Bioorganic & Medicinal Chemistry Letters

Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR and α-glucosidase ()
Publication date: Available online 18 August 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Yaling Zhang, Hongliang Gao, Renjie Liu, Juan Liu, Li Chen, Xiabing Li, Lijun Zhao, Wei Wang, Baolin Li A series of novel quinazoline-1-deoxynojirimycin hybrids were designed, synthesized and evaluated for their inhibitory activities against two drug target enzymes, epidermal growth factor receptor (EGFR) tyrosine kinase and α-glucosidase. Some synthesized compounds exhibited significantly inhibitory activities against the tested enzymes. Comparing with reference compounds gefitinib and lapatinib, compounds 7d, 8d, 9b and 9d showed higher inhibitory activities against EGFR (IC50: 1.79 ∼ 10.71 nM). Meanwhile the inhibitory activities of 7d, 8d and 9c against α-glucosidase (IC50 = 0.14, 0.09 and 0.25 µM, respectively) were obvious higher than that of miglitol (IC50 = 2.43 µM), a clinical using α-glucosidase inhibitor. Interestingly, compound 9d as a dual inhibitor showed high inhibitory activity to EGFRwt tyrosine kinase (IC50 = 1.79 nM), also to α-glucosidase (IC50 = 0.39 µM). The work could be very useful starting point for developing a new series of enzyme inhibitors targeting EGFR and/or α-glucosidase. Graphical abstract image
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Design, synthesis and preliminary antiproliferative activity studies of new diheteroaryl thioether derivatives ()
Publication date: Available online 18 August 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Zhong-Hua Li, Xue-Qi Liu, Tao-Qian Zhao, Peng-Fei Geng, Ying Liu, Bing Zhao, Wen-Ge Guo, Bin Yu, Hong-Min Liu A series of structurally new diheteroaryl thioether analogs was designed, prepared and screened toward MGC-803, MKN-45, EC-109 and H1650. Most of the target compounds displayed moderate to potent antiproliferative activities. Among them, compound 5 showed the best antiproliferative activity against the tested cell lines with the half maximal inhibitory concentration (IC50) values below 10 μM. In addition, flow cytometry analysis showed that compound 5 increased Bax expression, down-regulated expression of Bcl-2, cleaved caspases-3/9, finally inducing apoptosis of MKN-45 cells as well as arrested the cell cycle at G2/M phase. This study suggests that the diheteroaryl thioethers are a class of emerging chemotypes for developing antitumor agents or biological probes, and compound 5 could serve as a good starting point to design new apoptosis inducers. Graphical abstract image
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Evaluation of tetraether lipid-based liposomal carriers for encapsulation and retention of nucleoside-based drugs ()
Publication date: Available online 16 August 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Valentina Paolucci, Geoffray Leriche, Takaoki Koyanagi, Jerry Yang Although liposomal nanoparticles are one of the most versatile class of drug delivery systems, stable liposomal formulation of small neutral drug molecules still constitutes a challenge due to the low drug retention of current lipid membrane technologies. In this study, we evaluate the encapsulation and retention of seven nucleoside analog-based drugs in liposomes made of archaea-inspired tetraether lipids, which are known to enhance packing and membrane robustness compared to conventional bilayer-forming lipids. Liposomes comprised of the pure tetraether lipid generally showed improved retention of drugs (up to 4-fold) compared with liposomes made from a commercially available diacyl lipid. Interestingly, we did not find a significant correlation between the liposomal leakage rates of the molecules with typical parameters used to assess lipophilicity of drugs (such logD or topological polar surface area), suggesting that specific structural elements of the drug molecules can have a dominant effect on leakage from liposomes over general lipophilic character. Graphical abstract image
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Synthesis of some monosaccharide-related ester derivatives as insecticidal and acaricidal agents ()
Publication date: Available online 16 August 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Xiaobo Huang, Bingchuan Zhang, Hui Xu To develop natural-product-based pesticidal agents, a series of monosaccharide-related ester derivatives (17a-q and 18a-f), glucose (xylose)-piperic acid/piperic acid-like conjugates, were synthesized. Three-dimensional structures of compounds 17b, 17g, 17h, and 17n were unambiguously determined by single-crystal X-ray diffraction. Especially compounds 18e and 18f exhibited the most potent insecticidal and acaricidal activities against Mythimna separata and Tetranychus cinnabarinus. Their structure-activity relationships were also discussed. Graphical abstract image
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Synthesis of novel forskolin isoxazole derivatives with potent anti-cancer activity against breast cancer cell lines ()
Publication date: Available online 16 August 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Srinivas Burra, Vani Voora, Ch. Prasad Rao, P. Vijay Kumar, Rama Krishna Kancha, G.L. David Krupadanam Forskolin C1-isoxazole derivatives (3,5-regioisomers) (11a-e, 14,15a-h and 15,16a-g) were synthesized regioselectively by adopting 1,3-dipolar cycloadditions. These derivatives were tested using estrogen receptor positive breast cancer cell lines MCF-7 and BT-474. Majority of the compounds exhibited activity against the p53-positive MCF-7 breast cancer cells but not against the p53-negative BT-474 breast cancer cells. Among forskolin derivatives, compounds 11a, 11c, 14a, 14f, 14g, 14h, 15b, 16g and 17b exhibited higher anti-cancer activity against MCF-7 cell line with an IC50 ≤ 1µM. The derivative 14f exhibited highest activity in both p53-positive (MCF-7) and p53-negative (BT-474) breast cancer cell lines with an IC50 of 0.5µM. Graphical abstract image
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The discovery of IDX21437: design, synthesis and antiviral evaluation of 2’-α-chloro-2’-β-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors ()
Publication date: Available online 16 August 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): François-René Alexandre, Eric Badaroux, John P. Bilello, Stéphanie Bot, Tony Bouisset, Guillaume Brandt, Sylvie Cappelle, Christopher Chapron, Dominique Chaves, Thierry Convard, Clément Counor, Daniel Da Costa, David Dukhan, Marion Gay, Gilles Gosselin, Jean-François Griffon, Kusum Gupta, Brenda Hernandez-Santiago, Massimiliano LaColla, Marie-Pierre Lioure, Julien Milhau, Jean-Laurent Paparin, Jérôme Peyronnet, Christophe Parsy, Claire Pierra Rouvière, Houcine Rahali, Rachid Rahali, Aurélien Salanson, Maria Seifer, Ilaria Serra, David Standring, Dominique Surleraux, Cyril B. Dousson Herein we describe the discovery of IDX21437 35b, a novel RP D-aminoacid-based phosphoramidate prodrug of 2’-α-chloro-2’-β-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection. Graphical abstract image
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Synthesis and optimization of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as potent and orally-active metabotropic glutamate receptor 5 negative allosteric modulators ()
Publication date: Available online 16 August 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Wataru Hirose, Yoshihiro Kato, Itaru Natsutani, Makoto Takata, Maiko Kitaichi, Satoki Imai, Shun Hayashi, Yukiyo Arai, Kohei Hoshino, Kohzo Yoshida We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0.3 mg/kg, q.d.). Graphical abstract image
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Editorial board ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16
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GPCRs and EGFR – Cross-talk of membrane receptors in cancer ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Meryem Köse G protein-coupled receptors (GPCRs) and receptor-tyrosine kinases (RTKs) are two important classes of cell surface receptors proven to be highly tractable as drug targets. Both receptor classes are involved in various complex (patho-) physiological processes in the human body including cellular growth and differentiation. More recently, accumulating data suggest that GPCR-induced activation of EGFR, the prototyp of RTKs represents a major mechanism in various cancers. The present review will focus on this cross-talk with particular emphasis on intracellular scaffold proteins regulating EGFR transactivation. It will give an overview about the current status of the research and future directions, highlight recent trends in the field, and discuss the potential of therapeutic strategies combining GPCR and EGFR targeting on the one hand and specific targeting of the cross-talk on the other hand in cancer therapy. Graphical abstract image
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Influence of the cellular environment on ligand binding kinetics at membrane-bound targets ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Patrick M.L. Vanderheyden, Nerdjes Benachour While historically ‘in vitro’ binding data were obtained by analyzing equilibrium experiments, kinetic data are increasingly appreciated to provide information on the time a particular compound remains bound to its target. This information is of biological importance to understand the molecular mechanism of a drug not only to evaluate the time a particular receptor/enzyme is blocked in the case of antagonists/inhibitors but also to investigate its contribution to the efficacy to mediate signaling in the case of agonists. There is accumulating evidence that many drugs binding to either membrane-bound receptors or enzymes are found to display long duration of action which can be ascribed to slow dissociation from their target proteins. In the present review three such examples are discussed which encompass ligands that bind to membrane-bound proteins and from which it appears that the tight binding kinetics is influenced by the cellular/membrane environment of the target protein.
