiyoshi Yoshinari, Miyuki Yoshida, Kotaro Ogawa, Nobuo Shimma, Takuo Tsukuda, Jun Ohwada Phosphoinositide 3-kinase (PI3K) is a promising anti-cancer target, because various mutations and amplifications are observed in human tumors isolated from cancer patients. Our dihydropyrrolopyrimidine derivative with a phenylurea moiety showed strong PI3K enzyme inhibitory activity, but its pharmacokinetic property was poor because of lack of solubility. Herein, we report how we improved the solubility of our PI3K inhibitors by introducing a solubilizing group and ortho substituents to break molecular planarity. Graphical abstract image
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Pyrazolylbenzo[d]imidazoles as new potent and selective inhibitors of carbonic anhydrase isoforms hCA IX and XII ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Satish Kumar, Mariangela Ceruso, Tiziano Tuccinardi, Claudiu T. Supuran, Pawan K. Sharma Novel pyrazolylbenzo[d]imidazole derivatives (2a–2f) were designed, synthesized and evaluated against four human carbonic anhydrase isoforms belonging to α family comprising of two cytosolic isoforms hCA I and II as well as two transmembrane tumor associated isoforms hCA IX and XII. Starting from these derivatives that showed high potency but low selectivity in favor of tumor associated isoforms hCA IX and XII, we investigated the impact of removing the sulfonamide group. Thus, analogs 3a–3f without sulfonamide moiety were synthesized and biological assay revealed a good activity as well as an excellent selectivity as inhibitors for tumor associated hCA IX and hCA XII and the same was analyzed by molecular docking studies. Graphical abstract image
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Synthesis and evaluation of raloxifene derivatives as a selective estrogen receptor down-regulator ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Takuji Shoda, Masashi Kato, Takuma Fujisato, Takashi Misawa, Yosuke Demizu, Hideshi Inoue, Mikihiko Naito, Masaaki Kurihara Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. A selective estrogen receptor down-regulator (SERD) that acts as not only an inhibitor of ligand binding, but also induces the down-regulation of ER, would be useful for the treatment for ER-positive breast cancer. We previously reported that tamoxifen derivatives, which have a long alkyl chain, had the ability to down-regulate ERα. With the aim of expanding range of the currently available SERDs, we designed and synthesized raloxifene derivatives, which had various lengths of the long alkyl chains, and evaluated their SERD activities. All compounds were able to bind ERα, and RC10, which has a decyl group on the amine moiety of raloxifene, was shown to be the most potent compound. Our findings suggest that the ligand core was replaceable, and that the alkyl length was important for controlling SERD activity. Moreover, RC10 showed antagonistic activity and its potency was superior to that of 4,4′-(heptane-4,4-diyl)bis(2-methylphenol) (18), a competitive antagonist of ER without SERD activity. These results provide information that will be useful for the development of promising SERDs candidates. Graphical abstract image
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2-(Thienothiazolylimino)-1,3-thiazolidin-4-ones inhibit cell division cycle 25 A phosphatase ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Sophie Huber-Villaume, Germain Revelant, Estelle Sibille, Stéphanie Philippot, Angelica Morabito, Sandrine Dunand, Patrick Chaimbault, Denyse Bagrel, Gilbert Kirsch, Stéphanie Hesse, Hervé Schohn Cell division cycle dual phosphatases (CDC25) are essential enzymes that regulate cell progression in cell cycle. Three isoforms exist as CDC25A, B and C. Over-expression of each CDC25 enzyme is found in cancers of diverse origins. Thiazolidinone derivatives have been reported to display anti-proliferative activities, bactericidal activities and to reduce inflammation process. New 2-(thienothiazolylimino)-1,3-thiazolidin-4-ones were synthesized and evaluated as inhibitors of CDC25 phosphatase. Among the molecules tested, compound 6 inhibited CDC25A with an IC50 estimated at 6.2±1.0μM. The binding of thiazolidinone derivative 6 onto CDC25A protein was reversible. In cellulo, compound 6 treatment led to MCF7 and MDA-MB-231 cell growth arrest. To our knowledge, it is the first time that such 4-thiazolidinone derivatives are characterized as CDC25 potential inhibitor. Graphical abstract image
