Bioorganic & Medicinal Chemistry

Editorial board ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14
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Diverse size approach to incorporate and extend highly fluorescent unnatural nucleotides into DNA ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Binh Huy Le, Ja Choon Koo, Han Na Joo, Young Jun Seo We have prepared a series of size-diverse unnatural nucleotides containing fluorescent (dApyrTP, dUpyrTP, dUantTP, dUthiTP) and quencher (dUazoTP) units, as well as nucleotides presenting small functional groups (dAethTP, dAoctTP, dUethTP, dUiodTP), all based on deoxyadenosine and deoxyuridine, and examined their suitability for use in enzymatic incorporation and extension into DNA. We observed a size-dependence of the incorporation and extension capability (following the order dUiodTP = dUethTP = dUthiTP > dUazoTP > dUpyrTP > dUantTP) during primer extension. This result was supported by circular dichroism (CD) spectra, which revealed a trend in the different B-form DNA structures depending on the size of the unit at the 5-position of the deoxyuridine (dUiodTP > dUethTP > dUthiTP > dUpyrTP), obtained from the PCR products. Interestingly, dUthiTP could be incorporated and extended into long DNA strands during primer extension and even PCR amplification, with CD spectroscopy confirming a stable secondary B-form duplex DNA structure. We observed full-length extension products even when combining dUthiTP with a template containing 24 continuous dA units during the primer extension. Thus, we believe that dUthiTP is a promising fluorescent nucleotide for a diverse range of biological applications requiring multiple incorporation and extension directly without disruption of B-form DNA structures. Graphical abstract image
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Synthesis of oligonucleotides containing novel G-clamp analogue with C8-tethered group in phenoxazine ring: Implication to qPCR detection of the low-copy Kemerovo virus dsRNA ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Anna M. Varizhuk, Timofei S. Zatsepin, Andrey V. Golovin, Evgeny S. Belyaev, Yury I. Kostyukevich, Vladimir G. Dedkov, German A. Shipulin, George V. Shpakovski, Andrey V. Aralov Nowadays modified oligonucleotides are widely used in diagnostics and as novel therapeutics. Introduction of modified or unnatural residues into oligonucleotides allows fine tuning of their binding properties to complementary nucleic acids and leads to improved stability both in vitro and in vivo. Previously it was demonstrated that insertion of phenoxazine nucleotides with various groups in C9-position into oligonucleotides leads to a significant increase of duplex stability with complementary DNA and RNA. Here the synthesis of a novel G-clamp nucleoside analogue (G8AE-clamp) bearing 2-aminoethyl tether at C8-atom is presented. Introduction of such modified residues into oligonucleotides lead to enhanced specificity of duplex formation towards complementary DNA and RNA targets with increased thermal and 3′-exonuclease stability. According to CD-spectroscopy studies G8AE-clamp does not substantially disrupt helix geometry. Primers containing G8AE-clamp demonstrated superior sensitivity in qPCR detection of dsRNA of Kemerovo virus in comparison to native oligonucleotides. Graphical abstract image
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Carboxylated aurone derivatives as potent inhibitors of xanthine oxidase ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Oksana V. Muzychka, Oleksandr L. Kobzar, Antonina V. Popova, Mykhaylo S. Frasinyuk, Andriy I. Vovk Xanthine oxidase is a potential target for treatment of hyperuricemia and gout. In this study, a number of A- and B-ring carboxylated aurone derivatives were synthesized and evaluated for their ability to inhibit xanthine oxidase in vitro. According to the results obtained, two different ranges of inhibitory activity were observed. The aurones with carboxylic acid group at the 4′-position of B-ring were found to be potent inhibitors of the enzyme with IC50 values in the low micromolar range. The effects of these compounds were about 50 fold higher than of A-ring modified aurones with carboxymethoxy group at the 6-position. The binding modes of the carboxylated aurones in the active site of xanthine oxidase were explained using molecular docking calculations. Graphical abstract image
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Optimization and biological evaluation of 2-aminobenzothiazole derivatives as Aurora B kinase inhibitors ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Eun Lee, Ying An, Junhee Kwon, Keun Il Kim, Raok Jeon A strong relationship between abnormal functions of Aurora kinases and tumorigenesis has been reported for decades. Consequently, Aurora kinases serve as potential targets for anticancer agents. Here, we identified aminobenzothiazole derivatives as novel inhibitors of Aurora B kinase through bioisosteric replacement of the previous inhibitors, aminobenzoxazole derivatives. Most of the urea-linked aminobenzothiazole derivatives showed potent and selective inhibitory activity against Aurora B kinase over Aurora A kinase. Molecular modeling indicated that compound 15g bound well to the active site of Aurora B kinase and formed the essential hydrogen bonds. The potent compounds, 15g and 15k, were selected, and their biological effects were evaluated using HeLa cell lines. It was found that these compounds inhibited the phosphorylation of histone H3 at Ser10 and induced G2/M cell cycle arrest. We suggest that the reported compounds have the potential to be further developed as anticancer therapeutics. Graphical abstract image
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Click strategy using disodium salts of amino acids improves the water solubility of plinabulin and KPU-300 ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Fumika Yakushiji, Kyohei Muguruma, Yoshiki Hayashi, Takuya Shirasaka, Ryosuke Kawamata, Hironari Tanaka, Yushi Yoshiwaka, Akihiro Taguchi, Kentaro Takayama, Yoshio Hayashi Plinabulin and KPU-300 are promising anti-microtubule agents; however, the low water solubility of these compounds (<0.1µg/mL) has limited their pharmaceutical advantages. Here, we developed five water-soluble derivatives of plinabulin and KPU-300 with a click strategy using disodium salts of amino acids. The mother skeleton, diketopiperazine (DKP), was transformed into a monolactim-type alkyne and a copper-catalyzed alkyne azide cycloaddition (CuAAC) combined azides that was derived from amino acids as a water-solubilizing moiety. The conversion of carboxyl groups into disodium salts greatly improved the water solubility by 0.8 million times compared to the solubility of the parent molecules. In addition, the α-amino acid side chains of the water-solubilizing moieties affected both the water solubility and the half-lives of the compounds during enzymatic hydrolysis. Our effort to develop a variety of water-soluble derivatives using the click strategy has revealed that the replaceable water-solubilizing moieties can alter molecular solubility and stability under enzymatic hydrolysis. With this flexibility, we are approaching to the in vivo study using water-soluble derivative. Graphical abstract image
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Development of novel N-3-bromoisoxazolin-5-yl substituted 2,3-benzodiazepines as noncompetitive AMPAR antagonists ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Milad Espahbodinia, Roberta Ettari, Wei Wen, Andrew Wu, Yu-Chuan Shen, Li Niu, Silvana Grasso, Maria Zappalà In this work, we designed and synthesized novel N-3-bromoisoxazolin-5-yl substituted 2,3-benzodiazepines as noncompetitive AMPAR antagonists, with the aim that this heterocycle could establish favourable interactions with a putative binding pocket of the receptor, like the thiadiazole nucleus of GYKI 47409 does. Within this investigation, we identified some active molecules and, among these 2,3-benzodiazepines, 4c showed a much improved inhibitory potency as compared with unsubstituted 2,3-benzodiazepines. Graphical abstract image