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Novel 1,2-dihydroquinazolin-2-ones: Design, synthesis, and biological evaluation against Trypanosoma brucei ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): ThanhTruc Pham, Madeline Walden, Christopher Butler, Rosario Diaz-Gonzalez, Guiomar Pérez-Moreno, Gloria Ceballos-Pérez, Veronica Gomez-Pérez, Raquel García-Hernández, Henry Zecca, Emma Krakoff, Brian Kopec, Ogar Ichire, Caden Mackenzie, Marika Pitot, Luis Miguel Ruiz, Francisco Gamarro, Dolores González-Pacanowska, Miguel Navarro, Amy B. Dounay In 2014, a published report of the high-throughput screen of>42,000 kinase inhibitors from GlaxoSmithKline against T. brucei identified 797 potent and selective hits. From this rich data set, we selected NEU-0001101 (1) for hit-to-lead optimization. Through our preliminary compound synthesis and SAR studies, we have confirmed the previously reported activity of 1 in a T. brucei cell proliferation assay and have identified alternative groups to replace the pyridyl ring in 1. Pyrazole 24 achieves improvements in both potency and lipophilicity relative to 1, while also showing good in vitro metabolic stability. The SAR developed on 24 provides new directions for further optimization of this novel scaffold for anti-trypanosomal drug discovery. Graphical abstract image
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Discovery and structure-activity relationship of auriculatone: A potent hepatoprotective agent against acetaminophen-induced liver injury ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Meng Zhou, Min Wang, Rui-Feng Zhong, Xiang-Ming Liao, Lian-Li Deng, Guo-Bo Xu, Xun He, Jing Li, Yong-Jun Li, Ting Liu, Yong-Lin Wang, Shang-Gao Liao Acetaminophen (APAP, paracetamol) overdose has been the most frequent cause of drug-induced liver failure. APAP-induced liver toxicity can be fatal in many cases even with treatment of the clinically used N-acetylcysteine (NAC), and the need for novel therapeutic agents is apparent. Through evaluating the hepatoprotective effects of the co-occurring substances present in oleanolic acid tablets which have been used in China for decades as an adjuvant therapy for acute and chronic hepatitis, auriculatone was found to protect HL-7702 cells from APAP-induced liver injury comparable to NAC at the concentration of 10μM. Structure activity relationship on auriculatone and its analogs showed that absence of the C17 carboxyl group of auriculatone was essential to achieve good hepatoprotective activity, and that the C3-OH, C16 carbonyl and C12-C13 olefinic group were critical for retaining the exceptional activity of auriculatone. Any modifications in the current investigation were all detrimental to the hepatoprotective activity. Docking and drug-metabolizing activity studies demonstrated that CYP3A4 was likely the main target of auriculatone, and that auriculatone elicited the hepatoprotective effect possibly through inhibiting CYP3A4’s metabolism of APAP to the toxic metabolite NAPQI. The work may pave the way for the use of auriculatone in the treatment of APAP-induced liver injury. Graphical abstract image
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Design, synthesis and in vitro anti-mycobacterial evaluation of gatifloxacin-1H-1,2,3-triazole-isatin hybrids ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Zhi Xu, Shu Zhang, Xufeng Song, Min Qiang, Zaosheng Lv A set of novel gatifloxacin-1H-1,2,3-triazole-isatin hybrids 6a-l was designed, synthesized and evaluated for their in vitro anti-mycobacterial activities against M. tuberculosis (MTB) H37Rv and MDR-TB as well as cytotoxicity. The results showed that all the targets (MIC: 0.025–3.12μg/mL) exhibited excellent inhibitory activity against MTB H37Rv and MDR-TB, but were much more toxic (CC50: 7.8–62.5μg/mL) than the parent gatifloxacin (GTFX) (CC50: 125μg/mL). Among them, 61 (MIC: 0.025μg/mL) was 2–32 times more potent in vitro than the references INH (MIC: 0.05μg/mL), GTFX (MIC: 0.78μg/mL) and RIF (MIC: 0.39μg/mL) against MTB H37Rv. The most active conjugate 6 k (MIC: 0.06μg/mL) was 16–>2048 times more potent than the three references (MIC: 1.0–>128μg/mL) against MDR-TB. Both of the two hybrids warrant further investigations. Graphical abstract image
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Chemically generated IgG2 bispecific antibodies through disulfide bridging ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): James T. Patterson, Edwige Gros, Heyue Zhou, Ghazi Atassi, Lisa Kerwin, Lisa Carmody, Tong Zhu, Bryan Jones, Yanwen Fu, Gunnar F. Kaufmann Bispecific antibodies (BsAbs) are designed to engage two antigens simultaneously, thus, effectively expanding the ability of antibody-based therapeutics to target multiple pathways within the same cell, engage two separate soluble antigens, bind the same antigen with distinct paratopes, or crosslink two different cell types. Many recombinant BsAb formats have emerged, however, expression and purification of such constructs can often be challenging. To this end, we have developed a chemical strategy for generating BsAbs using native IgG2 architecture. Full-length antibodies can be conjugated via disulfide bridging with linkers bearing orthogonal groups to produce BsAbs. We report that an αHER2/EGFR BsAb was successfully generated by this approach and retained the ability to bind both antigens with no significant loss of potency. Graphical abstract image
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Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Fa-Qian Shen, Zhong-Chang Wang, Song-Yu Wu, Shen-Zhen Ren, Ruo-Jun Man, Bao-Zhong Wang, Hai-Liang Zhu In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50 =0.23±0.16μM for COX-2, IC50 =0.87±0.07μM for 5-LOX, IC50 =4.48±0.57μM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50 =0.41±0.28μM for COX-2, IC50 =7.68±0.55μM against A549) and Zileuton (IC50 =1.35±0.24μM for 5-LOX). Further investigation confirmed that 11g could induce human non-small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents. Graphical abstract image
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Isosorbide-based peptidomimetics as inhibitors of hepatitis C virus serine protease ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Aline C. Portela, Thalita G. Barros, Camilo H. da S. Lima, Luiza R.S. Dias, Pedro H.R. de A. Azevedo, Anna Sophia C.L. Dantas, Ronaldo Mohana-Borges, Gustavo T. Ventura, Sergio Pinheiro, Estela M.F. Muri Hepatitis C infection is a cause of chronic liver diseases such as cirrhosis and carcinoma. The current therapy for hepatitis C has limited efficacy and low tolerance. The HCV encodes a serine protease which is critical for viral replication, and few protease inhibitors are currently on the market. In this paper, we describe the synthesis and screening of novel isosorbide-based peptidomimetic inhibitors, in which the compounds 1d, 1e, and 1i showed significant inhibition of the protease activity in vitro at 100µM. The compound 1e also showed dose-response (IC50 =36±3µM) and inhibited the protease mutants D168A and V170A at 100µM, indicating it as a promising inhibitor of the HCV NS3/4A protease. Our molecular modeling studies suggest that the activity of 1e is associated with a change in the interactions of S2 and S4 subsites, since that the increased flexibility favors a decrease in activity against D168A, whereas the appearance of a hydrophobic cavity in the S4 subsite increase the inhibition against V170A strain. Graphical abstract image