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New trans dichloro (triphenylphosphine)platinum(II) complexes containing N-(butyl),N-(arylmethyl)amino ligands: Synthesis, cytotoxicity and mechanism of action ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Lisa Dalla Via, Aída Nelly García-Argáez, Enzo Agostinelli, Daniela Belli Dell’Amico, Luca Labella, Simona Samaritani Some new platinum(II) complexes have been prepared, of general formula trans-[PtCl2(PPh3){NH(Bu)CH2Ar}], where the dimension of the Ar residue in the secondary amines has been varied from small phenyl to large pyrenyl group. The obtained complexes, tested in vitro towards a panel of human tumor cell lines showed an interesting antiproliferative effect on both cisplatin-sensitive and -resistant cells. For the most cytotoxic derivative 2a the investigation on the mechanism of action highlighted the ability to induce apoptosis on resistant cells and interestingly, to inhibit the catalytic activity of topoisomerase II. Graphical abstract image
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Design, synthesis and anticonvulsant activity of new hybrid compounds derived from N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)-propanamides and -butanamides ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Krzysztof Kamiński, Anna Rapacz, Barbara Filipek, Jolanta Obniska The focused library of 21 new N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide, 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)propanamide, and 2-(2,5-dioxopyrrolidin-1-yl)butanamide derivatives as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules were obtained as close analogs of previously described N-benzyl derivatives and fuse the chemical fragments of clinically relevant antiepileptic drugs such as ethosuximide, levetiracetam, and lacosamide. The initial anticonvulsant screening was performed in mice (ip) using the ‘classical’ maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests, as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. Applying the rotarod test, the acute neurological toxicity was determined. The broad spectra of activity across the preclinical seizure models in mice (ip) displayed compounds 4, 5, 11, and 19. The most favorable anticonvulsant properties demonstrated 4 (ED50 MES=96.9mg/kg, ED50 scPTZ=75.4mg/kg, ED50 6Hz=44.3mg/kg) which showed TD50 =335.8mg/kg in the rotarod test that yielded satisfying protective indexes (PI MES=3.5, PI scPTZ=4.4, PI 6Hz=7.6). Consequently, compound 4 revealed comparable or better safety profile than model antiepileptic drugs (AEDs): ethosuximide, lacosamide, and valproic acid. In the in vitro assays, compound 4 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and diltiazem site of L-type calcium channels. Graphical abstract image
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Discovery of a novel covalent non-β-lactam inhibitor of the metallo-β-lactamase NDM-1 ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Tony Christopeit, Anastasia Albert, Hanna-Kirsti S. Leiros The inhibition of metallo-β-lactamases (MBL) can prevent the hydrolysis of β-lactam antibiotics and hence is a promising strategy for the treatment of antibiotic resistant infections. In this study, we present a novel reversible covalent inhibitor of the clinically relevant MBL New Delhi metallo-β-lactamase 1 (NDM-1). Electrospray ionization-mass spectrometry (ESI-MS) and single site directed mutagenesis were used to show that the inhibitor forms a covalent bond with Lys224 in the active site of NDM-1. The inhibitor was further characterized using an enzyme inhibition assay, a surface plasmon resonance (SPR) based biosensor assay and covalent docking. The determined inhibition constant (K I ∗) was 580nM and the inhibition constant for the initial complex (K I) was 76μM. To our knowledge, this inhibitor is the first example for a reversible covalent non-β-lactam inhibitor targeting NDM-1 and a promising starting point for the design of potent covalent inhibitors. Graphical abstract image
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Novel free fatty acid receptor 1 (GPR40) agonists based on 1,3,4-thiadiazole-2-carboxamide scaffold ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Mikhail Krasavin, Alexey Lukin, Nikolay Zhurilo, Alexey Kovalenko, Ihor Zahanich, Sergey Zozulya, Daniel Moore, Irina G. Tikhonova Free fatty acid receptor 1 (FFA1), previously known as GPR40 is a G protein-coupled receptor and a new target for treatment of type 2 diabetes. Two series of FFA1 agonists utilizing a 1,3,4-thiadiazole-2-caboxamide scaffold were synthetized. Both series offered significant improvement of the potency compared to the previously described 1,3,4-thiadiazole-based FFA1 agonists and high selectivity for FFA1. Molecular docking predicts new aromatic interactions with the receptor that improve agonist potency. The most potent compounds from both series were profiled for in vitro ADME properties (plasma and metabolic stability, Log D, plasma protein binding, hERG binding and CYP inhibition). One series suffered very rapid degradation in plasma and in presence of mouse liver microsomes. However, the other series delivered a lead compound that displayed a reasonable ADME profile together with the improved FFA1 potency. Graphical abstract image