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The impact of the halogen bonding on D2 and 5-HT1A/5-HT7 receptor activity of azinesulfonamides of 4-[(2-ethyl)piperidinyl-1-yl]phenylpiperazines with antipsychotic and antidepressant properties ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Anna Partyka, Rafał Kurczab, Vittorio Canale, Grzegorz Satała, Krzysztof Marciniec, Agnieszka Pasierb, Magdalena Jastrzębska-Więsek, Maciej Pawłowski, Anna Wesołowska, Andrzej J. Bojarski, Paweł Zajdel A series of azinesulfonamides of long-chain arylpiperazine derivatives with semi-rigid alkylene spacer was designed, synthesized, and biologically evaluated using in vitro methods for their affinity for dopaminergic D2 and serotoninergic 5-HT1A, 5-HT2A, 5-HT6 and 5-HT7 receptors. Docking to homology models revealed a possible halogen bond formation in complexes of the most potent ligands and the target receptors. The study allowed for the identification of compound 5-({4-(2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl)piperidin-1-yl}sulfonyl)quinoline (21), which behaved as D2, 5-HT1A and 5-HT7 receptor antagonist. In preliminary in vivo studies, compound 21 displayed distinct antipsychotic properties in the MK-801-evoked hyperactivity test in mice at a dose of 10mg/kg, and exerted antidepressant-like effect in a forced swim test in mice (MED=0.625mg/kg, i.p.). Graphical abstract image
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Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11β hydroxysteroid dehydrogenase type 1 inhibitor ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Linghang Zhuang, Colin M. Tice, Zhenrong Xu, Wei Zhao, Salvacion Cacatian, Yuan-Jie Ye, Suresh B. Singh, Peter Lindblom, Brian M. McKeever, Paula M. Krosky, Yi Zhao, Deepak Lala, Barbara A. Kruk, Shi Meng, Lamont Howard, Judith A. Johnson, Yuri Bukhtiyarov, Reshma Panemangalore, Joan Guo, Rong Guo, Frank Himmelsbach, Bradford Hamilton, Annette Schuler-Metz, Heike Schauerte, Richard Gregg, Gerard M. McGeehan, Katerina Leftheris, David A. Claremon A potent, in vivo efficacious 11β hydroxysteroid dehydrogenase type 1 (11β HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11β HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011. Graphical abstract image
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2-Aminomethylthieno[3,2-d]pyrimidin-4(3H)-ones bearing 3-methylpyrazole hinge binding moiety: Highly potent, selective, and time-dependent inhibitors of Cdc7 kinase ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Osamu Kurasawa, Misaki Homma, Yuya Oguro, Tohru Miyazaki, Kouji Mori, Noriko Uchiyama, Kenichi Iwai, Akihiro Ohashi, Hideto Hara, Sei Yoshida, Nobuo Cho In order to increase the success rate for developing new Cdc7 inhibitors for cancer therapy, we explored a new chemotype which can comply with the previously-constructed pharmacophore model. Substitution of a pyridine ring of a serendipitously-identified Cdc7 inhibitor 2b with a 3-methylpyrazole resulted in a 4-fold increase in potency and acceptable kinase selectivity, leading to the identification of thieno[3,2-d]pyrimidin-4(3H)-one as an alternative scaffold. Structure-activity relationship (SAR) study revealed that incorporation of a substituted aminomethyl group into the 2-position improved kinase selectivity. Indeed, a pyrrolidinylmethyl derivative 10c was a potent Cdc7 inhibitor (IC50 =0.70nM) with high selectivity (Cdk2/Cdc7≥14,000, ROCK1/Cdc7=200). It should be noted that 10c exhibited significant time-dependent Cdc7 inhibition with slow dissociation kinetics, cellular pharmacodynamic (PD) effects, and COLO205 growth inhibition. Additionally, molecular basis of high kinase selectivity of 10c is discussed by using the protein structures of Cdc7 and Cdk2. Graphical abstract image
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Synthesis and anticancer activity of novel aza-artemisinin derivatives ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Sampad Jana, Shabina Iram, Joice Thomas, Sandra Liekens, Wim Dehaen Three series of aza-artemisinin derivatives were synthesized for studies of anticancer activity. The first series of compounds were prepared via copper(I)-catalyzed azide alkyne cycloaddition, so called “click reaction”, starting from propargyl derivatives of 11-aza-artemisinin and various azides, whereas the second and third series of compounds were prepared by triazolization reaction starting from enolizable ketones and primary amines connected to artemisinin. In vitro studies of the 23 synthesized artemisinin derivatives unveiled that 9 compounds displayed antiproliferative activity in the low micromolar range, with 5d being the most promising compound showing 50% inhibition of Cem and HeLa cell growth at 0.92 and 1.2µM, respectively. Graphical abstract image
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Synthesis and evaluation of novel dual BRD4/HDAC inhibitors ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Seika Amemiya, Takao Yamaguchi, Yuichi Hashimoto, Tomomi Noguchi-Yachide Epigenetic regulation of gene expression via histone acetylation modulates many cellular processes, including apoptosis, the cell cycle, cell growth and differentiation, and inhibitors are promising drug candidates. We have previously developed inhibitors of BRD4, which recognizes acetylated lysine residue on histones and recruits transcription elongation factor to the transcription start site, while inhibitors of histone deacetylase (HDAC), which catalyzes the removal of acetyl groups on histones, are already in clinical use for cancer treatment. Based on the idea that polypharmacological agents with multiple targets would have a more robust action, we set out to develop dual BRD4/HDAC inhibitors. Here, we describe the design and synthesis of N 6-[2-(7-hydroxyamino-7-oxoheptyloxy)benzoyl]adenine (5d) as a BRD4/HDAC dual inhibitor. This compound showed HL-60 cell growth-inhibitory and apoptosis-inducing activity, as well as all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation-enhancing activity, and c-MYC production-inhibitory activity. Interestingly, it also showed growth-inhibitory activity towards BRD4 inhibitor-resistant cells. Graphical abstract image
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Site-specific conjugation of fibroblast growth factor 2 (FGF2) based on incorporation of alkyne-reactive unnatural amino acid ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): K.W. Swiderska, A. Szlachcic, A. Czyrek, M. Zakrzewska, J. Otlewski Recent advances in site-specific protein modification include the increasingly popular incorporation of unnatural amino acid(s) using amber codon, a method developed by Schultz and coworkers. In this study, we employ this technique to introduce propargyllysine (PrK) in human fibroblast growth factor 2 (FGF2). Owing to an alkyne moiety in its side chain, PrK is compatible with Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). We successfully tested CuAAC-mediated conjugation of FGF2 with two compounds – a fluorophore carboxyrhodamine 110 or a cytotoxic drug monomethyl auristatin E (MMAE). In the case of the MMAE conjugate we improved the initial poor conjugation yield to achieve nearly 100% efficiency after extensive optimization. The detergent-based optimization approach may help overcome problems with the CuAAC reaction yield for protein modification with hydrophobic compounds, such as MMAE. Graphical abstract image
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Succinamide derivatives of melampomagnolide B and their anti-cancer activities ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Venumadhav Janganati, Jessica Ponder, Shraddha Thakkar, Craig T. Jordan, Peter A. Crooks A series of succinamide derivatives of melampomagnolide B have been synthesized by coupling MMB monosuccinate (2) with various heterocyclic amines to afford compounds 3a–3l. MMB monosuccinate was also reacted with terminal diaminoalkanes to afford dimeric succinamido analogs of MMB (4a–4h). These succinamide analogs of MMB were evaluated for their anti-cancer activity against a panel of sixty human cancer cell lines. Analogs 3d–3i and dimers 4f–4g exhibited promising anti-cancer activity with GI50 values ranging from 0.28 to 33.5µM against most of the cell lines in the panel. The dimeric analogs 4f and 4g were identified as lead compounds with GI50 values in the nanomolar range (GI50 =280–980nM) against several cell lines in the panel; i.e. leukemia cell lines CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPMI-8226 and SR; and solid tumor cell lines NCI-H522 (non-small cell lung cancer), SW-620 and HCT-116 (colon cancer), LOX IMVI (melanoma), RXF 393 (renal cancer), and MCF7, BT-549 and MDA-MB-468 (breast cancer). Succinamide analogs 3a, 3c–3l and 4b–4h were also evaluated for their apoptotic activity against M9-ENL1 acute myelogenous leukemia cells; compounds 3h–3j and 4g were equipotent with parthenolide, exhibiting LC50 values in the range 4.1–8.1μM. Molecular docking studies indicate that these molecules interact covalently with the highly conserved Cys-46 residue of the N-terminal lobe (1–109) of human IKKβ to inhibit the NFκB transcription factor complex, resulting in down-regulation of anti-apoptotic genes under NFκB control. Graphical abstract image