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Augmenting the efficacy of anti-cocaine catalytic antibodies through chimeric hapten design and combinatorial vaccination ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Cody J. Wenthur, Xiaoqing Cai, Beverly A. Ellis, Kim D. Janda Given the need for further improvements in anti-cocaine vaccination strategies, a chimeric hapten (GNET) was developed that combines chemically-stable structural features from steady-state haptens with the hydrolytic functionality present in transition-state mimetic haptens. Additionally, as a further investigation into the generation of an improved bifunctional antibody pool, sequential vaccination with steady-state and transition-state mimetic haptens was undertaken. While GNET induced the formation of catalytically-active antibodies, it did not improve overall behavioral efficacy. In contrast, the resulting pool of antibodies from GNE/GNT co-administration demonstrated intermediate efficacy as compared to antibodies developed from either hapten alone. Overall, improved antibody catalytic efficiency appears necessary to achieve the synergistic benefits of combining cocaine hydrolysis with peripheral sequestration. Graphical abstract image
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3,5-Bis(3-dimethylaminomethyl-4-hydroxybenzylidene)-4-piperidone and related compounds induce glutathione oxidation and mitochondria-mediated cell death in HCT-116 colon cancer cells ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Eshwari Addala, Hossein Rafiei, Swagatika Das, Brian Bandy, Umashankar Das, Subhas S. Karki, Jonathan R. Dimmock This study aims at investigating the cytotoxicity and some of the modes of action of 3,5-bis(3-dimethylamino-4-hydroxybenzylidene)-4-piperidone trihydrochloride 3 and two related compounds 2 (which lacks the dimethylaminomethyl groups) and 4 (which has an additional dimethylaminoethyl substituent in both aryl rings) in order to ascertain the contribution of dimethylaminoethyl substituent to bioactivity. The bioactivities of 2–4 were compared with curcumin 5. Both 2 and 3 displayed submicromolar GI50 values towards HCT-116 cells and were significantly more potent than 4, 5 and 5-fluorouracil (5-FU). All of the compounds displayed greater toxicity towards HCT-116 cells than human CRL-1790 non-malignant colon cells. In HCT-116 cells, the compounds 2, 3 and 5 increased the ratio of oxidised to reduced glutathione and destabilized the mitochondrial membrane potential. Both 2 and 5 produced an increase in mitochondrial superoxide and a burst in intracellular reactive oxygen species in HCT 116 cells. In addition, 2 and 4 stimulated respiration in rat liver mitochondria while 2 and 5 induced mitochondrial swelling. The results suggest that 2 and 5 cause oxidation or cross-linking of the thiols which control the mitochondrial permeability transition. Graphical abstract image
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Synthesis and in vitro antiproliferative activities of (5-aryl-1,2,4-oxadiazole-3-yl) methyl d-ribofuranosides ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Romina E. Avanzo, José M. Padrón, Norma B. D'Accorso, Mirta L. Fascio The emergence of multidrug resistance cell lines is one of the major obstacles in the success of cancer chemotherapeutic treatment. Therefore, it remains a big challenge the development of new and effective drugs to defeat cancer. The presence of nitrogen heterocycles in the architectural design of drugs has led to the discovery of new leading compounds. Herein, we report the synthesis, characterization and in vitro antiproliferative activity against six cancer cell lines of d-ribofuranoside derivatives bearing a 1,2,4-oxadiazolic ring, with the aim of developing new active compounds. Most of these derivatives exhibit significant antiproliferative activities in the micromolar range. Noteworthy, the most potent compound of the series showed better selectivity towards the more resistant colon cancer cell line WiDr. Graphical abstract image
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Chemical screening and development of novel gibberellin mimics ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Kai Jiang, Hiroaki Shimotakahara, Ming Luo, Masato Otani, Hidemitsu Nakamura, Said Salama Moselhy, Khalid Omer Abualnaja, Abdulrahman Labeed Al-Malki, Taha Abduallah Kumosani, Nobutaka Kitahata, Takeshi Nakano, Masatoshi Nakajima, Tadao Asami Gibberellin (GA) plays versatile roles in the regulation of plant growth and development and therefore is widely used as a regulator in agriculture. We performed a chemical library screening and identified a chemical, named 67D, as a stimulator of seed germination that was suppressed by paclobutrazol (PAC), a GA biosynthesis inhibitor. In vitro binding assays indicated that 67D binds to the GID1 receptor. Further studies on the structure–activity relationship identified a chemical, named chemical 6, that strongly promoted seed germination suppressed by PAC. Chemical 6 was further confirmed to promote the degradation of RGA (for repressor of ga1-3), a DELLA protein, and suppress the expression levels of GA3ox1 in the same manner as GA does. 67D and its analogs are supposed to be agonists of GID1 and are expected to be utilized in agriculture and basic research as an alternative to GA. Graphical abstract image
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Synthesis and biological evaluation of pyrrole-based chalcones as CYP1 enzyme inhibitors, for possible prevention of cancer and overcoming cisplatin resistance ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Ibidapo S. Williams, Prashant Joshi, Linda Gatchie, Mohit Sharma, Naresh K. Satti, Ram A. Vishwakarma, Bhabatosh Chaudhuri, Sandip B. Bharate Inhibitors of CYP1 enzymes may play vital roles in the prevention of cancer and overcoming chemo-resistance to anticancer drugs. In this letter, we report synthesis of twenty-three pyrrole based heterocyclic chalcones which were screened for inhibition of CYP1 isoforms. Compound 3n potently inhibited CYP1B1 with an IC50 of ∼0.2μM in Sacchrosomes™ and CYP1B1-expressing live human cells. However, compound 3j which inhibited both CYP1A1 and CYP1B1 with an IC50 of ∼0.9µM, using the same systems, also potently antagonized B[a]P-mediated induction of AhR signaling in yeast (IC50, 1.5µM), fully protected human cells from B[a]P toxicity and completely reversed cisplatin resistance in human cells that overexpress CYP1B1 by restoring cisplatin’s cytotoxicity. Molecular modeling studies were performed to rationalize the observed potency and selectivity of enzyme inhibition by compounds 3j and 3n. Graphical abstract image
