Bioorganic & Medicinal Chemistry Letters

Editorial board ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1
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Factors affecting the uncaging efficiency of 500 nm light-activatable BODIPY caging group ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1 Author(s): Minoru Kawatani, Mako Kamiya, Hironori Takahashi, Yasuteru Urano Photoremovable protective groups, or caging groups, enable us to regulate the activities of bioactive molecules in living cells upon photoirradiation. Nevertheless, requirement of UV light for activating caging group is a significant limitation due to its cell toxicity and its poor tissue penetration. Our group previously reported a 500 nm light-activatable caging group based on BODIPY scaffold, however, its uncaging efficiency was lower than those of conventional caging groups. Here we show that the uncaging quantum yield (QY) of BODIPY caging group depends upon the driving force of photo-induced electron transfer (PeT). We also found that the uncaging QY increased in less polar solvents. We applied these findings to develop BODIPY-caged capsaicin, which is well localized to low-polarity intracellular compartments, as a tool to stimulate TRPV1 in live cells in response to blue-green light. Graphical abstract image
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Identification of a 4-fluorobenzyl l-valinate amide benzoxaborole (AN11736) as a potential development candidate for the treatment of Animal African Trypanosomiasis (AAT) ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1 Author(s): Tsutomu Akama, Yong-Kang Zhang, Yvonne R. Freund, Pamela Berry, Joanne Lee, Eric E. Easom, Robert T. Jacobs, Jacob J. Plattner, Michael J. Witty, Rosemary Peter, Tim G. Rowan, Kirsten Gillingwater, Reto Brun, Bakela Nare, Luke Mercer, Musheng Xu, Jiangong Wang, Hao Liang Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15 nM against T. congolense and 1.3 nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10 mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies. Graphical abstract image
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Isosteric ribavirin analogues: Synthesis and antiviral activities ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1 Author(s): Nikolay I. Zhurilo, Mikhail V. Chudinov, Andrey V. Matveev, Olga S. Smirnova, Irina D. Konstantinova, Anatoly I. Miroshnikov, Alexander N. Prutkov, Lyubov E. Grebenkina, Natalya V. Pulkova, Vitaly I. Shvets The novel isosteric ribavirin analogues were synthesized by two different ways. Some of them showed significant antiviral action against hepatitis C virus (HCV), herpes simplex (HCV-1) and influenza A virus comparable to that of ribavirin itself. The data obtained confirm the proposed theory of the ribavirin possible antiviral activity mechanism related with bioisosterism. Graphical abstract image
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Design and synthesis of a biaryl series as inhibitors for the bromodomains of CBP/P300 ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1 Author(s): Kwong Wah Lai, F. Anthony Romero, Vickie Tsui, Maureen H. Beresini, Gladys de Leon Boenig, Sarah M. Bronner, Kevin Chen, Zhongguo Chen, Edna F. Choo, Terry D. Crawford, Patrick Cyr, Susan Kaufman, Yingjie Li, Jiangpeng Liao, Wenfeng Liu, Justin Ly, Jeremy Murray, Weichao Shen, John Wai, Fei Wang, Caicai Zhu, Xiaoyu Zhu, Steven Magnuson A novel, potent, and orally bioavailable inhibitor of the bromodomain of CBP, compound 35 (GNE-207), has been identified through SAR investigations focused on optimizing al bicyclic heteroarene to replace the aniline present in the published GNE-272 series. Compound 35 has excellent CBP potency (CBP IC50 = 1 nM, MYC EC50 = 18 nM), a selectively index of >2500-fold against BRD4(1), and exhibits a good pharmacokinetic profile. Graphical abstract image