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Design, synthesis and biological evaluation of novel tetrahydroisoquinoline quaternary derivatives as peripheral κ-opioid receptor agonists ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Ting Guo, Zongjie Gan, Jie Chen, Dechuan Wang, Ling He, Qiao Song, Yungen Xu A novel series of tetrahydroisoquinoline quaternary derivatives 4 were synthesized as peripheral κ-opioid receptor agonists. All the target compounds were evaluated in κ-opioid receptor binding assays, and compounds 4l, 4m, and 4n exhibited high affinity for κ-opioid receptor. Furthermore, compound 4l (κK i =0.94nM) produced potent antinociceptive activity in the mouse acetic acid-induced writhing assay, with lower sedative side effects than the parent compound MB-1c. Graphical abstract image
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Antiproliferative activity and apoptosis inducing effects of nitric oxide donating derivatives of evodiamine ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Nan Zhao, Kang-tao Tian, Ke-guang Cheng, Tong Han, Xu Hu, Da-hong Li, Zhan-lin Li, Hui-ming Hua The first series of nitric oxide donating derivatives of evodiamine were designed and prepared. NO releasing ability of all target derivatives was evaluated in BGC-823, Bel-7402 and L-02 cells. The cytotoxicity was evaluated against three human tumor cell lines (Bel-7402, A549 and BGC-823) and normal human liver cells L-02. The nitrate derivatives 11a and 11b only exhibited moderate activity and furoxan-based derivatives 13a–c, 14a and 14b showed promising activity. 13c showed good cytotoxic selectivity between tumor and normal liver cells and was further investigated for its apoptotic properties on human hepatocarcinoma Bel-7402 cells. The molecular mode of action revealed that 13c caused cell-cycle arrest at S phase and induced apoptosis in Bel-7402 cells through mitochondria-related caspase-dependent pathways. Graphical abstract image
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Stable and biocompatible cystine knot peptides from the marine sponge Asteropus sp. ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Mingzhi Su, Huayue Li, Haibo Wang, Eun La Kim, Hyung Sik Kim, Eun-Hee Kim, Jaewon Lee, Jee H. Jung Two new cystine knot peptides, asteropsins F (ASPF) and G (ASPG), were isolated from the marine sponge Asteropus sp. ASPF and ASPG are composed of 33 and 32 amino acids, respectively, and contain six cysteines which are involved in three disulfide bonds. They shared the characteristic features of the asteropsin family, such as, N-terminal pyroglutamate modification, incorporation of cis prolines, and the unique anionic profile, which distinguish them from other knottin families. Tertiary structures of the peptides were determined by high resolution NMR. ASPF and ASPG were found to be remarkably resistant not only to digestive enzymes (chymotrypsin, pepsin, elastase, and trypsin) but also to thermal degradation. In addition, these peptides were pharmacologically inert; non-hemolytic to human and fish red blood cells, non-stimulatory to murine macrophage cells, and nontoxic in vitro or in vivo. These observations support their stability and biocompatibility as suitable carrier scaffolds for the design of oral peptide drug. Graphical abstract image
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Bismuth(III) complexes with 2-acetylpyridine- and 2-benzoylpyridine-derived hydrazones: Antimicrobial and cytotoxic activities and effects on the clonogenic survival of human solid tumor cells ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Isabella P. Ferreira, Elisa D.L. Piló, Angel A. Recio-Despaigne, Jeferson G. Da Silva, Jonas P. Ramos, Lucas B. Marques, Pedro H.D.M. Prazeres, Jacqueline A. Takahashi, Elaine M. Souza-Fagundes, Willian Rocha, Heloisa Beraldo Complexes [Bi(2AcPh)Cl2]·0.5H2O (1), [Bi(2AcpClPh)Cl2] (2), [Bi(2AcpNO2Ph)Cl2] (3), [Bi(2AcpOHPh)Cl2]·2H2O (4), [Bi(H2BzPh)Cl3]·2H2O (5), [Bi(H2BzpClPh)Cl3] (6), [Bi(2BzpNO2Ph)Cl2]·2H2O (7) and [Bi(H2BzpOHPh)Cl3]·2H2O (8) were obtained with 2-acetylpyridine phenylhydrazone (H2AcPh), its -para-chloro-phenyl- (H2AcpClPh), -para-nitro-phenyl (H2AcpNO2Ph) and -para-hydroxy-phenyl (H2AcpOHPh) derivatives, as well as with the 2-benzoylpyridine phenylhydrazone analogues (H2BzPh, H2BzpClPh, H2BzpNO2Ph, H2BzpOHPh). Upon coordination to bismuth(III) antibacterial activity against Gram-positive and Gram-negative bacterial strains significantly improved