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Discovery of a potent angiotensin converting enzyme inhibitor via virtual screening ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Zhipeng Ke, Zhenzhen Su, Xinzhuang Zhang, Zeyu Cao, Yue Ding, Liang Cao, Gang Ding, Zhenzhong Wang, Haichun Liu, Wei Xiao Prompted by the prominent role of angiotensin converting enzyme (ACE) in hypertension, heart failures, myocardial infarction and diabetic nephropathy, we have attempted to discover novel ACE inhibitors through ligand-based virtual screening. Molecular docking method and rigorously validated model was utilized to search a natural compounds database. Finally, 36 compounds were randomly selected and subjected to in vitro ACE kinase inhibitory assay using fluorescence assays method. The results showed that three compounds (Licochalcone A, Echinatin and EGCG) have strong potential to be developed as a new class of ACE inhibitors. Further chemical modification via fragment modifications guided by structure and ligand-based computational methodologies can lead to discover better agents as potential clinical candidates. Graphical abstract image
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Synthesis and antibacterial evaluation of novel 11-O-carbamoyl clarithromycin ketolides ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Li Jia, Mi Yan, Yan Shen, Yinhui Qin, Shengsheng Qiang, Shutao Ma A series of novel 11-O-carbamoyl clarithromycin ketolides were designed, synthesized and evaluated for their in vitro antibacterial activity. The results showed that the majority of the target compounds displayed improved activity compared with references against erythromycin-resistant S. pneumoniae A22072 expressing the mef gene, S. pneumoniae B1 expressing the erm gene and S. pneumoniae AB11 expressing the mef and erm genes. In particular, compounds 9, 18, 19 and 22 showed the most potent activity against erythromycin-resistant S. pneumoniae A22072 with the MIC values of 0.5μg/mL. Furthermore, compounds 11, 18, 19, 24 and 29 were also found to exhibit favorable antibacterial activity against erythromycin-susceptible S. pyogenes with the MIC values of 0.125–1μg/mL, and moderate activity against erythromycin-susceptible S. aureus ATCC25923 and B. subtilis ATCC9372. Graphical abstract image
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Synthesis and biological evaluation of novel 1,2,3-triazole derivatives as anti-tubercular agents ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Abdul Aziz Ali, Dhrubajyoti Gogoi, Amrita K. Chaliha, Alak K. Buragohain, Priyanka Trivedi, Prakash J. Saikia, Praveen S. Gehlot, Arvind Kumar, Vinita Chaturvedi, Diganta Sarma A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular ‘click chemistry’ approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78μg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages). Molecular docking of the target compounds into the active site of DprE1 (Decaprenylphosphoryl-β-d-ribose-2′-epimerase) enzyme revealed noteworthy information on the plausible binding interactions. Graphical abstract image
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Development of a prodrug of hydantoin based TACE inhibitor ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Ling Tong, Seong Heon Kim, Lei Chen, Aneta Kosinski, Bandarpalle B. Shankar, Vinay Girijavallabhan, De-Yi Yang, Wensheng Yu, Guowei Zhou, Neng-Yang Shih, Shiying Chen, Mengwei Hu, Daniel Lundell, Xiaoda Niu, Shelby Umland, Joseph A. Kozlowski Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors led to fused bi-heteroaryl hydantoin series that demonstrate sub-nanomolar potency (Ki) as well as excellent activity in human whole blood (hWBA). However, lead compound 2 posed some formulation challenges which prevented it for further development. A prodrug approach was investigated to address this issue. The pivalate prodrug 3 can be formulated as stable neutral form and demonstrated improved DMPK properties when compared with parent compound. Graphical abstract image
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Synthesis, antioxidant and antiproliferative activities of 1,3,4-thiadiazoles derived from phenolic acids ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Katarina Jakovljević, Ivana Z. Matić, Tatjana Stanojković, Ana Krivokuća, Violeta Marković, Milan D. Joksović, Nevena Mihailović, Marija Nićiforović, Ljubinka Joksović Two 2-amino-1,3,4-thiadiazoles containing phenolic hydroxyl groups were combined with different carboxylic acid chlorides giving sixteen amide derivatives with good antioxidant and antiproliferative potential. The compound 3′c with an adamantane ring displayed excellent DPPH radical scavenging activity and good cytotoxic activity against human acute promyelocytic leukemia HL-60 cells, while 1,3,4-thiadiazole 3′h with 4-chlorophenyl moiety was found to be the most effective in inhibition of survival of lung carcinoma A549 cells. All examined thiadiazoles except 3a and 3′a exerted higher cytotoxic activities on A549 and HL-60 cancer cells when compared with normal fibroblasts MRC-5, pointing to selectivity in their antiproliferative action. Some of the most active novel compounds 3c, 3′c, 3′g and 3′h induced significant increase in the percentage of HL-60 cells in the subG1 cell cycle phase in comparison with the control cells. The induction of cell death in HL-60 cells by these compounds was at least partially dependent on activation of caspase-3 and caspase-8. The compounds 3c and 3′c exerted strong antiangiogenic activity. Furthermore, compounds 3c, 3′c, 3′g and 3′h showed the ability to down-regulate the MMP2 and VEGFA expression levels in the treated HL-60 cells when compared with the control cell samples. Graphical abstract image
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Discovery of DS79182026: A potent orally active hepcidin production inhibitor ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Takeshi Fukuda, Riki Goto, Toshihiro Kiho, Kenjiro Ueda, Sumie Muramatsu, Masami Hashimoto, Anri Aki, Kengo Watanabe, Naoki Tanaka Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of benzisoxazole compounds as orally active hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model. Graphical abstract image
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α-Pyrone derivatives with cytotoxic activities, from the endophytic fungus Phoma sp. YN02-P-3 ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Xia-Nan Sang, Shao-Fei Chen, Ming-Xu Tang, Hai-Feng Wang, Xiao An, Xiao-Jie Lu, Dan Zhao, Yu-Bo Wang, Jiao Bai, Hui-Ming Hua, Gang Chen, Yue-Hu Pei Four new α-pyrone derivatives phomones C-F (1−4) together with four known compounds (5−8) were isolated from the endophytic fungus Phoma sp. YN02-P-3. Compound 1 is the first example of 6-α,β-unsaturated ester-2-pyrone dimers via intermolecular symmetrical [2+2] cycloaddition. The chemical structures of these compounds were determined from spectroscopic data (1D/2D NMR, MS and IR). The acetylated product (9) of 1 along with compounds 1–8 were then tested for their cytotoxicity against HL-60, PC-3 and HCT-116 cell lines. Compounds 2, 3, 5 and 9 with acetyl groups showed significant inhibitory activities against the three cell lines with IC50 values in the range 0.52–9.85μM. while compounds 1, 4 and 6–8 that possess no acetyl group showed no inhibitory activity (IC50 >50μM), indicating that the acetyl group at 10- or 12- are essential for their cytotoxic activities. The structure-activity relationships of these phomones were also reported. Graphical abstract image