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Synthesis and in vitro evaluations of 6-(hetero)-aryl-imidazo[1,2-b]pyridazine-3-sulfonamide’s as an inhibitor of TNF-α production ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1 Author(s): Shivaji S. Pandit, Mahesh R. Kulkarni, Yashwant B. Pandit, Nitin P. Lad, Vijay M. Khedkar Tumor necrosis factor-α is an important pro-inflammatory cytokine having a key role in hosts defensive process of immune systems and its over expression led to a diverse range of inflammatory diseases such as Rheumatoid arthritis, Cronh’s disease, psoriasis, etc. This paper describes our medicinal chemistry efforts on imidazo[1,2-b]pyridazine scaffold: design, synthesis and biological evaluation. By the introducing sulfonamide functionality at 3 positions and substituting 6 positions with (hetero)-aryl groups’, a small library of compounds was prepared. All synthesized compounds were screened for lipopolysaccharide (LPS) mediated TNF-α production inhibitory activity. Biological data revealed that the majority of the compounds of this series showed moderate to potent TNF-α production inhibitory activity. Compound 5u and 5v are the most potent compounds from the series with activity of IC50 = 0.5 µM and 0.3 µM respectively. A short SAR demonstrates that 3-sulfonyl-4-arylpiperidine-4-carbonitrile moiety on imidazo[1,2-b]pyridazine showed better activity compared to the 3-(4-aryllpiperazin-1-yl) sulfonyl) in hPBMC assay. The molecular modeling studies revealed that the potent TNF-α production inhibitory activity 5v due to the extra stability of complex because of an extra pi-pi (π-π) stacking, hydrogen-bonding interactions. Graphical abstract image
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Discovery of 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent and orally bioavailable tissue-nonspecific alkaline phosphatase (TNAP) inhibitor ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1 Author(s): Anthony B. Pinkerton, Eduard Sergienko, Yalda Bravo, Russell Dahl, Chen-Ting Ma, Qing Sun, Michael R. Jackson, Nicholas D.P. Cosford, José Luis Millán Tissue-nonspecific alkaline phosphatase (TNAP) is an ectoenzyme crucial for bone matrix mineralization via its ability to hydrolyze extracellular inorganic pyrophosphate (ePPi), a potent mineralization inhibitor, to phosphate (Pi). By the controlled hydrolysis of ePPi, TNAP maintains the correct ratio of Pi to ePPi and therefore enables normal skeletal and dental calcification. In other areas of the body low ePPi levels lead to the development of pathological soft-tissue calcification, which can progress to a number of disorders. TNAP inhibitors have been shown to prevent these processes via an increase of ePPi. Herein we describe the use of a whole blood assay to optimize a previously described series of TNAP inhibitors resulting in 5-((5-chloro-2-methoxyphenyl)sulfonamido)nicotinamide (SBI-425), a potent, selective and oral bioavailable compound that robustly inhibits TNAP in vivo. Graphical abstract image
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Selective incorporation of foreign functionality into fibrin gels through a chemically modified DNA aptamer ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1 Author(s): Hiroto Fujita, Yusuke Inoue, Masayasu Kuwahara We found for the first time that a thrombin-binding DNA aptamer (TBA) is selectively entrapped in fibrin gels during the gel growth reaction catalyzed by thrombin. Furthermore, using this phenomenon, we successfully demonstrated multiple incorporation of amphiphilic aliphatic groups into fibrin gels via chemically modified TBA. Graphical abstract image
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Antiplasmodial alkaloids from bulbs of Amaryllis belladonna Steud. ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1 Author(s): Namki Cho, Yongle Du, Ana Lisa Valenciano, Maria L. Fernández-Murga, Michael Goetz, Jason Clement, Maria B. Cassera, David G.I. Kingston A bioassay-guided fractionation and chemical investigation of Amaryllis belladonna Steud. bulbs resulted in the isolation and identification of the new crinane alkaloid 1,4-dihydroxy-3-methoxy powellan (1), along with the 3 known crinane alkaloids 2–4 and the two lycorane alkaloids 5–6. The structures were elucidated by interpretation of combined HR-ESIMS, CD and 2D NMR spectroscopic data. Among these isolated compounds the lycorane-type alkaloid acetylcaranine (5) exhibited strong antiplasmodial activity, while compounds 3 and 4 were moderately active, and compounds 1 and 6 were inactive. Graphical abstract image