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Screening for bioactive natural products from a 67-compound library of Glycyrrhiza inflata ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Yan Lin, Yi Kuang, Kai Li, Shuang Wang, Wei Song, Xue Qiao, Gulnar Sabir, Min Ye Licorice shows a variety of pharmacological activities. This work aims to discover bioactive natural products from one botanical source of licorice, Glycyrrhiza inflata. A total of 67 free phenolics were isolated to form a compound library. Based on the bioactivities of licorice, these compounds were screened using cell- or enzyme-based bioassay methods. A total of 11 compounds exhibited potent cytotoxic activities against three human cancer cell lines (HepG2, SW480 and MCF7), while showed little toxicity on human normal cell lines LO2 and HEK293T. A number of chalcones showed remarkable anti-inflammatory activities. Among them, 2 (licochalcone B, IC50 8.78μM), 10 (licoagrochalcone C, IC50 9.35μM) and 13 (licochalcone E, IC50 9.09μM) exhibited the most potent inhibitory activities on LPS-induced NO production, whereas 1, 8, 10, 12 and 13 (IC50 13.9, 7.27, 2.44, 6.67 and 3.83μM) showed potent inhibitory activities on NF-κB transcription. Nine prenylated phenolics were found to be PTP1B inhibitors. Particularly, licoagrochalcone A (4), kanzonol C (7), 2′-hydroxyisolupalbigenin (35), gancaonin Q (45), glisoflavanone (50) and glabrol (53) showed IC50 values of 0.31–0.97μM. Compounds 24 (semilicoisoflavone B, IC50 0.25μM), 26 (allolicoisoflavone B, IC50 0.80μM) and 64 (glabridin, IC50 0.10μM) showed noticeable tyrosinase inhibitory activities. Most of the above bioactive compounds were reported for the first time. Graphical abstract image
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Novel sulfonamide-containing 2-indolinones that selectively inhibit tumor-associated alpha carbonic anhydrases ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Nilgün Karalı, Atilla Akdemir, Füsun Göktaş, Pınar Eraslan Elma, Andrea Angeli, Merih Kızılırmak, Claudiu T. Supuran Human carbonic anhydrases IX and XII are upregulated in many tumors and form a novel target for new generation anticancer drugs. Here we report the synthesis of novel 2-indolinone derivatives with the sulfonamide group as a zinc binding moiety. Enzyme inhibition assays confirmed that the compounds showed selectivity against hCA IX and XII over the widely distributed off-targets hCA I and II. Molecular modelling studies were performed to suggest modes of binding for these compounds. Graphical abstract image
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Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2′-piperidin)-1-ones as potassium-competitive acid blockers ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Toshihiro Imaeda, Koji Ono, Kazuo Nakai, Yasunobu Hori, Jun Matsukawa, Terufumi Takagi, Yasushi Fujioka, Naoki Tarui, Mitsuyo Kondo, Akio Imanishi, Nobuhiro Inatomi, Masahiro Kajino, Fumio Itoh, Haruyuki Nishida With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2′-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers. Graphical abstract image
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A novel serine racemase inhibitor suppresses neuronal over-activation in vivo ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Hisashi Mori, Ryogo Wada, Satoyuki Takahara, Yoshikazu Horino, Hironori Izumi, Tetsuya Ishimoto, Tomoyuki Yoshida, Mineyuki Mizuguchi, Takayuki Obita, Hiroaki Gouda, Shuichi Hirono, Naoki Toyooka Serine racemase (SRR) is an enzyme that produces d-serine from l-serine. d-Serine acts as an endogenous coagonist of NMDA-type glutamate receptors (NMDARs), which regulate many physiological functions. Over-activation of NMDARs induces excitotoxicity, which is observed in many neurodegenerative disorders and epilepsy states. In our previous works on the generation of SRR gene knockout (Srr-KO) mice and its protective effects against NMDA- and Aβ peptide-induced neurodegeneration, we hypothesized that the regulation of NMDARs’ over-activation by inhibition of SRR activity is one such therapeutic strategy to combat these disease states. In the previous study, we performed in silico screening to identify four compounds with inhibitory activities against recombinant SRR. Here, we synthesized 21 derivatives of candidate 1, one of four hit compounds, and performed screening by in vitro evaluations. The derivative 13J showed a significantly lower IC50 value in vitro, and suppressed neuronal over-activation in vivo. Graphical abstract image
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Design, synthesis and evaluation of indole-2-carboxamides with pan anti-mycobacterial activity ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Nicholas D. Franz, Juan Manuel Belardinelli, Michael A. Kaminski, Louis C. Dunn, Vinicius Calado Nogueira de Moura, Michael A. Blaha, Dan D. Truong, Wei Li, Mary Jackson, E. Jeffrey North Current treatment regimens for non-tuberculous mycobacteria (NTM) and tuberculosis (TB) generally require long duration of therapy with multiple drugs, some of which are broad spectrum antibiotics. Despite some advances in antimicrobial compounds, there remains a need in therapy for antibiotics with specific mycobacterial targets. It has been shown that MmpL3 is an essential transporter required for the translocation of mycolic acids to the mycobacterial cell envelope. Here, we synthesized a series of indole-2-carboxamides that inhibit MmpL3 and have potent pan-activity against mycobacterial species. The compounds were tested against several fast and slow-growing Mycobacterium species, including M. abscessus, M. massiliense, M. bolletii, M. chelonae, M. tuberculosis, M. avium, M. xenopi and M. smegmatis. The target of these indole-based compounds makes them selective for mycobacteria, while showing no clinically relevant bactericidal activity against S. aureus or P. aeruginosa. These compounds were tested against THP-1, a human-cell line, and showed minimal in vitro cytotoxicity and good selectivity indices. The data shown and discussed suggest that lead indole-2-carboxamides are strong contenders for further preclinical testing as NTM therapeutics. Graphical abstract image
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Synthesis of nοvel artemisinin dimers with polyamine linkers and evaluation of their potential as anticancer agents ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): George E. Magoulas, Tzoanna Tsigkou, Lina Skondra, Margarita Lamprou, Panagiota Tsoukala, Vassiliki Kokkinogouli, Evangelia Pantazaka, Dionissios Papaioannou, Constantinos M. Athanassopoulos, Evangelia Papadimitriou The natural product artemisinin and derivatives thereof are currently considered as the drugs of choice for the treatment of malaria. At the same time, a significant number of such drugs have also shown interesting anticancer activity. In the context of the present research work, artemisinin was structurally modified and anchored to naturally occurring polyamines to afford new artemisinin dimeric conjugates whose potential anticancer activity was evaluated. All artemisinin conjugates tested were more effective than artemisinin itself in decreasing the number of MCF7 breast cancer cells. The effect required conjugation and was not due to the artemisinin analogue or the polyamine, alone or in combination. To elucidate potential mechanism of action, we used the most effective conjugates 6, 7, 9 and 12 and found that they decreased expression and secretion of the angiogenic growth factor pleiotrophin by the cancer cells themselves, and inhibited angiogenesis in vivo and endothelial cell growth in vitro. These data suggest that the new artemisinin dimers are good candidates for the development of effective anticancer agents. Graphical abstract image
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Discovery of Novel and Potent Stearoyl Coenzyme A Desaturase 1 (SCD1) Inhibitors as Anticancer Agents ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Keisuke Imamura, Naoki Tomita, Youichi Kawakita, Yoshiteru Ito, Kouji Ono, Noriyuki Nii, Tohru Miyazaki, Kazuko Yonemori, Michiko Tawada, Hiroyuki Sumi, Yoshihiko Satoh, Yukiko Yamamoto, Ikuo Miyahisa, Masako Sasaki, Yoshinori Satomi, Megumi Hirayama, Ryuichi Nishigaki, Hironobu Maezaki A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of ‘non-spiro’ 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch–Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/kg, bid) in 786-O mouse xenograft model. In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies. Graphical abstract image