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Discovery of novel 2-(3-phenylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Yoshihiro Usui, Fumiaki Uehara, Shinsuke Hiki, Kazutoshi Watanabe, Hiroshi Tanaka, Aya Shouda, Satoshi Yokoshima, Keiichi Aritomo, Takashi Adachi, Kenji Fukunaga, Shinji Sunada, Mika Nabeno, Ken-Ichi Saito, Jun-ichi Eguchi, Keiji Yamagami, Shouichi Asano, Shinji Tanaka, Satoshi Yuki, Narihiko Yoshii, Masatake Fujimura, Takashi Horikawa We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 2-phenylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the phenyl moiety revealed that a 4-fluoro-2-methoxy group afforded potent inhibitory activity toward GSK-3β. Based on docking studies, new hydrogen bonding between the nitrogen atom of the piperazine moiety and the oxygen atom of the main chain of Gln185 has been indicated, which may contribute to increased activity compared with that of the corresponding phenylmorpholine analogues. Effect of the stereochemistry of the phenylpiperazine moiety is also discussed. Graphical abstract image
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Discovery of novel 2-(4-aryl-2-methylpiperazin-1-yl)-pyrimidin-4-ones as glycogen synthase kinase-3β inhibitors ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Toshiyuki Kohara, Kazuki Nakayama, Kazutoshi Watanabe, Shin-ichi Kusaka, Daiki Sakai, Hiroshi Tanaka, Kenji Fukunaga, Shinji Sunada, Mika Nabeno, Ken-Ichi Saito, Jun-ichi Eguchi, Akiko Mori, Shinji Tanaka, Tomoko Bessho, Keiko Takiguchi-Hayashi, Takashi Horikawa We herein describe the results of further evolution of glycogen synthase kinase (GSK)-3β inhibitors from our promising compounds containing a 3-methylmorpholine moiety. Transformation of the morpholine moiety into a piperazine moiety resulted in potent GSK-3β inhibitors. SAR studies focused on the nitrogen atom of the piperazine moiety revealed that a phenyl group afforded potent inhibitory activity toward GSK-3β. Docking studies indicated that the phenyl group on the piperazine nitrogen atom and the methyl group on the piperazine make cation-π and CH-π interactions with GSK-3β respectively. 4-Methoxyphenyl analogue 29 showed most potent inhibitory activity toward GSK-3β with good in vitro and in vivo pharmacokinetic profiles, and 29 demonstrated a significant decrease in tau phosphorylation after oral administration in mice. Graphical abstract image
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Selective inhibitors of human mPGES-1 from structure-based computational screening ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Ziyuan Zhou, Yaxia Yuan, Shuo Zhou, Kai Ding, Fang Zheng, Chang-Guo Zhan Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs. Although various mPGES-1 inhibitors have been reported in literature, few have entered clinical trials and none has been proven clinically useful so far. It is highly desired for developing the next generation of therapeutics for inflammation-related diseases to design and discover novel inhibitors of mPGES-1 with new scaffolds. Here, we report the identification of a series of new, potent and selective inhibitors of human mPGES-1 with diverse scaffolds through combined computational and experimental studies. The computationally modeled binding structures of these new inhibitors of mPGES-1 provide some interesting clues for rational design of modified structures of the inhibitors to more favorably bind with mPGES-1. Graphical abstract image
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Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutinin ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Zoë V.F. Wright, Nicholas C. Wu, Rameshwar U. Kadam, Ian A. Wilson, Dennis W. Wolan Influenza is a highly contagious respiratory viral infection responsible for up to 50,000 deaths per annum in the US alone. The need for new therapeutics with novel modes of action is of paramount importance. We determined the X-ray structure of Arbidol with influenza hemagglutinin and found it was located in a distinct binding pocket. Herein, we report a structure-activity relationship study based on the co-complex combined with bio-layer interferometry to assess the binding of our compounds. Addition of a meta-hydroxy group to the thiophenol moiety of Arbidol to replace a structured water molecule in the binding pocket resulted in a dramatic increase in affinity against both H3 (1150-fold) and H1 (98-fold) hemagglutinin subtypes. Our analogues represent novel leads to yield more potent compounds against hemagglutinin that block viral entry. Graphical abstract image
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Design, synthesis, biological evaluation and molecular modelling studies of novel diaryl substituted pyrazolyl thiazolidinediones as potent pancreatic lipase inhibitors ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Sridhar S.N.C., Deendyal Bhurta, Dharmvir Kantiwal, Ginson George, Vikramdeep Monga, Atish T. Paul A series of novel diaryl substituted pyrazolyl 2,4-thiazolidinediones were synthesized via reaction of appropriate pyrazolecarboxaldehydes with 2,4-thiazolidinedione (TZD) and nitrobenzyl substituted 2,4-thiazolidinedione. The resulting compounds were screened in vitro for pancreatic lipase (PL) inhibitory activity. Two assay protocols were performed viz., methods A and B using p-nitrophenyl butyrate and tributyrin as substrates, respectively. Compound 11e exhibited potent PL inhibitory activity (IC50 =4.81µM and Xi50 =10.01, respectively in method A and B), comparable to that of the standard drug, orlistat (IC50 =0.99µM and Xi50 =3.72). Presence of nitrobenzyl group at N-3 position of TZD and nature of substituent at para position of phenyl ring at C-3 position of pyrazole ring notably affected the PL inhibitory activity of the tested compounds. Enzyme inhibition kinetics of 11e revealed its reversible competitive inhibition, similar to that of orlistat. Molecular docking studies validated the rationale of pharmacophoric design and are in accordance to the in vitro results. Compound 11e exhibited a potential MolDock score of −153.349kcal/mol. Further, the diaryl pyrazolyl wing exhibited hydrophobic interactions with the amino acids of the hydrophobic lid domain. Moreover, the carbonyl group at 2nd position of the TZD ring existed adjacent to Ser 152 (≈3Å) similar to that of orlistat. A 10ns molecular dynamics simulation of 11e–PL complex revealed a stable binding conformation of 11e in the active site of PL (Maximum RMSD≈3Å). The present study identified novel thiazolidinedione based leads with promising PL inhibitory activity. Further development of the leads might result in potent PL inhibitors. Graphical abstract image