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The discovery and optimization of naphthalene-linked P2-P4 Macrocycles as inhibitors of HCV NS3 protease ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1 Author(s): Michael Bowsher, Sheldon Hiebert, Rongti Li, Alan X. Wang, Jacques Friborg, Fei Yu, Dennis Hernandez, Ying-Kai Wang, Herbert Klei, Ramkumar Rajamani, Kathy Mosure, Jay O. Knipe, Nicholas A. Meanwell, Fiona McPhee, Paul M. Scola Naphthalene-linked P2-P4 macrocycles within a tri-peptide-based acyl sulfonamide chemotype have been synthesized and found to inhibit HCV NS3 proteases representing genotypes 1a and 1b with single digit nanomolar potency. The pharmacokinetic profile of compounds in this series was optimized through structural modifications along the macrocycle tether as well as the P1 subsite. Ultimately a compound with oral bioavailability of 100% in rat, and a long half-life in plasma was obtained. However, compounds in this macrocyclic series exhibited cardiac effects in an isolated rabbit heart model and for this reason further optimization efforts were discontinued. Graphical abstract image
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Synthesis and biological evaluation of water-soluble derivatives of chiral gossypol as HIV fusion inhibitors targeting gp41 ()
Publication date: 1 January 2018 Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 1 Author(s): Jian Yang, Long-Long Li, Ju-Rong Li, Jing-Xiang Yang, Fang Zhang, Gang Chen, Rui Yu, Wen-Jie Ouyang, Shu-Wen Wu A series of novel or known water-soluble derivatives of chiral gossypol were synthesized and screened in vitro for their anti-HIV-1 activity. (−)-gossypol derivative was more active against HIV-1 than the corresponding (+)-gossypol derivative, respectively. Among these derivatives, d-glucosamine derivative of (−)-gossypol, oligopeptide derivative of (−)-gossypol and taurine derivative of (−)-gossypol, such as compounds 1a, 3a and 14a, showed significant inhibitory activities against HIV-1 replication, HIV-1 mediated cell-cell fusion and HIV gp41 6-helix bundle formation as some amino acid derivatives of (−)-gossypol. Graphical abstract image
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Editorial board ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24
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Drug-target interactions that involve the replacement or displacement of magnesium ions ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Nicholas A. Meanwell Metal ions play important roles in protein and RNA structure and function and the construction of ligands frequently focuses on the exploitation of functionality designed to engage a metal. However, there are circumstances where functionality can be incorporated into a ligand to emulate the metal ion, allowing target engagement by displacing or replacing the metal and directly interacting with the metal-binding elements in the target. In this Digest, we illustrate protein and RNA modulators that exploit this design principle, with all of the examples based on the displacement or replacement of a magnesium ion, and which can confer a potency advantage. Moreover, this approach relies upon an inversion of the physical chemical properties of a more conventional metal-binding ligand. Graphical abstract image
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New Caspase-1 inhibitor by scaffold hopping into bio-inspired 3D-fragment space ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Anne Brethon, Laurent Chantalat, Olivier Christin, Laurence Clary, Jean-François Fournier, Marcus Gastreich, Craig S. Harris, Tatiana Isabet, Jonathan Pascau, Etienne Thoreau, Didier Roche, Vincent Rodeschini Virtual fragmentation of a library of 12,000 compounds inspired by natural products led to a dataset of 153,000 fragments that was used as a source to identify effective P2-P3 scaffold replacement solutions for peptidic Caspase-1 inhibitors. Our strategy led to the identification of an original 2-azabicyclo-octane scaffold (2-ABO) that was further elaborated into the potent Caspase-1 inhibitor CD10847 (IC50 = 17 nM). The crystal structure of Caspase-1 in complex with CD10847 was obtained, and its binding mode was shown to be similar to the one predicted by docking and in good agreement with other known inhibitors. Graphical abstract image