except for complex (4). The cytotoxic effects of the compounds under study were evaluated on HL-60, Jurkat and THP-1 leukemia, and on MCF-7 and HCT-116 solid tumor cells, as well as on non-malignant Vero cells. In general, 2-acetylpyridine-derived hydrazones proved to be more potent and more selective as cytotoxic agents than the corresponding 2-benzoylpyridine-derived counterparts. Exposure of HCT-116 cells to H2AcpClPh, H2AcpNO2Ph and complex (3) led to 99% decrease of the clonogenic survival. The IC50 values of these compounds were three-fold smaller when cells were cultured in soft-agar (3D) than when cells were cultured in monolayer (2D), suggesting that they constitute interesting scaffolds, which should be considered in further studies aiming to develop new drug candidates for the treatment of colon cancer. Graphical abstract image
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Triterpene sapogenin–polyarginine conjugates exhibit promising antibacterial activity against Gram-positive strains ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Heiya Na, Xiangpeng Li, Cunbin Zou, Chenhong Wang, Chao Wang, Keliang Liu Triterpene sapogenins are a group of biologically active compounds with antibacterial activity. However, the limited solubility and poor bioavailability of triterpene sapogenins restrict their therapeutic application. Polyarginine peptides are small cationic peptides with high affinities for multiple negatively charged cell membranes and possess moderate antibacterial activities. In this study, we designed and synthesized a series of sapogenin–polyarginine conjugates in which the triterpene sapogenin moiety was covalently appended to the positively charged polyarginine via click chemistry. A clear synergistic effect was found, and the conjugates exhibited potent and selective antibacterial activity against Gram-positive strains. Among them, BAc-R3 was the most promising compound, which was also proven to be nontoxic toward mammalian cells as well as stable in plasma. The mechanism of BAc-R3 primarily involves an interaction with the bacterial membrane, similar to that of antimicrobial peptides (AMPs). This scaffold design opens an avenue for the further development of novel antibiotics comprised of the combination of a peptide and a natural product. Graphical abstract image
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Systematic evaluation of methyl ester bioisosteres in the context of developing alkenyldiarylmethanes (ADAMs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) for anti-HIV-1 chemotherapy ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Ayako Hoshi, Takeshi Sakamoto, Jun Takayama, Meiyan Xuan, Mari Okazaki, Tracy L. Hartman, Robert W. Buckheit, Christophe Pannecouque, Mark Cushman The alkenyldiarylmethanes (ADAMs) are a class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) targeting HIV-1. Four chemically and metabolically stabilized ADAMs incorporating N-methoxyimidoyl halide replacements of the methyl esters of the lead compound were previously reported. In this study, twenty-five new ADAMs were synthesized in order to investigate the biological consequences of installing nine different methyl ester bioisosteres at three different locations. Attempts to define a universal rank order of methyl ester bioisosteres and discover the ‘best’ one in terms of inhibitory activity versus HIV-1 reverse transcriptase (RT) led to the realization that the potencies are critically dependent on the surrounding structure at each location, and therefore the definition of universal rank order is impossible. This investigation produced several new non-nucleoside reverse transcriptase inhibitors in which all three of the three methyl esters of the lead compound were replaced by methyl ester bioisosteres, resulting in compounds that are more potent as HIV-1 RT inhibitors and antiviral agents than the lead compound itself and are expected to also be more metabolically stable than the lead compound. Graphical abstract image
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Comparing the efficacy of photodynamic and sonodynamic therapy in non-melanoma and melanoma skin cancer ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Conor McEwan, Heather Nesbitt, Dean Nicholas, Oisin N. Kavanagh, Kevin McKenna, Philip Loan, Iain G. Jack, Anthony P. McHale, John F. Callan Sonodynamic therapy (SDT) involves the activation of a non-toxic sensitiser drug using low-intensity ultrasound to produce cytotoxic reactive oxygen species (ROS). Given the low tissue attenuation of ultrasound, SDT provides a significant benefit over the more established photodynamic therapy (PDT) as it enables activation of sensitisers at a greater depth within human tissue. In this manuscript, we