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Novel derivatives of deoxycholic acid bearing aliphatic or cyclic diamine moieties at the C-3 position: Synthesis and evaluation of anti-proliferative activity ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Irina I. Popadyuk, Andrey V. Markov, Valeriya O. Babich, Oksana V. Salomatina, Evgeniya B. Logashenko, Marina A. Zenkova, Nariman F. Salakhutdinov A new library of deoxycholic acid derivatives bearing nitrogen-containing moieties at the C-3 position was synthesised from epoxy derivative 1 via an epoxide ring-opening reaction promoted by aliphatic or cyclic diamines and fully characterised by NMR and mass-spectroscopy. The synthesised compounds were screened for cytotoxicity against four human tumour cell lines. The results showed that some of the novel diamine-bearing derivatives displayed improved anti-proliferative activities over the parent compound DCA. Among them, a 1-methylpiperazine containing compound (6) showed promising activity and the highest selectivity against tumour cells of enterohepatic origin (HepG2: IC50 =3.6µM, SI=9.0; HuTu-80: IC50 =4.6µM, SI=6.9) and was identified as a lead molecule. Graphical abstract image
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Bioactive polyprenylated benzophenone derivatives from the fruits extracts of Garcinia xanthochymus ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Ui Joung Youn, Tawanun Sripisut, Gabriella Miklossy, James Turkson, Surat Laphookhieo, Leng Chee Chang Two new polycyclic prenylated xanthones (1 and 2) and a new phenylpropanoid glycoside (3), along with seven known compounds (4–10) were isolated from the fruits of Garcinia xanthochymus. The structures were elucidated by 1D- and 2D-NMR, and HRMS experiments. The isolates were evaluated for their inhibitory effects against the viability of U251MG glioblastoma and MDA-MB-231 breast cancer cells that harbor an aberrantly active signal transducer and exhibit activation of transcription 3 (STAT3), and compared to normal NIH3T3 mouse fibroblasts. Among the isolates, compounds 1, 2, 5, and 6–9 inhibited the viability of glioma cancer cells with IC50 values in the range of 1.6–6.5μM. Furthermore, treatment of U251MG with 6 and 7 inhibited intracellular STAT3 tyrosine phosphorylation and glioma cell migration in vitro, respectively. Graphical abstract image
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Discovery of dual Axl/VEGF-R2 inhibitors as potential anti-angiogenic and anti-metastatic drugs for cancer chemotherapy ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Dane Goff, Jing Zhang, Thilo Heckrodt, Jiaxin Yu, Pingyu Ding, Raj Singh, Sacha Holland, Weiqun Li, Mark Irving Axl tyrosine kinase has been shown to be involved in multiple pathways contributing to tumor development, angiogenesis, and metastasis. High Axl expression has been observed in many human tumors where it appears to confer aggressive tumor behavior. Here we present several series of dual Axl-VEGF-R2 kinase inhibitors based on extensive optimization of an acyl diaminotriazole. It was hypothesized that dual inhibition of these two receptor tyrosine kinases may have a synergistic affect in inhibiting tumor angiogenesis and metastasis. One of these molecules, R916562 showed comparable activity to Sunitinib in two mouse tumor xenograft models and a mouse corneal micropocket model. Graphical abstract image
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AuNP-CTG based probing system targeting CAG repeat DNA and RNA sequences ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Binh Huy Le, Han Na Joo, Do won Hwang, Kyu Wan Kim, Young Jun Seo We have developed a AuNP-CTG based probing system that is applicable to the detection of many units of CAG repeat sequences which was synthesized by a rolling circle amplification (RCA) system with changes in fluorescence. We also demonstrate that our AuNP-CTG based probing system could transfect without using transfection reagent and detect target CAG repeat sequences in HeLa cells with dramatic changes in fluorescence. This AuNP-CTG based probing system could also be used, in conjunction with the CAG repeat RCA system, to detect target DNA. This system was so sensitive to the target DNA that it could detect even picomolar amounts with amplification of the fluorescence signal. Furthermore, we have used our gold-based CAG probing system for the detection of RNA CAG repeat sequences. Graphical abstract image
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Flavonoid glycosides from Barringtonia acutangula ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Le Thi Vien, Quach Thi Thanh Van, Tran Thi Hong Hanh, Phan Thi thanh Huong, Nguyen Thi Kim Thuy, Nguyen The Cuong, Nguyen Hai Dang, Nguyen Van Thanh, Nguyen Xuan Cuong, Nguyen Hoai Nam, Phan Van Kiem, Chau Van Minh Using various chromatographic separation techniques, ten flavonoid glycosides, including six new compounds namely barringosides A−F (1–6), were isolated from a methanol extract of the Barringtonia acutangula leaves. The structure elucidation was confirmed by spectroscopic analyses, including 1D and 2D NMR, and HR ESI MS. Their inhibitory effects on LPS-induced NO production in RAW264.7 cells were also evaluated. Among the isolated compounds, quercetin 3-O-β-d-(6-p-hydroxybenzoyl)galactopyranoside (9) showed significant effect with an IC50 of 20.00±1.68µM. This is the first report of these flavonoid glycosides from Barringtonia genus and their inhibition on LPS-induced NO production in RAW264.7 cells was reported here for the first time. Graphical abstract image
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Optimization of 1H-indazol-3-amine derivatives as potent fibroblast growth factor receptor inhibitors ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Jing Cui, Xia Peng, Dingding Gao, Yang Dai, Jing Ai, Yingxia Li Fibroblast growth factor receptor (FGFR) is a potential target for cancer therapy because of its critical role in promoting cancer formation and progression. In a continuing effort to improve the cellular activity of hit compound 7r bearing an indazole scaffold, which was previously discovered by our group, several compounds harnessing fluorine substituents were designed, synthesized and biological evaluated. Besides, the region extended out to the ATP binding pocket toward solvent was also explored. Among them, compound 2a containing 2,6-difluoro-3-methoxyphenyl residue exhibited the most potent activities (FGFR1: less than 4.1nM, FGFR2: 2.0±0.8nM). More importantly, compound 2a showed an improved antiproliferative effect against KG1 cell lines and SNU16 cell lines with IC50 values of 25.3±4.6nM and 77.4±6.2nM respectively. Graphical abstract image