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Identification and preliminary structure–activity relationships of 1-Indanone derivatives as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Dingding Gao, Yingxia Li Indoleamine 2,3-dioxygenase 1 (IDO1) plays a vital role in the catabolism of tryptophan along with the kynurenine pathway which is involved in many human diseases including cancer, Alzheimer’s disease, etc. In this study, compound 1 bearing a 1-Indanone scaffold was identified as a novel IDO1 inhibitor by structure-based virtual screening, with moderate to good enzymatic and cellular inhibitory activities. Also, surface plasmon resonance analysis validated the direct interaction between compound 1 and IDO1 protein. The preliminary SAR was further explored and the binding mode with IDO1 protein was predicted by experiment along with molecular docking. Subsequent ADME properties of these active compounds were analyzed in silico, and the results showed good pharmacokinetic efficiencies. We believe this study contributes a lot to the structural diversity for the future development of highly potent IDO1 inhibitors. Graphical abstract image
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18F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Liang Wang, Jiajun Ye, Yingfang He, Winnie Deuther-Conrad, Jinming Zhang, Xiaojun Zhang, Mengchao Cui, Jörg Steinbach, Yiyun Huang, Peter Brust, Hongmei Jia We have designed and synthesized a series of indole-based σ2 receptor ligands containing 5,6-dimethoxyisoindoline or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline as pharmacophore. In vitro competition binding assays showed that all ten ligands possessed low nanomolar affinity (K i =1.79–5.23nM) for σ2 receptors and high subtype selectivity (K i (σ2)/K i (σ1)=56–708). Moreover, they showed high selectivity for σ2 receptor over the vesicular acetylcholine transporter (>1000-fold). The corresponding radiotracers [18F]16 and [18F]21 were prepared by an efficient one-pot, two-step reaction sequence with a home-made automated synthesis module, with 10–15% radiochemical yield and radiochemical purity of >99%. Both radiotracers showed high brain uptake and σ2 receptor binding specificity in mice. Graphical abstract image
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Synthesis, spectroscopic characterization and biological evaluation of unsymmetrical aminosquarylium cyanine dyes ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Sofia Friães, Amélia M. Silva, Renato E. Boto, Diana Ferreira, José R. Fernandes, Eliana B. Souto, Paulo Almeida, Luis F. Vieira Ferreira, Lucinda V. Reis New unsymmetrical aminosquarylium cyanine dyes were synthesized and their potential as photosensitizers evaluated. New dyes, derived from benzothiazole and quinoline, were prepared by nucleophilic substitution of the corresponding O-methylated, the key intermediate that was obtained by methylation with CF3SO3CH3 of the related zwitterionic unsymmetrical dye, with ammonia and methylamine, respectively. All three news dyes herein described displayed intense and narrow bands in the Vis/NIR region (693–714nm) and their singlet oxygen formation quantum yields ranged from 0.03 to 0.05. In vitro toxicity, in Caco-2 and HepG2 cells, indicated that dark toxicity was absent for concentrations up to 5µM (for the less active dye) or up to 1µM (for the two more active dyes). The three dyes present potential as photosensitizers, differing in irradiation conditions and period of incubation in the presence of irradiated dye. The less active dye needs a longer irradiation period to exhibit phototoxicity which is only evident after longer period of contact with cells (24h). However, the remaining two more active dyes produce higher phototoxicity, even at shorter incubation periods (1h), with shorter irradiation time (7min). Although in different extents, these dyes show promising in vitro results as photosensitizers. Graphical abstract image
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Synthesis and pharmacological evaluation of novel chromone derivatives as balanced multifunctional agents against Alzheimer's disease ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Fan Li, Jia-Jia Wu, Jin Wang, Xue-Lian Yang, Pei Cai, Qiao-Hong Liu, Ling-Yi Kong, Xiao-Bing Wang In a continuing effort to develop multitargeted compounds as potential treatment agents against Alzheimer’s disease (AD), a series of chromone derivatives were designed, synthesized and evaluated. In vitro assay indicated that most of the target compounds have both MAOs inhibition activities, antioxidant activity and biometal chelating ability. Especially, compound s19 exhibits good inhibitory potency for inhibition of MAOs (IC50 value of 5.12μM for hMAO-A and 0.816μM for hMAO-B), moderate inhibition of Aβ aggregation (75.1% at 20μM), metal chelation, control of ROS generation and antioxidant activity (ORAC=3.62). In addition, s19 could reduce PC12 cells death induced by oxidative stress and penetrate the blood–brain barrier (BBB). Taken together, these results suggested that s19 might be a promising multitargeted compound for AD treatment. Graphical abstract image
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Structure-activity relationships for flavone interactions with amyloid β reveal a novel anti-aggregatory and neuroprotective effect of 2′,3′,4′-trihydroxyflavone (2-D08) ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Dylan T. Marsh, Sukanya Das, Jessica Ridell, Scott D. Smid Naturally-occurring flavonoids have well documented anti-aggregatory and neuroprotective properties against the hallmark toxic protein in Alzheimer’s disease, amyloid β (Aβ). However the extensive diversity of flavonoids has limited the insight into the precise structure-activity relationships that confer such bioactive properties against the Aβ protein. In the present study we have characterised the Aβ binding properties, anti-aggregatory and neuroprotective effects of a discreet set of flavones, including the recently described novel protein sumoylation inhibitor 2′,3′,4′-trihydroxyflavone (2-D08). Quercetin, transilitin, jaceosidin, nobiletin and 2-D08 were incubated with human Aβ1–42 for 48h in vitro and effects on Aβ fibrillisation kinetics and morphology measured using Thioflavin T (ThT) and electron microscopy respectively, in addition to effects on neuronal PC12 cell viability. Of the flavones studied, only quercetin, transilitin and 2-D08 significantly inhibited Aβ1–42 aggregation and toxicity in PC12 cells. Of those, 2-D08 was the most effective inhibitor. The strong anti-amyloid activity of 2-D08 indicates that extensive hydroxylation in the B ring is the most important determinant of activity against β amyloid within the flavone scaffold. The lack of efficacy of jaceosidin and nobiletin indicate that extension of B ring hydroxylation with methoxyl groups result in an incremental loss of anti-fibrillar and neuroprotective activity, highlighting the constraint to vicinal hydroxyl groups in the B ring for effective inhibition of aggregation. These findings reveal further structural insights into anti-amyloid bioactivity of flavonoids in addition to a novel and efficacious anti-aggregatory and neuroprotective effect of the semi-synthetic flavone and sumoylation inhibitor 2′,3′,4′-trihydroxyflavone (2-D08). Such modified flavones may facilitate drug development targeting multiple pathways in neurodegenerative disease. Graphical abstract image