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Structure-activity relationship study of Aib-containing amphipathic helical peptide-cyclic RGD conjugates as carriers for siRNA delivery ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Shun-ichi Wada, Anna Takesada, Yurie Nagamura, Eri Sogabe, Rieko Ohki, Junsuke Hayashi, Hidehito Urata The conjugation of Aib-containing amphipathic helical peptide with cyclo(-Arg-Gly-Asp-d-Phe-Cys-) (cRGDfC) at the C-terminus of the helix peptide (PI) has been reported to be useful for constructing a carrier for targeted siRNA delivery into cells. In order to explore structure–activity relationships for the development of potential carriers for siRNA delivery, we synthesized conjugates of Aib-containing amphipathic helical peptide with cRGDfC at the N-terminus (PII) and both the N- and C-termini (PIII) of the helical peptide. Furthermore, to examine the influence of PI helical chain length on siRNA delivery, truncated peptides containing 16 (PIV), 12 (PV), and 8 (PVI) amino acid residues at the N-terminus of the helical chain were synthesized. PII and PIII, as well as PI, could deliver anti-luciferase siRNA into cells to induce the knockdown of luciferase stably expressed in cells. In contrast, all of the truncated peptides were unlikely to transport siRNA into cells. Graphical abstract image
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Identification of a diverse synthetic abietane diterpenoid library and insight into the structure-activity relationships for antibacterial activity ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Wei Hou, Guanjun Zhang, Zhi Luo, Di Li, Haoqiang Ruan, Benfang Helen Ruan, Lin Su, Hongtao Xu A diverse natural product-like (NPL) synthetic abietane diterpenoid library containing 86 compounds were obtained and the SARs were studied based on their antibacterial potential. Further in vitro cytotoxic and in silico drug-like properties evaluation showed that the potent antibacterial compound 84 had good drug-like properties and displayed low cytotoxicity toward noncancerous mammalian cells, indicating the study of AA and DHAA might be a good starting point for the search of novel antimicrobial molecules. Future work should be focused on the optimization of their potency and selectivity. Graphical abstract image
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Uracil-amino acid as a scaffold for β-sheet peptidomimetics: Study of photophysics and interaction with BSA protein ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Subhendu Sekhar Bag, Afsana Yashmeen We report herein the uracil-di-aza-amino acid (UrAA) as a new family of molecular scaffold to induce β-hairpin structure with H-bonded β-sheet conformation in a short peptide. This has been demonstrated in two conceptual fluorescent pentapeptides wherein triazolylpyrenyl alanine and/or triazolylmethoxynapthyl alanine ( TPyAlaDo and/or TMNapAlaDo ) are embedded into two arms of the uracil-amino acid via an intervening leucine. Conformational analysis by CD, IR, variable temperature and 2D NMR spectroscopy reveals the β-hairpin structures for both the peptides. Study of photophysical property reveals that the pentapeptide containing fluorescent triazolyl unnatural amino acids TMNapAlaDo and TPyAlaDo at the two termini exhibits dual path entry to exciplex emission-either via FRET from TMNapAlaDo to TPyAlaDo or via direct excitation of a FRET acceptor, TPyAlaDo . The other pentapeptide with TPyAlaDo/TPyAlaDo pair shows excimer emission. Furthermore, both the peptides maintaining their fundamental photophysics are found to interact with BSA as only a test biomolecule. Graphical abstract image
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Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1 ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Allan M. Prior, Xufen Yu, Eun-Jung Park, Tamara P. Kondratyuk, Yan Lin, John M. Pezzuto, Dianqing Sun In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 μM; 21, IC50 = 3.05 μM; and 27, IC50 = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group. Graphical abstract image