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Oxindole-based intraocular pressure reducing agents ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Ekaterina V. Zaryanova, Nataly A. Lozinskaya, Olga V. Beznos, Maria S. Volkova, Nataly B. Chesnokova, Nikolay S. Zefirov The study represents the new findings at the crossroads of chemistry and medicine, particularly between medicinal and organic chemistry and ophthalmology. In this work we describe how the chemical reactivity of indolinone scaffold may be used to create small molecule ligands with strong biological response comparable with and larger than that of endogenous hormone. The synthesis of oxindole-based melatonin and 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT) analogues was proposed and their ability to influence intraocular pressure (IOP) was studied in vivo. Time-dependent study revealed the prolonged effect (more than 6h) of the lead-compound. This effect in combination with high IOP reducing effect (41±6%) in low concentrations of the active compound (0.1wt%) and with high water solubility represents a great potential of low-cost oxindole derivatives as potent antiglaucoma agents. Graphical abstract image
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Design and synthesis of 4-morpholino-6-(1,2,3,6-tetrahydropyridin-4-yl)-N-(3,4,5-trimethoxyphenyl)-1,3,5-triazin-2-amine analogues as tubulin polymerization inhibitors ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Suresh Narva, Surendar Chitti, Suresh Amaroju, Debanjan Bhattacharjee, Bala Bhaskara Rao, Nishant Jain, Mallika Alvala, Kondapalli Venkata Gowri Chandra Sekhar A series of thirty-seven 1,3,5-triazine analogues have been synthesized, characterized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines such as HeLa, HepG2, A549 and MCF-7. Most of the 1,3,5-triazine analogues exhibited promising antiproliferative activity against tested cancer cell lines. Among all the synthesized compounds, 8j showed potent activity against the cancer cell lines such as HeLa, HepG2, A549 and MCF-7 with IC50 12.3±0.8, 9.6±0.4, 10.5±1.0 and 11.7±0.5μM respectively. 8j was taken up for elaborate biological studies and the cells in the cell cycle were arrested in G2/M phase. In addition, 8j was examined for its effect on the microtubule system with a tubulin polymerization assay, immunofluorescence. 8j showed remarkable inhibition of tubulin polymerization. Molecular docking studies were also carried out to understand the binding pattern. The studies suggested that 8j has a good binding affinity of −7.949 towards nocodazole binding site of tubulin while nocodazole has −7.462. Graphical abstract image
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One-pot two-step facile synthesis of 2,3,4,5-tetra substituted dihydrooxazoles and their antimicrobial activity ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Shailendra Tiwari, Poonam Pathak, Kamal Pratap Singh, Ram Sagar New 2,3,4,5-tetra substituted dihydrooxazoles derivatives were efficiently synthesized starting from benzaldehyde, aryl thiosemicarbazide and benzoin using designed synthetic route. Newly synthesized 2,3,4,5-tetra substituted dihydrooxazole derivatives were screened for their antibacterial and antifungal activities against different strains of pathogenic bacteria and fungi. The minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC) were determined for the test compounds using positive and negative control. Compounds 4b, 4d, 4f, 4i, 4k and 4m, have shown good antibacterial activity whereas compounds 4e, 4g, 4h, 4j, 4l and 4n have displayed better antifungal activity. Graphical abstract image
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Synthesis of novel 2-pyrazoline analogues with potent anti-inflammatory effect mediated by inhibition of phospholipase A2: Crystallographic, in silico docking and QSAR analysis ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Devirammanahalli Mahadevaswamy Lokeshwari, Dileep Kumar Achutha, Bharath Srinivasan, Naveen Shivalingegowda, Lokanath Neratur Krishnappagowda, Ajay Kumar Kariyappa Oxidative-stress induces inflammatory diseases. Further, infections caused by drug-resistant microbial strains are on the rise. This necessitates the discovery of novel small-molecules for intervention therapy. A series of 3-(2,3-dichlorophenyl)-1-(aryl)prop-2-en-1-ones are synthesized as intermediates via Claisen-Schmidt reaction approach. Subsequently, these intermediates were transformed into 2-pyrazolines by their reaction with phenylhydrazine hydrochlorides in methanol and few drops of acetic acid under reflux conditions. Synthesized compounds were characterized by spectroscopic, crystallographic and elemental analyses studies and then, were evaluated for their in vitro antimicrobial and anti-inflammatory activities. Amongst the series, 3-(4-chlorophenyl)-5-(2,3-dichlorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5e), 5-(2,3-dichlorophenyl)-3-(4-fluorophenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5c) and 5-(2,3-dichlorophenyl)-3-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazole (5h) showed significant inhibition of phospholipase A2 with IC50 values of 10.2, 11.1 and 11.9µM, respectively. Protein structure modelling and docking studies indicated that the compounds showed binding to a highly conserved calcium-binding pocket on the enzyme. Further, compounds (5e), 1-(3-chlorophenyl)-5-(2,3-dichlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole (5b), and 1-(3-chlorophenyl)-3-(4-chlorophenyl)-5-(2,3-dichlorophenyl)-4,5-dihydro-1H-pyrazole (5f) showed excellent antimicrobial activities against various bacterial and fungal strains. In conclusion, this study is a successful attempt at the synthesis and characterization of chalcone derivatives that can target phospholipase A2, an enzyme that is a prominent player in the physiological inflammatory cascade. Thus, these compounds show promise for development as next-generation nonsteroidal anti-inflammatory drugs. Graphical abstract image
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Synthesis and evaluation of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives as xanthine oxidase inhibitors ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Ting-jian Zhang, Qing-xia Wu, Song-ye Li, Lin Wang, Qi Sun, Yi Zhang, Fan-hao Meng, Hua Gao This study mainly focused on the modification of the X2 position in febuxostat analogs. A series of 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid derivatives (1a-s) with an N atom occupying the X2 position was designed and synthesized. Evaluation of their inhibitory potency in vitro on xanthine oxidase indicated that these compounds exhibited micromolar level potencies, with IC50 values ranging from 0.21µM to 26.13μM. Among them, compound 1s (IC50 =0.21μM) showed the most promising inhibitory effects and was 36-fold more potent than allopurinol, but was still 13-fold less potent than the lead compound Y-700, which meant that a polar atom fused at the X2 position could be unfavorable for potency. The Lineweaver-Burk plot revealed that compound 1s acted as a mixed-type xanthine oxidase inhibitor. Analysis of the structure-activity relationships demonstrated that a more lipophilic ether tail (e.g., meta-methoxybenzoxy) at the 4′-position could benefit the inhibitory potency. Molecular modeling provided a reasonable explanation for the structure–activity relationships observed in this study. Graphical abstract image