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Synthesis and preliminary biological evaluation of radiolabeled 5-BDBD analogs as new candidate PET radioligands for P2X4 receptor ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Min Wang, Mingzhang Gao, Jill A. Meyer, Jonathan S. Peters, Hamideh Zarrinmayeh, Paul R. Territo, Gary D. Hutchins, Qi-Huang Zheng P2X4 receptor has become an interesting molecular target for treatment and PET imaging of neuroinflammation and associated brain diseases such as Alzheimer’s disease. This study reports the first design, synthesis, radiolabeling and biological evaluation of new candidate PET P2X4 receptor radioligands using 5-BDBD, a specific P2X4 receptor antagonist, as a scaffold. 5-(3-Hydroxyphenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD analog, [11C]9) and 5-(3-Bromophenyl)-1-[11C]methyl-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one (N-[11C]Me-5-BDBD, [11C]8c) were prepared from their corresponding desmethylated precursors with [11C]CH3OTf through N-[11C]methylation and isolated by HPLC combined with SPE in 30–50% decay corrected radiochemical yields with 370–1110GBq/µmol specific activity at EOB. 5-(3-[18F]Fluorophenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]F-5-BDBD, [18F]5a) and 5-(3-(2-[18F]fluoroethoxy)phenyl)-1,3-dihydro-2H-benzofuro[3,2-e][1,4]diazepin-2-one ([18F]FE-5-BDBD, [18F]11) were prepared from their corresponding nitro- and tosylated precursors by nucleophilic substitution with K[18F]F/Kryptofix 2.2.2 and isolated by HPLC-SPE in 5–25% decay corrected radiochemical yields with 111–740GBq/µmol specific activity at EOB. The preliminary biological evaluation of radiolabeled 5-BDBD analogs indicated these new radioligands have similar biological activity with their parent compound 5-BDBD. Graphical abstract image
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Development of WNK signaling inhibitors as a new class of antihypertensive drugs ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Mari Ishigami-Yuasa, Yuko Watanabe, Takayasu Mori, Hiroyuki Masuno, Shinya Fujii, Eriko Kikuchi, Shinichi Uchida, Hiroyuki Kagechika Pseudohypoaldosteronism type II (PHAII) is characterized by hyperkalemia and hypertension despite a normal glomerular filtration rate. Abnormal activation of the signal cascade of with-no-lysine kinase (WNK) with OSR1 (oxidative stress-responsive kinase 1)/SPAK (STE20/SPS1-related proline/alanine-rich kinase) and NCC (NaCl cotransporter) results in characteristic salt-sensitive hypertension. Thus, inhibitors of the WNK-OSR1/SPAK-NCC cascade are candidates for a new class of antihypertensive drugs. In this study, we developed novel inhibitors of this signal cascade from the 9-aminoacridine lead compound 1, one of the hit compounds obtained by screening our chemical library for WNK-SPAK binding inhibitors. Among the synthesized acridine derivatives, several acridine-3-amide and 3-urea derivatives, such as 10 (IC50: 6.9μM), 13 (IC50: 2.6μM), and 20 (IC50: 4.8μM), showed more potent inhibitory activity than the lead compound 1 (IC50: 15.4μM). Compounds 10 and 20 were confirmed to inhibit phosphorylation of NCC in vivo. Graphical abstract image
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Effect of the 3-halo substitution of the 2′-deoxy aminopyridinyl-pseudocytidine derivatives on the selectivity and stability of antiparallel triplex DNA with a CG inversion site ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Lei Wang, Yosuke Taniguchi, Hidenori Okamura, Shigeki Sasaki Triplex formation against a target duplex DNA has the potential to become a tool for the genome research. However, there is an intrinsic restriction on the duplex DNA sequences capable of forming the triplex DNA. Recently, we demonstrated the selective formation of the stable antiparallel triplexes containing the CG inversion sites using the 2′-deoxy-1-methylpseudocytidine derivative (ΨdC), whose amino group was conjugated with the 2-aminopyridine at its 5-position as an additional hydrogen bonding unit (AP-ΨdC). The 1-N of 2-aminopyridine was supposed to be protonated to form the hydrogen bond with the guanine of the CG inversion site. In this study, to test the effect of the 3-substitution of the 2-aminopyridine unit of AP-ΨdC on the triplex stability, we synthesized the 3-halogenated 2-aminopyridine derivatives of AP-ΨdC. The pKa values 1-N of the 2-aminopyridine unit of AP-ΨdC as the monomer nucleoside were determined to be 6.3 for 3-CH3 (MeAP-ΨdC), 6.1 for 3-H (AP-ΨdC), 4.3 for 3-Cl (ClAP-ΨdC), 4.4 for 3-Br (BrAP-ΨdC), and 4.7 for 3-I (IAP-ΨdC), suggesting that all the halogenated AP-ΨdCs are not protonated under neutral conditions. Interestingly, although the recognition selectivity depends on the sequence context, the TFO having the sequence of the 3′-G-(IAP-ΨdC)-A-5′ context showed the selective triplex formation with the CG inversion site. These results suggest that the protonation at the 1-N position plays an important role in the stable and selective triplex formation of AP-ΨdC derivatives in any sequences. Graphical abstract image
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Searching for novel N1-substituted benzimidazol-2-ones as non-nucleoside HIV-1 RT inhibitors ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Stefania Ferro, Maria Rosa Buemi, Laura De Luca, Fatima E. Agharbaoui, Christophe Pannecouque, Anna-Maria Monforte Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an integral part of the currently available combination antiretroviral therapy (cART) contributing to reduce the AIDS-mortality and turned the disease from lethal to chronic. In this context we recently reported a series of 6-chloro-1-(3-methylphenylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors. In this paper, we describe the design and the synthesis of two novel series of benzimidazolone analogues in which the linker moiety between the phenyl ring and the sulfonyl group was modified and new small lipophilic groups on the benzyl sulfonyl pendant were introduced. All the new obtained compounds were evaluated as RT inhibitors and were also tested against RTs containing single amino acid mutations. Finally, molecular docking studies were performed in order to rationalize the observed activity of the most promising compound. Graphical abstract image
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Halogen-substituted catechol bisphosphates are potent and selective inhibitors of the transcription factor STAT5b ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Nagarajan Elumalai, Kalaiselvi Natarajan, Thorsten Berg The transcription factor STAT5b is an antitumor target. Recently, we presented the small molecules Stafib-1 and Stafib-2 as potent, selective inhibitors of the STAT5b SH2 domain. Here we report that halogen substitutions on the terminal phenyl ring of Stafib-1 and a close derivative are tolerated and specificity over the STAT5a SH2 domain is maintained, albeit with a slight reduction in activity. Our data demonstrate that the synthetic methodology used for generating Stafib-1 and Stafib-2 can be utilized to synthesize a small library of halogen-substituted derivatives, and extend the panel of catechol bisphosphate-based submicromolar and selective STAT5b inhibitors. Graphical abstract image
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Synthesis and evaluation of c-di-4′-thioAMP as an artificial ligand for c-di-AMP riboswitch ()
Publication date: 15 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 14 Author(s): Kazuto Shiraishi, Noriko Saito-Tarashima, Yosuke Igata, Keiji Murakami, Yasuko Okamoto, Yoichiro Miyake, Kazuhiro Furukawa, Noriaki Minakawa Cyclic-di-adenosine monophosphate (c-di-AMP) is a bacterial second messenger that binds to an RNA receptor called riboswitch and regulates its downstream genes involving cell wall metabolism, ion transport, and spore germination. Therefore, the c-di-AMP riboswitch can be a novel target of antibiotics. In this study, we synthesized c-di-4′-thioAMP (1), which possesses a sulfur atom instead of an oxygen atom in the furanose ring, as a candidate of a bioisoster for natural c-di-AMP. The resulting 1 bound to the c-di-AMP riboswitch with a micromolar affinity (34.8μM), and the phosphodiesterase resistance of 1 was >12-times higher than that of c-di-AMP. Thus, 1 can be considered to be a stable ligand against a c-di-AMP riboswitch. Graphical abstract image
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Editorial board ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13