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Glycyrrhiza glabra extract and quercetin reverses cisplatin resistance in triple-negative MDA-MB-468 breast cancer cells via inhibition of cytochrome P450 1B1 enzyme ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Rajni Sharma, Linda Gatchie, Ibidapo S. Williams, Shreyans K. Jain, Ram A. Vishwakarma, Bhabatosh Chaudhuri, Sandip B. Bharate The development of multi-drug resistance to existing anticancer drugs is one of the major challenges in cancer treatment. The over-expression of cytochrome P450 1B1 enzyme has been reported to cause resistance to cisplatin. With an objective to discover cisplatin-resistance reversal agents, herein, we report the evaluation of Glycyrrhiza glabra (licorice) extracts and its twelve chemical constituents for inhibition of CYP1B1 (and CYP1A1) enzyme in Sacchrosomes and live human cells. The hydroalcoholic extract showed potent inhibition of CYP1B1 in both Sacchrosomes as well as in live cells with IC50 values of 21 and 16 µg/mL, respectively. Amongst the total of 12 constituents tested, quercetin and glabrol showed inhibition of CYP1B1 in live cell assay with IC50 values of 2.2 and 15 µM, respectively. Both these natural products were found to be selective inhibitors of CYP1B1, and does not inhibit CYP2 and CYP3 family of enzymes (IC50 > 20 µM). The hydroalcoholic extract of G. glabra and quercetin (4) showed complete reversal of cisplatin resistance in CYP1B1 overexpressing triple negative MDA-MB-468 breast cancer cells. The selective inhibition of CYP1B1 by quercetin and glabrol over CYP2 and CYP3 family of enzymes was studied by molecular modeling studies. Graphical abstract image
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Scutellarin inhibits Hela cell growth and glycolysis by inhibiting the activity of pyruvate kinase M2 ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Lin You, Hong Zhu, Chun Wang, Fang Wang, Yongjun Li, Yan Li, Yonglin Wang, Bin He Scutellarin, one of natural flavonoids, is widely and clinically used for treating many diseases in China. Recently, scutellarin has demonstrated a broad spectrum of anti-proliferative activities against multiple cancer cell lines. However, the molecular mechanism of action remains to be investigated. We herein report the design and synthesis of biotinylated scutellareins as probes, which can be applied to discover scutellarein interacting proteins. Finally, we show that scutellarin directly targets pyruvate kinase M2 (PKM2) and inhibits its cytosolic activity to decrease glycolytic metabolism; on the other hand, scutellarin may also participate in regulating cell cycle and apoptotic proteins by activating MEK/ERK/PIN1 signaling pathway to promote the nuclear translocation of PKM2. Graphical abstract image
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(E)-3-(3,4,5-Trimethoxyphenyl)-1-(pyridin-4-yl)prop-2-en-1-one, a heterocyclic chalcone is a potent and selective CYP1A1 inhibitor and cancer chemopreventive agent ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Neill J. Horley, Kenneth J.M. Beresford, Supriya Kaduskar, Prashant Joshi, Glen J.P. McCann, Ketan C. Ruparelia, Ibidapo S. Williams, Linda Gatchie, Vinay R. Sonawane, Sandip B. Bharate, Bhabatosh Chaudhuri The overexpression of CYP1 family of enzymes is reported to be associated with development of human carcinomas. It has been well reported that CYP1A1 specific inhibitors prevents carcinogenesis. Herein, thirteen pyridine-4-yl series of chalcones were synthesized and screened for inhibition of CYP1 isoforms 1A1, 1B1 and 1A2 in Sacchrosomes™ and live human HEK293 cells. The structure-activity relationship analysis indicated that chalcones bearing tri-alkoxy groups (8a and 8k) on non-heterocyclic ring displayed selective inhibition of CYP1A1 enzyme, with IC50 values of 58 and 65 nM, respectively. The 3,4,5-trimethoxy substituted derivative 8a have shown >10-fold selectivity towards CYP1A1 with respect to other enzymes of the CYP1 sub-family and >100-fold selectivity with respect to CYP2 and CYP3 family of enzymes. The potent and selective CYP1A1 inhibitor 8a displayed antagonism of B[a]P mediated activation of aromatic hydrocarbon receptor (AhR) in yeast cells, and also protected human cells from CYP1A1-mediated B[a]P toxicity in human cells. This potent and selective inhibitor of CYP1A1 enzyme have a potential for development as cancer chemopreventive agent. Graphical abstract image