compare the efficacy of aminolevulinic acid (ALA) mediated PDT and SDT in a squamous cell carcinoma (A431) cell line as well as the ability of these treatments to reduce the size of A431 ectopic tumours in mice. Similarly, the relative cytotoxic ability of Rose Bengal mediated PDT and SDT was investigated in a B16-melanoma cell line and also in a B16 ectopic tumour model. The results reveal no statistically significant difference in efficacy between ALA mediated PDT or SDT in the non-melanoma model while Rose Bengal mediated SDT was significantly more efficacious than PDT in the melanoma model. This difference in efficacy was, at least in part, attributed to the dark pigmentation of the melanoma cells that effectively filtered the excitation light preventing it from activating the sensitiser while the use of ultrasound circumvented this problem. These results suggest SDT may provide a better outcome than PDT when treating highly pigmented cancerous skin lesions. Graphical abstract image
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Inhibitors of secreted phospholipase A2 suppress the release of PGE2 in renal mesangial cells ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Sofia Vasilakaki, Efrosini Barbayianni, Victoria Magrioti, Oleksandr Pastukhov, Violetta Constantinou-Kokotou, Andrea Huwiler, George Kokotos The upregulation of PGE2 by mesangial cells has been observed under chronic inflammation condition. In the present work, renal mesangial cells were stimulated to trigger a huge increase of PGE2 synthesis and were treated in the absence or presence of known PLA2 inhibitors. A variety of synthetic inhibitors, mainly developed in our labs, which are known to selectively inhibit each of GIVA cPLA2, GVIA iPLA2, and GIIA/GV sPLA2, were used as tools in this study. Synthetic sPLA2 inhibitors, such as GK115 (an amide derivative based on the non-natural amino acid (R)-γ-norleucine) as well as GK126 and GK241 (2-oxoamides based on the natural (S)-α-amino acid leucine and valine, respectively) presented an interesting effect on the suppression of PGE2 formation. Graphical abstract image
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Identification, synthesis and evaluation of SARS-CoV and MERS-CoV 3C-like protease inhibitors ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Vathan Kumar, Kian-Pin Tan, Ying-Ming Wang, Sheng-Wei Lin, Po-Huang Liang Severe acute respiratory syndrome (SARS) led to a life-threatening form of atypical pneumonia in late 2002. Following that, Middle East Respiratory Syndrome (MERS-CoV) has recently emerged, killing about 36% of patients infected globally, mainly in Saudi Arabia and South Korea. Based on a scaffold we reported for inhibiting neuraminidase (NA), we synthesized the analogues and identified compounds with low micromolar inhibitory activity against 3CLpro of SARS-CoV and MERS-CoV. Docking studies show that a carboxylate present at either R1 or R4 destabilizes the oxyanion hole in the 3CLpro. Interestingly, 3f, 3g and 3m could inhibit both NA and 3CLpro and serve as a starting point to develop broad-spectrum antiviral agents. Graphical abstract image
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Synthesis of 4-(thiazol-2-ylamino)-benzenesulfonamides with carbonic anhydrase I, II and IX inhibitory activity and cytotoxic effects against breast cancer cell lines ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Nagwa M. Abdel Gawad, Noha H. Amin, Mohammed T. Elsaadi, Fatma M.M. Mohamed, Andrea Angeli, Viviana De Luca, Clemente Capasso, Claudiu T. Supuran A series of 4-(thiazol-2-ylamino)-benzenesulfonamides was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibitory and cytotoxic activity on human breast cancer cell line MCF-7. Human (h) CA isoforms I, II and IX were included in the study. The new sulfonamides showed excellent inhibition of all three isoforms, with K Is in the range of 0.84–702nM against hCA I, of 0.41–288nM against hCA II and of 5.6–29.2 against the tumor-associated hCA IX, a validated anti-tumor target, with a sulfonamide (SLC-0111) in Phase I clinical trials for the treatment of hypoxic, metastatic solid tumors overexpressing CA IX. The new compounds showed micromolar inhibition of growth efficacy against breast cancer MCF-7 cell lines. Graphical abstract image