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Discovery of a biarylamide series of potent, state-dependent NaV1.7 inhibitors ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Laurie B. Schenkel, Erin F. DiMauro, Hanh N. Nguyen, Nagasree Chakka, Bingfan Du, Robert S. Foti, Angel Guzman-Perez, Michael Jarosh, Daniel S. La, Joseph Ligutti, Benjamin C. Milgram, Bryan D. Moyer, Emily A. Peterson, John Roberts, Violeta L. Yu, Matthew M. Weiss The NaV1.7 ion channel has garnered considerable attention as a target for the treatment of pain. Herein we detail the discovery and structure-activity relationships of a novel series of biaryl amides. Optimization led to the identification of several state-dependent, potent and metabolically stable inhibitors which demonstrated promising levels of selectivity over NaV1.5 and good rat pharmacokinetics. Compound 18, which demonstrated preferential inhibition of a slow inactivated state of NaV1.7, was advanced into a rat formalin study where upon reaching unbound drug levels several fold over the rat NaV1.7 IC50 it failed to demonstrate a robust reduction in nociceptive behavior. Graphical abstract image
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3-Oxo-γ-costic acid fungal-transformation generates eudesmane sesquiterpenes with in vitro tumor-inhibitory activity ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Mohamed-Elamir F. Hegazy, Ahmed A. El-Beih, Ahmed R. Hamed, Abeer A. Abd El Aty, Naglaa S. Mohamed, Paul W. Paré While select eudesmane sesquiterpenes exhibit anti-neoplastic activity, tumor-inhibition for costic-acids has not been established. Here biological activity of 3-oxo-γ-costic acid (1), previously isolated from Chiliadenus montanus, as well as new sesquiterpenes (2–5) and the known derivative, 3-oxoeudesma-1,4,11(13)-trien-7-1061αH-l2-oic acid (6), all produced from 1 by the fungus Athelia rolfsii, are reported. Structures were elucidated using MS and NMR spectroscopy with activity-screening utilizing human colon- and lung-tumor lines, Caco-2 and A549 respectively. Compound 1 exhibited anti-proliferative activity against Caco-2 (IC50 39µM) and 2 was active against A549 (IC50 74µM) suggesting therapeutic potential for the original substrate and a bio-transformed product. Graphical abstract image
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Potent antiobesity effect of a short-length peptide YY-analogue continuously administered in mice ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Naoki Nishizawa, Ayumu Niida, Yusuke Adachi, Yasushi Masuda, Satoshi Kumano, Kotaro Yokoyama, Tomoko Asakawa, Hideki Hirabayashi, Nobuyuki Amano, Shiro Takekawa, Tetsuya Ohtaki, Taiji Asami The gastrointestinal peptide, peptide YY3–36 (PYY3–36) and its shorter peptide analogues have been reported to reduce appetite by activating the neuropeptide Y2 receptor (Y2R), which is associated with obesity and other metabolic diseases. A 14-amino acid PYY analogue, Ac-[d-Pro24,Cha27,28,36,Aib31]PYY(23–36) (3), showed high binding affinity and agonist activity for the Y2R, similar to that of PYY3–36, but had weak anorectic activity upon continuous administration in lean mice. Three amino acid substitutions [Pya(4)26, Aib28, Lys30], which contributed to the decreased hydrophobicity of 3, efficiently increased its anorectic activity. The compound containing these three amino acids, Ac-[d-Pro24,Pya(4)26,Cha27,36,Aib28,31,Lys30]PYY(23–36) (22), exerted more potent and durable food intake suppression than that by PYY3–36 in lean mice, as well as excellent Y2R agonist activity (EC50: 0.20nM) and good subcutaneous bioavailability (66.6%). The 11-day continuous administration of 22 at 1mg/kg/day successfully produced antiobese and antidiabetic effects, with more than 20% body weight loss in obese and Type 2 diabetes ob/ob model mice. Graphical abstract image
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Macrocyclic inhibitors of Factor XIa: Discovery of alkyl-substituted macrocyclic amide linkers with improved potency ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): James R. Corte, Wu Yang, Tianan Fang, Yufeng Wang, Honey Osuna, Amy Lai, William R. Ewing, Karen A. Rossi, Joseph E. Myers, Steven Sheriff, Zhen Lou, Joanna J. Zheng, Timothy W. Harper, Jeffrey M. Bozarth, Yiming Wu, Joseph M. Luettgen, Dietmar A. Seiffert, Mimi L. Quan, Ruth R. Wexler, Patrick Y.S. Lam Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface area and improved the oral bioavailability for the series, albeit at the cost of a decrease in potency. Graphical abstract image
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Diaminopimelic acid (DAP) analogs bearing isoxazoline moiety as selective inhibitors against meso-diaminopimelate dehydrogenase (m-Ddh) from Porphyromonas gingivalis ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Hongguang Ma, Victoria N. Stone, Huiqun Wang, Glen E. Kellogg, Ping Xu, Yan Zhang Two diastereomeric analogs (1 and 2) of diaminopimelic acid (DAP) bearing an isoxazoline moiety were synthesized and evaluated for their inhibitory activities against meso-diaminopimelate dehydrogenase (m-Ddh) from the periodontal pathogen, Porphyromonas gingivalis. Compound 2 showed promising inhibitory activity against m-Ddh with an IC50 value of 14.9µM at pH 7.8. The two compounds were further tested for their antibacterial activities against a panel of periodontal pathogens, and compound 2 was shown to be selectively potent to P. gingivalis strains W83 and ATCC 33277 with minimum inhibitory concentration (MIC) values of 773µM and 1.875mM, respectively. Molecular modeling studies revealed that the inversion of chirality at the C-5 position of these compounds was the primary reason for their different biological profiles. Based on these preliminary results, we believe that compound 2 has properties consistent with it being a lead compound for developing novel pathogen selective antibiotics to treat periodontal diseases. Graphical abstract image
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Antileishmanial potential of fused 5-(pyrazin-2-yl)-4H-1,2,4-triazole-3-thiols: Synthesis, biological evaluations and computational studies ()
Publication date: 15 August 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 16 Author(s): Sanjeev R. Patil, Ashish Asrondkar, Vrushali Patil, Jaiprakash N. Sangshetti, Firoz A. Kalam Khan, Manoj G. Damale, Rajendra H. Patil, Anil S. Bobade, Devanand B. Shinde A series of newer 1,2,4-triazole-3-thiol derivatives 5(a–m) and 6(a–i) containing a triazole fused with pyrazine moiety of pharmacological significance have been synthesized. All the synthesized compounds were screened for their in vitro antileishmanial and antioxidant activities. Compounds 5f (IC50 =79.0µM) and 6f (IC50 =79.0µM) were shown significant antileishmanial activity when compared with standard sodium stibogluconate (IC50 =490.0µM). Compounds 5b (IC50 =13.96µM) and 6b (IC50 =13.96µM) showed significant antioxidant activity. After performing molecular docking study and analyzing overall binding modes it was found that the synthesized compounds had potential to inhibit L. donovani pteridine reductase 1 enzyme. In silico ADME and metabolic site prediction studies were also held out to set an effective lead candidate for the future antileishmanial and antibacterial drug discovery initiatives. Graphical abstract image
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