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Discovery of the first low-shift positive allosteric modulators for the muscarinic M1 receptor ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Alexander Flohr, Roman Hutter, Barbara Mueller, Claudia Bohnert, Mélanie Pellisson, Hervé Schaffhauser Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and drug developers for the potential treatment of Alzheimer’s disease or Schizophrenia. The precognitive potential of M1 activation has however not been clinically demonstrated as a result of side effects associated both with agonists and positive allosteric modulators (PAM’s) of the M1-receptor. To avoid excessive activation of the M1-receptor we have designed a new screening format and developed the first low-shift positive allosteric modulators for the M1 receptor. Low-shift PAM’s offer the potential of “use-dependent” attenuation of transmitter-signaling while avoiding pseudo-agonistic behavior in vivo as a common limitation of the so far described high-shift PAM’s. With these novel M1-PAM’s, the M1 receptor is potentially the first GPCR for which both, high- and low shift PAM’s have become available. Graphical abstract image
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Synthesis and antidepressant activity of a series of arylalkanol and aralkyl piperazine derivatives targeting SSRI/5-HT1A/5-HT7 ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Zheng-Song Gu, Ying Xiao, Qing-Wei Zhang, Jian-Qi Li A series of arylalkanol and aralkyl piperazine derivatives have been synthesized and evaluated for 5-HT reuptake inhibitory abilities and binding affinities at the 5-HT1A/5-HT7 receptors. Antidepressant activities of the compounds in vivo were screened using the forced swimming test (FST). The results indicated that the compound 8j exhibited high affinities for the 5-HT1A/5-HT7 receptors (5-HT1A, ki = 0.84 nM; 5-HT7, ki = 12 nM) coupling with moderate 5-HT reuptake inhibitory activity (RUI, IC50 = 100 nM) and showed a marked antidepressant-like activity in the FST model. Graphical abstract image
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Hybrid DNA i-motif: Aminoethylprolyl-PNA (pC5) enhance the stability of DNA (dC5) i-motif structure ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Chandrasekhar Reddy Gade, Nagendra K. Sharma This report describes the synthesis of C-rich sequence, cytosine pentamer, of aep-PNA and its biophysical studies for the formation of hybrid DNA:aep-PNAi-motif structure with DNA cytosine pentamer (dC5) under acidic pH conditions. Herein, the CD/UV/NMR/ESI-Mass studies strongly support the formation of stable hybrid DNA i-motif structure with aep-PNA even near acidic conditions. Hence aep-PNA C-rich sequence cytosine could be considered as potential DNA i-motif stabilizing agents in vivo conditions. Graphical abstract image
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Design, synthesis and biological evaluation of novel oseltamivir derivatives as potent neuraminidase inhibitors ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Zhen Wang, Li Ping Cheng, Xing Hua Zhang, Wan Pang, Liang Li, Jin Long Zhao Neuraminidase (NA) is one of the particular potential targets for novel antiviral therapy. In this work, a series of neuraminidase inhibitors with the cyclohexene scaffold were studied based upon the combination of 3D-QSAR, molecular docking, and molecular dynamics techniques. The results indicate that the built 3D-QSAR models yield reliable statistical information: the correlation coefficient (r2) and cross-validation coefficient (q2) of CoMFA (comparative molecular field analysis) are 0.992 and 0.819; the r2 and q2 of CoMSIA (comparative molecular similarity analysis) are 0.992 and 0.863, respectively. Molecular docking and MD simulations were conducted to confirm the detailed binding mode of enzyme-inhibitor system. The new NA inhibitors had been designed, synthesized, and their inhibitory activities against group-1 neuraminidase were determined. One agent displayed excellent neuraminidase inhibition, with IC50 value of 39.6 μM against NA, while IC50 value for oseltamivir is 61.1 μM. This compound may be further investigated for the treatment of infection by the new type influenza virus. Graphical abstract image