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Medicinal chemistry of antischistosomal drugs: Praziquantel and oxamniquine ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Vinícius Barros Ribeiro da Silva, Bruna Rafaella Koresch Leiva Campos, Jamerson Ferreira de Oliveira, Jean-Luc Decout, Maria do Carmo Alves de Lima Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a strong barrier to a country development. Schistosomiasis, a NTD, is a tropical and subtropical disease caused by the trematode Schistosoma mansoni (Africa, Middle East, Caribbean, Brazil, Venezuela, Suriname), japonicum (China, Indonesia, the Philippines), mekongi (several districts of Cambodia and the Lao People's Democratic Republic), intercalatum and guianensis (areas of tropical rainforests in Central Africa) and hematobium (Middle East Africa, Corsica, France) whose adult forms inhabit the mesenteric vessels of the host, while the intermediate forms are found in the aquatic gastropod snails of the genus Biomphalaria. Currently, praziquantel (PZQ) is the first line drug chosen for the treatment of schistosomiasis according to the World Health Organization (WHO) Model List of Essential Medicines, 2015. PZQ chemotherapy is considered to be the most important development for decades in the treatment of schistosomiasis. Beside the PZQ, oxamniquine (OXA) has been first described in 1969 and launched in Brazil by Pfizer under the name of Mansil® for oral administration. It has a lower cost when compared to PZQ, being active in the intestinal and hepatosplenic infections caused exclusively by S. mansoni, single species in Brazil. Both PZQ and OXA have limitations, as low efficacy in the treatment of acute schistosomiasis, low activity against S. mansoni in immature stages and resistance or tolerance, which is the reason why further research are still necessary for the development of a second generation of antischistosomal drugs. For the development of new PZQ analogs, three main strategies can be adopted: (a) synthesis and evaluation of PZQ analogues; (b) rational design of new pharmacophores; (c) discovery of new active compounds from screening programs on a large scale. Such (b) approach is difficult as the target of PZQ still unknown, the synthesis of new active analogues is possible from delineation of structure-activity relationships for PZQ. Thus, we proposed for a review article an accurate analysis of PZQ and OXA medicinal properties and uses, focusing on the pharmacochemical aspects of both drugs through 178 bibliographic references. The mechanisms of action will be discussed, with the latest information available in the literature (for the first time in the case of the oxamniquine). Cases of resistance are also discussed. As both drugs are available as a racemic mixture the biological impact of their stereochemistry to activity and side effects are reviewed. The results obtained for the combination of PZQ and artemisinin derivatives against immature worms are also introduced in the discussion. Using the information about more than 200 PZQ new derivatives synthetized during almost 35years since its discovery, a deep structure-activity relationship (SAR) is also proposed in this study. Graphical abstract image
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Lathyrol and epoxylathyrol derivatives: Modulation of Cdr1p and Mdr1p drug-efflux transporters of Candida albicans in Saccharomyces cerevisiae model ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Andreia Mónico, Shweta Nim, Noélia Duarte, Manpreet Kaur Rawal, Rajendra Prasad, Attilio Di Pietro, Maria-José U. Ferreira Macrocyclic diterpenes were previously found to be able to modulate the efflux pump activity of Candida albicans multidrug transporters. Most of these compounds were jatrophanes, but only a few number of lathyrane-type diterpenes was evaluated. Therefore, the aim of this study was to evaluate the ability of nineteen structurally-related lathyrane diterpenes (1–19) to overcome the drug-efflux activity of Cdr1p and Mdr1p transporters of C. albicans, and get some insights on their structure-activity relationships. The transport assay was performed by monitoring Nile Red (NR) efflux in a Saccharomyces cerevisiae strain overexpressing the referred efflux pumps from C. albicans. Moreover, a chemosensitization assay was performed in order to evaluate the type of interaction between the inhibitory compounds and the antifungal drug fluconazole. Compounds 1–13 were previously isolated from Euphorbia boetica or obtained by derivatization, and compounds 14–19 were prepared by chemical transformations of compound 4. In the transport assays, compounds 14–19 revealed the strongest inhibitory activity of the Cdr1p efflux pump, ranging from 65 to 85%. Concerning Mdr1p efflux pump, the most active compounds were 1, 3, 6, 8, and 12 (75–85%). When used in combination with fluconazole, epoxyboetirane K (2) and euphoboetirane N (18) revealed synergistic effects in the AD-CDR1 yeast strain, overexpressing the Cdr1p transporter, through their ability to reduce the effective concentration of the antifungal drug by 23- and 52-fold, respectively. Graphical abstract image
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Design and synthesis of 1,2,3-triazolo linked benzo[d]imidazo[2,1-b]thiazole conjugates as tubulin polymerization inhibitors ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Siddiq Pasha Shaik, M.V.P.S. Vishnuvardhan, Faria Sultana, A.V. Subba Rao, Chandrakant Bagul, Debanjan Bhattacharjee, Jeevak Sopanrao Kapure, Nishant Jain, Ahmed Kamal 1,2,3-Triazolo linked benzo[d]imidazo[2,1-b]thiazole conjugates (5a–v) were designed, synthesized and evaluated for their cytotoxic potency against some human cancer cell lines like DU-145 (prostate), HeLa (cervical), MCF-7 (breast) HepG2 (liver) and A549 (lung). Preliminary results revealed that some of these conjugates like 5f and 5k exhibited significant antiproliferative effect against human breast cancer cells (MCF-7) with IC50 values of 0.60 and 0.78µM respectively. Flow cytometric analysis of the cell cycle demonstrated an increase in the percentage of cells in the G2/M phase which was further authenticated by elevation of cyclin B1 protein levels. Immunocytochemistry revealed loss of intact microtubule structure in cells treated with 5f and 5k, and western blot analysis revealed that these conjugates accumulated more tubulin in the soluble fraction. Moreover, the conjugates caused apoptosis of the cells that was confirmed by mitochondrial membrane potential and Annexin V-FITC assay. Molecular docking studies indicated that these conjugates occupy the colchicine binding site of the tubulin protein. Graphical abstract image
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Identification of a novel fluoropyrrole derivative as a potassium-competitive acid blocker with long duration of action ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Haruyuki Nishida, Yasuyoshi Arikawa, Keizo Hirase, Toshihiro Imaeda, Nobuhiro Inatomi, Yasunobu Hori, Jun Matsukawa, Yasushi Fujioka, Teruki Hamada, Motoo Iida, Mitsuyoshi Nishitani, Akio Imanishi, Hideo Fukui, Fumio Itoh, Masahiro Kajino With the aim to find a novel long-lasting potassium-competitive acid blocker (P-CAB) that would perfectly overcome the limitations of proton pump inhibitors (PPIs), we tried various approaches based on pyrrole derivative 1b as a lead compound. As part of a comprehensive approach to identification of a new drug, we explored excellent compounds that have low lipophilicity by introducing a polar hetero-aromatic group at position 5 of the pyrrole ring. Among the compounds synthesized, fluoropyrrole derivative 37c, which has a 2-F-3-Py group at the fifth position, lower pKa, and much lower ClogP and logD values than 1b dose, showed potent gastric-acid suppressive action resulting from gastric H+,K+-ATPase inhibition in animal models. Its maximum intragastric pH elevation effect was strong in rats, and its duration of action was much longer than that of either lansoprazole or lead compound 1b in dogs. Therefore, compound 37c can be considered a promising new P-CAB with long duration of action. Graphical abstract image
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Design and optimization of purine derivatives as in vivo active PDE10A inhibitors ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Liu Chen, Danqi Chen, Le Tang, Jing Ren, Jiaojiao Chen, Xuechu Zhen, Yu-Chih Liu, Chenhua Zhang, Haibin Luo, Jingkang Shen, Bing Xiong Phosphodiesterases are important enzymes regulating signal transduction mediated by second messenger molecules cAMP or cGMP. PDE10A is a unique member in the PDE family because of its selective expression in medium spiny neurons. It is recognized as anti-psychotic drug target. Based on the structural similarity between our previous chemistry work on 8-aminoimidazo[1,2-a]pyrazines and the PDE10A inhibitors reported by Bartolome-Nebreda et al., we initialized a project for developing PDE10A inhibitors. After several rounds of optimization, we were able to obtain a few compounds with good PDE10A enzymatic activity. And after further PDE enzymatic selectivity study, metabolic stability assay and in vivo pharmacological tests we identified two inhibitors as interesting lead compounds with the potential for further PDE10A lead optimizatioin. Graphical abstract image