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Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Yu-Shun Yang, Bing Yang, Yan Zou, Guigen Li, Hai-Liang Zhu A series of novel dioxin-containing triaryl pyrazoline derivatives C1–C20 have been synthesized. Their B-Raf inhibitory and anti-proliferation activities were evaluated. Compound C6 displayed the most potent biological activity against B-RafV600E and WM266.4 human melanoma cell line with corresponding IC50 value of 0.04μM and GI50 value of 0.87μM, being comparable with the positive controls and more potent than our previous best compounds. Moreover, C6 was selective for B-RafV600E from B-RafWT, C-Raf and EGFR and low toxic. The docking simulation suggested the potent bioactivity might be caused by breaking the limit of previous binding pattern. A new 3D QSAR model was built with the activity data and binding conformations to conduct visualized SAR discussion as well as to introduce new directions. Stretching the backbone to outer space or totally reversing the backbone are both potential orientations for future researches. Graphical abstract image
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Synthesis and structure–activity relationships of novel hybrid ferrocenyl compounds based on a bicyclic core skeleton for breast cancer therapy ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Changhao Li, Chu Tang, Zhiye Hu, Chenxi Zhao, Chenlu Li, Silong Zhang, Chune Dong, Hai-Bing Zhou, Jian Huang Breast cancer is the most frequent cancer in women worldwide, and incidence is increasing year by year. Although current selective estrogen receptor modulators (SERMs) have clear advantages in the treatment of hormone-responsive breast cancer, they are ineffective for ER(−). In this study, we describe the design and synthesis of a series of dual-acting estrogen receptor (ER) and histone deacetylase (HDAC) inhibitors with incorporation of the ferrocenyl moiety, leading to novel hybrid ferrocenyl complexes (FcOBHS–HDACis) for breast cancer therapy. It is worth to note that these ferrocenyl conjugates could not only potently inhibit HDACs and the proliferation of ERα positive (ER(+)) breast cancer cells (MCF-7), but also show significant antiproliferative effect on ER(−) breast cancer cells (MDA-MB-231). Thus, the FcOBHS–HDACi conjugates represent a novel approach to the development of efficiently dual-acting agents for treatment of breast cancer. Graphical abstract image
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Antiplasmodial activities of gold(I) complexes involving functionalized N-heterocyclic carbenes ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Catherine Hemmert, Arba Pramundita Ramadani, Luca Boselli, Álvaro Fernández Álvarez, Lucie Paloque, Jean-Michel Augereau, Heinz Gornitzka, Françoise Benoit-Vical A series of twenty five molecules, including imidazolium salts functionalized by N-, O- or S-containing groups and their corresponding cationic, neutral or anionic gold(I) complexes were evaluated on Plasmodium falciparum in vitro and then on Vero cells to determine their selectivity. Among them, eight new compounds were synthesized and fully characterized by spectroscopic methods. The X-ray structures of three gold(I) complexes are presented. Except one complex (18), all the cationic gold(I) complexes show potent antiplasmodial activity with IC50 in the micro- and submicromolar range, correlated with their lipophilicity. Structure–activity relationships enable to evidence a lead-complex (21) displaying a good activity (IC50 =210nM) close to the value obtained with chloroquine (IC50 =514nM) and a weak cytotoxicity. Graphical abstract image
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Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Sheng-Biao Wang, Mu-Tian Cui, Xiao-Feng Wang, Emika Ohkoshi, Masuo Goto, De-Xuan Yang, Linna Li, Shoujun Yuan, Susan L. Morris-Natschke, Kuo-Hsiung Lee, Lan Xie Current results identified 4-substituted 2-phenylaminoquinazoline compounds as novel Mer tyrosine kinase (Mer TK) inhibitors with a new scaffold. Twenty-one 2,4-disubstituted quinazolines (series 4–7) were designed, synthesized, and evaluated against Mer TK and a panel of human tumor cell lines aimed at exploring new Mer TK inhibitors as novel potential antitumor agents. A new lead, 4b, was discovered with a good balance between high potency (IC50 0.68μM) in the Mer TK assay and antiproliferative activity against MV4-11 (GI50 8.54μM), as well as other human tumor cell lines (GI50 <20μM), and a desirable druglike property profile with low log P value (2.54) and high aqueous solubility (95.6μg/mL). Molecular modeling elucidated an expected binding mode of 4b with Mer TK and necessary interactions between them, thus supporting the hypothesis that Mer TK might be a biologic target of this kind of new active compound. Graphical abstract image
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Corrigendum to “Purinylpyridinylamino-based DFG-in/αC-helix-out B-Raf inhibitors: Applying mutant versus wild-type B-Raf selectivity indices for compound profiling” [Bioorg. Med. Chem. 24 (2016) 2215–2234] ()
Publication date: 1 July 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 13 Author(s): Longbin Liu, Matthew R. Lee, Joseph L. Kim, Douglas A. Whittington, Howard Bregman, Zihao Hua, Richard T. Lewis, Matthew W. Martin, Nobuko Nishimura, Michele Potashman, Kevin Yang, Shuyan Yi, Karina R. Vaida, Linda F. Epstein, Carol Babij, Manory Fernando, Josette Carnahan, Mark H. Norman
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Synthesis and Anticancer Activity of Novel 4-Morpholino-7,8-dihydro-5H-thiopyrano[4,3-d]-pyrimidine Derivatives Bearing Chromone Moiety ()
Publication date: Available online 16 June 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Chengyu Sun, Chen Chen, Shan Xu, Jianqiang Wang, Yan Zhu, Dejia Kong, Hong Tao, Mengjia Jin, Pengwu Zheng, Wufu Zhu Herein, we designed and synthesized of a novel series of 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine derivatives bearing chromone moiety (10a–j, 13a–j). All the compounds were evaluated for the IC50 values against five cancer cell lines (A549,PC-3,MCF-7,Hela and HepG2). Seven of the target compounds exhibited moderate to excellent cytotoxicity. For these compounds, we tested their inhibitory activities against mTOR kinase, and four of them were tested their inhibitory activities against PI3Kα kinase in further.The results indicated that the optimized compound 10j showed excellent inhibitory activity and cytotoxicity against mTOR kinase, PI3Kα kinase and five cancer cell lines with IC50 values of 1.1μM, 0.92μM and 8.77∼14.3 μM .Structure–activity relationships (SARs) and docking studies indicated that the thiopyrano[4,3-d]pyrimidine scaffolds exerted little effect on antitumor activities of target compounds. Substitutions of chromone moiety at C-6 position with carboxyl were benefit to the antitumor activities. Graphical abstract image
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Doxifluridine-conjugated 2-5A analog shows strong RNase L activation ability and tumor suppressive effect ()
Publication date: Available online 16 June 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Yoshiaki Kitamura, Seiya Kito, Remi Nakashima, Katsuki Tanaka, Kumi Nagaoka, Yukio Kitade RNase L is activated by 2′,5′-oligoadenylates (2-5A) at subnanomolar levels to cleave single-stranded RNA. We previously reported the hypothesis that the introduction of an 8-methyladenosine residue at the 2′-terminus of the 2-5A tetramer shifts the 2-5A binding site of RNase L. In this study, we synthesized various 5′-modified 2-5A analogs with 8-methyladenosine at the 2′-terminus. The doxifluridine-conjugated 8-methyladenosine-substituted 2-5A analog was significantly more effective as an activator of RNase L than the parent 5′-monophophorylated 2-5A tetramer and showed a tumor suppressive effect against human cervical cancer cells. Graphical abstract image
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Novel Drug Design for Chagas Disease via Targeting Trypanosoma cruzi Tubulin: Homology Modeling and Binding Pocket Prediction on Trypanosoma cruzi Tubulin Polymerization Inhibition by Naphthoquinone Derivatives ()
Publication date: Available online 16 June 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Charles O. Ogindo, Mozna H. Khraiwesh, Matthew George, Yakini Brandy, Nailah Brandy, Ayele Gugssa, Mohammad Ashraf, Muneer Abbas, William M. Southerland, Clarence M. Lee, Oladapo Bakare, Yayin Fang Chagas disease, also called American trypanosomiasis, is a parasitic disease caused by Trypanosoma cruzi (T. cruzi). Recent findings have underscored the abundance of the causative organism, (T. cruzi), especially in the southern tier states of the US and the risk burden for the rural farming communities there. Due to a lack of safe and effective drugs, there is an urgent need for novel therapeutic options for treating Chagas disease. We report here our first scientific effort to pursue a novel drug design for treating Chagas disease via the targeting of T. cruzi tubulin. First, the anti T. cruzi tubulin activities of five naphthoquinone derivatives were determined and correlated to their anti-trypanosomal activities. The correlation between the ligand activities against the T. cruzi organism and their tubulin inhibitory activities was very strong with a Pearson’s r value of 0.88 (P value < 0.05), indicating that this class of compounds could inhibit the activity of the trypanosome organism via T. cruzi tubulin polymerization inhibition. Subsequent molecular modeling studies were carried out to understand the mechanisms of the anti-tubulin activities, wherein, the homology model of T. cruzi tubulin dimer was generated and the putative binding site of naphthoquinone derivatives was predicted. The correlation coefficient for ligand anti-tubulin activities and their binding energies at the putative pocket was found to be r = 0.79, a high correlation efficiency that was not replicated in contiguous candidate pockets. The homology model of T. cruzi tubulin and the identification of its putative binding site lay a solid ground for further structure based drug design, including molecular docking and pharmacophore analysis. This study presents a new opportunity for designing potent and selective drugs for Chagas disease. Graphical abstract image