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Synthesis and biological evaluation of novel selective androgen receptor modulators (SARMs) Part III: Discovery of 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2f as a clinical candidate ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Katsuji Aikawa, Moriteru Asano, Koji Ono, Noriyuki Habuka, Jason Yano, Keith Wilson, Hisashi Fujita, Hitoshi Kandori, Takahito Hara, Megumi Morimoto, Takashi Santou, Masuo Yamaoka, Masaharu Nakayama, Atsushi Hasuoka We previously reported that 4-(pyrrolidin-1-yl)benzonitrile derivative 1b was a selective androgen receptor modulator (SARM) that exhibited anabolic effects on organs such as muscles and the central nervous system (CNS), but neutral effects on the prostate. From further modification, we identified that 4-(5-oxopyrrolidine-1-yl)benzonitrile derivative 2a showed strong AR binding affinity with improved metabolic stabilities. Based on these results, we tried to enhance the AR agonistic activities by modifying the substituents of the 5-oxopyrrolidine ring. As a consequence, we found that 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-(trifluoromethyl)benzonitrile (2f) had ideal SARM profiles in Hershberger assay and sexual behavior induction assay. Furthermore, 2f showed good pharmacokinetic profiles in rats, dogs, monkeys, excellent nuclear selectivity and acceptable toxicological profiles. We also determined its binding mode by obtaining the co-crystal structures with AR. Graphical abstract image
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Alkyne-linked reduction-activated protecting groups for diverse functionalization on the backbone of oligonucleotides ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Hisao Saneyoshi, Kazuhiko Kondo, Koichi Iketani, Akira Ono A versatile conjugatable/bioreduction-responsive protecting group for phosphodiester moieties was designed, synthesized and incorporated into oligonucleotide strands. Subsequently, controlled pore glass-supported oligonucleotides were conjugated to a variety of functional molecules using a copper-catalyzed azide-alkyne cycloaddition reaction. The functionalized protecting groups were deprotected by a nitroreductase/NADH reduction system to give “naked” oligonucleotides. This method allowed the synthesis of oligonucleotide prodrugs bearing the functionalized protecting group at the desired sites and desired residues on oligodeoxyribonucleotide (ODN) backbones. Graphical abstract image
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Synthesis and cytotoxic activity of new artemisinin hybrid molecules against human leukemia cells ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Antonios S. Letis, Ean-Jeong Seo, Sotiris S. Nikolaropoulos, Thomas Efferth, Athanassios Giannis, Manolis A. Fousteris A series of new artemisinin-derived hybrids which incorporate cholic acid moieties have been synthesized and evaluated for their antileukemic activity against sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 cells. The new hybrids 20–28 showed IC50 values in the range of 0.019µM–0.192µM against CCRF-CEM cells and between 0.345µM and 7.159µM against CEM/ADR5000 cells. Amide hybrid 25 proved the most active compound against both CCRF-CEM and CEM/ADR5000 cells with IC50 value of 0.019±0.001µM and 0.345±0.031µM, respectively. A relatively low cross resistance to hybrids 20–28 in the range of 5.7-fold to 46.1-fold was measured. CEM/ADR5000 cells showed higher resistance than CCRF-CEM to all the tested compounds. Interestingly, the lowest cross resistance to 23 was observed (5.7-fold), whereas hybrid 25 showed 18.2-fold cross-resistant to CEM/ADR5000 cells. Hybrid 25 which proved even more potent than clinically used doxorubicin against CEM/ADR5000 cells may serve as a promising antileukemic agent against both sensitive and multidrug-resistant cells. Graphical abstract image
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Antioxidant and anticholinesterase potential of diterpenoid alkaloids from Aconitum heterophyllum ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Hanif Ahmad, Shujaat Ahmad, Syed Adnan Ali Shah, Abdul Latif, Mumtaz Ali, Farman Ali Khan, Muhammad Nawaz Tahir, Farzana Shaheen, Abdul Wadood, Manzoor Ahmad Extensive chromatographic separations performed on the basic (pH=8–10) chloroform soluble fraction of Aconitum heterophyllum resulted in the isolation of three new diterpenoid alkaloids, 6β-Methoxy, 9β-dihydroxylheteratisine (1), 1α,11,13β-trihydroxylhetisine (2), 6,15β-dihydroxylhetisine (3), and the known compounds iso-atisine (4), heteratisine (5), hetisinone (6), 19-epi-isoatisine (7), and atidine (8). Structures of the isolated compounds were established by means of mass and NMR spectroscopy as well as single crystal X-ray crystallography. Compounds 1–8 were screened for their antioxidant and enzyme inhibition activities followed by in silico studies to find out the possible inhibitory mechanism of the tested compounds. This work is the first report demonstrating significant antioxidant and anticholinesterase potentials of diterpenoid alkaloids isolated from a natural source. Graphical abstract image
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Inhibition of amyloid β aggregation and protective effect on SH-SY5Y cells by triterpenoid saponins from the cactus Polaskia chichipe ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Koji Fujihara, Shin Koike, Yuki Ogasawara, Kunio Takahashi, Kiyotaka Koyama, Kaoru Kinoshita Alzheimer’s disease (AD) destroys brain function, especially in the hippocampus, and is a social problem worldwide. A major pathogenesis of AD is related to the accumulation of amyloid beta (Aβ) peptides, resulting in neuronal cell death in the brain. Here, we isolated four saponins (1–4) and elucidated their structures from 1D and 2D NMR and HRFABMS spectral data. The structures of 1 and 2 were determined as new saponins which have cochalic acid as the aglycon, and 3 was determined as a new saponin with oleanolic acid as the aglycon. Compound 4 was confirmed as the known saponin chikusetsusaponin V (=ginsenoside R0). Isolated saponins (1–4) and six previously reported saponins (5–10) were tested for their inhibitory effects of Aβ aggregation and their protective effects on SH-SY5Y cells against Aβ-associated toxicity. As the results, compounds 3 and 4 showed inhibitory effect of Aβ aggregation and compounds 5–8 exerted the protective effects on SH-SY5Y cells against Aβ-associated toxicity. Graphical abstract image
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Lipase-catalyzed kinetic resolution as key step in the synthesis of enantiomerically pure σ ligands with 2-benzopyran structure ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Inga Knappmann, Kirstin Lehmkuhl, Jens Köhler, Dirk Schepmann, Martin Giera, Franz Bracher, Bernhard Wünsch In order to obtain enantiomerically pure σ1 receptor ligands with a 2-benzopyran scaffold an Oxa-Pictet-Spengler reaction with the enantiomerically pure 2-phenylethanol derivatives (R)-4 and (S)-4 was envisaged. The kinetic resolution of racemic alcohol (±)-4 using Amano Lipase PS-C II and isopropenyl acetate in tert-butyl methyl ether led to the (R)-configured alcohol (R)-4 in 42% yield with an enantiomeric excess of 99.6%. The (S)-configured alcohol (S)-4 was obtained by Amano Lipase PS-C II catalyzed hydrolysis of enantiomerically enriched acetate (S)-5 (76.9% ee) and provided (S)-4 in 26% yield and 99.7% ee. The absolute configuration of alcohol (R)-4 was determined by exciton coupled CD spectroscopy of the bis(bromobenzoate) (R)-7. The next important step for the synthesis of 2-benzopyrans 2 and 3 was the Oxa-Pictet-Spengler reaction of the enantiomerically pure alcohols (R)-4 and (S)-4 with piperidone ketal 8 and chloropropionaldehyde acetal 12. The conformationally restricted spirocyclic 2-benzopyrans 2 revealed higher σ1 affinity than the more flexible aminoethyl derivatives 3. The (R)- and (R,R)-configured enantiomers (R)-2 and (R,R)-3 represent the eutomers of this class of compounds with eudismic ratios of 4.8 (2b) and 4.5 (2c). High σ1/σ2 selectivity (>49) was found for the most potent σ1 ligands (R)-2b, (R)-2c, (R)-2d, and (S)-2d (K i(σ1) 9–15nM). Graphical abstract image
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Synthesis and biological activity of new phthalimides as potential anti-inflammatory agents ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Duc-Hiep Bach, Jian-Yu Liu, Won Kyung Kim, Ji-Young Hong, So Hyun Park, Donghwa Kim, Si-Ning Qin, Thi-Thu-Trang Luu, Hyen Joo Park, Yong-Nan Xu, Sang Kook Lee The overproduction of nitric oxide (NO) plays an important role in a variety of pathophysiological processes, including inflammation. Therefore, the suppression of NO production is a promising target in the design of anti-inflammatory agents. In the present study, a series of phthalimide analogs was synthesized, and their anti-inflammatory activities were evaluated using lipopolysaccharide (LPS)-stimulated NO production in cultured murine macrophage RAW264.7 cells. A structure-activity relationship study showed that the free hydroxyl group at C-4 and C-6 and the bulkiness of the N-substituted alkyl chain are associated with biological activity. Among the series of phthalimide derivatives, compound IIh exhibited potent inhibitory activity, with an IC50 value of 8.7µg/mL. Further study revealed that the inhibitory activity of compound IIh was correlated with the down-regulation of the mRNA and protein expression of LPS-stimulated inducible nitric oxide synthase (iNOS). Compound IIh also suppressed the induction of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β in LPS-stimulated RAW 264.7 cells. The anti-inflammatory activity of compound IIh was also found to be associated with the suppression of the Toll-like receptor (TLR)4 signaling pathway by down-regulating the activation of interferon regulatory factor 3 (IRF-3) and interferon-β and signal transducer expression. These findings demonstrate that novel phthalimides might be potential candidates for the development of anti-inflammatory agents. Graphical abstract image
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Identification of novel 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazoles: Lead generation and optimization toward potent and orally active EP1 receptor antagonists ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Kentaro Umei, Yosuke Nishigaya, Kazuya Tatani, Yasushi Kohno, Nobuyuki Tanaka, Shigeki Seto Herein we described the design, synthesis and evaluation of a novel series of benzo[d]thiazole derivatives toward an orally active EP1 antagonist. Lead generation studies provided benzo[d]thiazole core from the four designed scaffolds. Optimization of this scaffold in terms of EP1 antagonist potency and ligand-lipophilicity efficiency (LLE; pIC50-clogP) led to a 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazole derivative, 7r (IC50 1.1nM; LLE 4.7), which showed a good pharmacological effect when administered intraduodenally in a 17-phenyl trinor-PGE2 (17-PTP)-induced overactive bladder model in rats. Graphical abstract image
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Development of the optical sensor for discriminating isomers of fatty acids based on emissive network polymers composed of polyhedral oligomeric silsesquioxane ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Hayato Narikiyo, Takahiro Kakuta, Hiroki Matsuyama, Masayuki Gon, Kazuo Tanaka, Yoshiki Chujo It was shown that water-soluble network polymers composed of polyhedral oligomeric silsesquioxane (POSS) had hydrophobic spaces inside the network because of strong hydrophobicity of the cubic silica cage. In this study, the water-soluble POSS network polymers connected with triphenylamine derivatives (TPA-POSS) were synthesized, and their functions as a sensor for discriminating the geometric isomers of fatty acids were investigated. Accordingly, in the photoluminescence spectra, different time-courses of intensity and peak wavelengths of the emission bands were detected from the TPA-POSS-containing solution in the presence of cis- or trans-fatty acids during incubation. Furthermore, variable time-dependent changes were obtained by changing coexisting ratios between two geometric isomers. From the mechanistic investigation, it was implied that these changes could be originated from the difference in the degree of interaction between the POSS networks and each fatty acid. Our data could be applicable for constructing a sensing material for generation and proportion of trans-fatty acids in the oil. Graphical abstract image
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Synthesis and biological research of novel azaacridine derivatives as potent DNA-binding ligands and topoisomerase II inhibitors ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Dan Li, Zigao Yuan, Shaopeng Chen, Cunlong Zhang, Lu Song, Chunmei Gao, Yuzong Chen, Chunyan Tan, Yuyang Jiang DNA and DNA-related enzymes are one of the most effective and common used intracellular anticancer targets in clinic and laboratory studies, however, most of DNA-targeting drugs suffered from toxic side effects. Development of new molecules with good antitumor activity and low side effects is important. Based on computer aided design and our previous studies, a series of novel azaacridine derivatives were synthesized as DNA and topoisomerases binding agents, among which compound 9 displayed the best antiproliferative activity with an IC50 value of 0.57μM against U937 cells, which was slightly better than m-AMSA. In addition, compound 9 displayed low cytotoxicity against human normal liver cells (QSG-7701), the IC50 of which was more than 3 times lower than m-AMSA. Later study indicated that all the compounds displayed topoisomerases II inhibition activity at 50μM. The representative compound 9 could bind with DNA and induce U937 apoptosis through the exogenous pathway. Graphical abstract image
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Exploration of pyrrole derivatives to find an effective potassium-competitive acid blocker with moderately long-lasting suppression of gastric acid secretion ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Haruyuki Nishida, Ikuo Fujimori, Yasuyoshi Arikawa, Keizo Hirase, Koji Ono, Kazuo Nakai, Nobuhiro Inatomi, Yasunobu Hori, Jun Matsukawa, Yasushi Fujioka, Akio Imanishi, Hideo Fukui, Fumio Itoh With the aim to discover a novel excellent potassium-competitive acid blocker (P-CAB) that could perfectly overcome the limitations of proton pump inhibitors (PPIs), we tested various approaches based on pyrrole derivative 1 as a lead compound. As part of a comprehensive approach to identify a new effective drug, we tried to optimize the duration of action of the pyrrole derivative. Among the compounds synthesized, fluoropyrrole derivative 20j, which has a 2-F-3-Py group at position 5, fluorine atom at position 4, and a 4-Me-2-Py sulfonyl group at the first position of the pyrrole ring, showed potent gastric acid-suppressive action and moderate duration of action in animal models. On the basis of structural properties including a slightly larger ClogP value (1.95), larger logD value (0.48) at pH 7.4, and fairly similar pKa value (8.73) compared to those of the previously optimized compound 2a, compound 20j was assumed to undergo rapid transfer to the stomach and have a moderate retention time there after single administration. Therefore, compound 20j was selected as a new promising P-CAB with moderately long duration of action. Graphical abstract image
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Development of nonsteroidal glucocorticoid receptor modulators based on N-benzyl-N-(4-phenoxyphenyl)benzenesulfonamide scaffold ()
Publication date: 1 July 2017 Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 13 Author(s): Hiromasa Yoshioka, Ayumi Yamada, Yuko Nishiyama, Hiroyuki Kagechika, Yuichi Hashimoto, Shinya Fujii N-Benzyl-N-(4-phenoxyphenyl)benzenesulfonamide derivatives were developed as a novel class of nonsteroidal glucocorticoid receptor (GR) modulators, which are promising drug candidates for treating immune-related disorders. Focusing on the similarity of the GR and progesterone receptor (PR) ligand-binding domain (LBD) structures, we adopted our recently developed PR antagonist 10 as a lead compound and synthesized a series of derivatives. We found that the N-(4-phenoxyphenyl)benzenesulfonamide skeleton serves as a versatile scaffold for GR antagonists. Among them, 4-cyano derivative 14m was the most potent, with an IC50 value of 1.43μM for GR. This compound showed good selectivity for GR; it retained relatively weak antagonistic activity toward PR (IC50 for PR: 8.00μM; 250-fold less potent than 10), but showed no activity toward AR, ERα or ERβ. Interestingly, the 4-amino derivative 15a exhibited transrepression activity toward NF-κB in addition to GR-antagonistic activity, whereas 14m did not. The structure-activity relationship for transrepression was different from that for GR-antagonistic activity. Computational docking simulations suggested that 15a might bind to the ligand-binding pocket of GR in a different manner from 14m. These findings open up new possibilities for developing novel nonsteroidal GR modulators with distinctive activity profiles. Graphical abstract image
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