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Chemoenzymatic synthesis and antileukemic activity of novel C9- and C14-functionalized parthenolide analogs ()
Publication date: Available online 16 June 2016 Source:Bioorganic & Medicinal Chemistry Author(s): Vikas Tyagi, Hanan Alwaseem, Kristen M. O’Dwyer, Jessica Ponder, Qi Ying Li, Craig T. Jordan, Rudi Fasan Parthenolide is a naturally occurring terpene with promising anticancer properties, in particular in the context of acute myeloid leukemia (AML). Optimization of this natural product has been challenged by limited opportunities for the late-stage functionalization of this molecule without affecting the pharmacologically important α-methylene-γ-lactone moiety. Here, we report the further development and application of a chemoenzymatic strategy to afford a series of new analogs of parthenolide functionalized at the aliphatic positions C9 and C14. Several of these compounds were determined to be able to kill leukemia cells and patient-derived primary AML specimens with improved activity compared to parthenolide, exhibiting LC50 values in the low micromolar range. These studies demonstrate that different O−H functionalization chemistries can be applied to elaborate the parthenolide scaffold and that modifications at the C9 or C14 position can effectively enhance the antileukemic properties of this natural product. The C9-functionalized analogs 09-26-epi1 and 09-27-epi2 were identified as the most interesting compounds in terms of antileukemic potency and selectivity toward AML versus healthy blood cells. Graphical abstract image
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Editorial board ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12
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Synthesis, anticancer activity, and SAR analyses of compounds containing the 5:7-fused 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Min Xie, Rena G. Lapidus, Mariola Sadowska, Martin J. Edelman, Ramachandra S. Hosmane Described herein are our limited structure–activity relationship (SAR) studies on a 5:7-fused heterocycle (1), containing the 4,6,8-triaminoimidazo[4,5-e][1,3]diazepine ring system, whose synthesis and potent broad-spectrum anticancer activity we reported a few years ago. Our SAR efforts in this study are mainly focused on judicial attachment of substituents at N-1 and N6-positions of the heterocyclic ring. Our results suggest that there is some subtle correlation between the substituents attached at the N-1 position and those attached at the N6-position of the heterocycle. It is likely that there is a common hydrophobic binding pocket on the target protein that is occupied by the substituents attached at the N-1 and N6-positions of the heterocyclic ligand. This pocket appears to be large enough to hold either a C-18 alkyl chain of N6 and no attachment at N-1, or a combined C-10 at N6 and a CH2Ph at N-1. Any alkyl chain shorter or longer than C-10 at N6 with a CH2Ph attached at N-1, would result in decrease of biological activity. Graphical abstract image
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Discovery of pyrazinone based compounds that potently inhibit the drug-resistant enzyme variant R155K of the hepatitis C virus NS3 protease ()
Publication date: 15 June 2016 Source:Bioorganic & Medicinal Chemistry, Volume 24, Issue 12 Author(s): Anna Karin Belfrage, Eldar Abdurakhmanov, Eva Åkerblom, Peter Brandt, Anna Oshalim, Johan Gising, Anna Skogh, Johan Neyts, U. Helena Danielson, Anja Sandström Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors with variations in the C-terminus. Biochemical evaluation was performed using genotype 1a, both the wild-type and the drug resistant enzyme variant, R155K. Surprisingly, compounds without an acidic sulfonamide retained good inhibition, challenging our previous molecular docking model. Moreover, selected compounds in this series showed nanomolar potency against R155K NS3 protease; which generally confer resistance to all HCV NS3 protease inhibitors approved or in clinical trials. These results further strengthen the potential of this novel substance class, being very different to the approved drugs and clinical candidates, in the development of inhibitors less sensitive to drug resistance. Graphical abstract image
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