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Aspergillus candidus is a newly recognized source of sphaeropsidin A: Isolation, semi-synthetic derivatization and anticancer evaluation ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Yan Li, Robert Scott, Annie R. Hooper, Geoffrey A. Bartholomeusz, Alexander Kornienko, Gerald F. Bills This report details a search for alternative strains that produce the diterpenoid sphaeropsidin A (SphA) among A. candidus strains from the USDA Northern Regional Research Laboratories Culture Collection. We identified two strains that produced SphA using a limited set of test media. An initial scaled-up fermentation of NRRL 313 and isolation effort led to the procurement of sufficient quantities of SphA to prepare five semi-synthetic analogues (1–5) and evaluate their anticancer effects against glioblastoma cells D423 and Gli56 grown in 2D and 3D cultures. Although, the effectiveness of the synthetic analogues varied depending on the cell line and the type of cell culture, compound 5, bearing an aromatic ring at C16, displayed a stronger toxicity towards both D423 and Gli56 cell lines in 2D cultures and D423 spheroids in 3D culture than either SphA or compounds 1–4. Graphical abstract image
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New terpenoids and thiophene derivatives from the aerial parts of Artemisia sieversiana ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Xu-Dong Zhou, Chen Zhang, Shan He, Bin Zheng, Ke-Wu Zeng, Ming-Bo Zhao, Yong Jiang, Peng-Fei Tu One new highly oxygenated nortriterpene, named sieverlactone (1), one new sesquiterpene, 1β,10β-epoxy-8α-acetoxyachillin (2), one new natural product, 5-propinyl-thiophene-2-carboxylic acid (3), and one new thiophene, 3-hydroxy-5-propinyl-2-acetyl-thiophene (4), together with 10 other known compounds (5−14), were isolated from the dried aerial parts of Artemisia sieversiana. Their structures were elucidated by a combination of extensive spectroscopic analysis, including 1D, 2D NMR spectroscopic and mass spectrometric data. Meanwhile, the stereochemistry of 1 and 2 was confirmed by single-crystal X-ray diffraction technique using Cu radiation. All the isolates were evaluated for their anti-neuroinflammatory effects on the lipopolysaccharide-induced nitric oxide production in BV-2 murine microglial cells. Compounds 2, 5, and 6 exhibited the significant activities with IC50 values of 6.5 ± 0.5, 11.9 ± 0.7, and 10.1 ± 0.3 μM, respectively, comparable to the positive control, quercetin, with an IC50 value of 16.3 ± 0.4 μM. Graphical abstract image
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Novel all-hydrocarbon stapled p110α[E545K] peptides as blockers of the oncogenic p110α[E545K]-IRS1 interaction ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Xiao Hu, Yanhua He, Liping Wu, Yujun Hao, Zhenghe Wang, Weiping Zheng To follow up on our recent discovery of the 18-amino acid all-hydrocarbon [i, i + 4]-stapled p110α[E545K] peptide 1 that was shown to potently block the intracellular p110α[E545K]-IRS1 interaction (a protein-protein interaction uniquely present in cancer cells expressing p110α[E545K]) and the growth of the xenograft tumors formed by cancers harboring this mutation, in the current study we prepared and examined six derivatives of 1, i.e. stapled peptides 2-A, 2-B, 3-A, 3-B, 4-A, 4-B. We found that 2-A, 2-B, 4-A, and 4-B had higher % α-helicity than 1; moreover, the enhanced % α-helicity also led to an enhanced proteolytic stability. When compared with 1, the structurally simplified 14-amino acid 4-A and 4-B were found to more potently deactivate the AKT phosphorylation at Ser473 in the p110α[E545K]-expressing colon cancer cells, whose activation was previously demonstrated by us to be specifically derived from the p110α[E545K]-IRS1 interaction. The preliminary findings from the current study have laid a foundation for future more extensive studies on the stapled p110α[E545K] peptides newly identified in the current study. Graphical abstract image
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Identification of pyruvate dehydrogenase kinase 1 inhibitors with anti-osteosarcoma activity ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Aiping Fang, Huiqiang Luo, Liping Liu, Haibo Fan, Yaying Zhou, Yuqin Yao, Yue Zhang Overexpression of pyruvate dehydrogenase kinases (PDKs), especially PDK1 has been observed in a variety of cancers. Thus, targeting PDK1 offers an attractive opportunity for the development of cancer therapies. In this letter, we reported the identification of two novel PDK1 inhibitors as anti-osteosarcoma agents. We found that TM-1 and TM-2 inhibited PDK1 with the IC50 values of 2.97 and 3.41 μM, respectively. Furthermore, TM-1 and TM-2 dose-dependently reduced phosphorylation of pyruvate dehydrogenase complex in MG-63 osteosarcoma cells. Finally, TM-1 and TM-2 were found to inhibit the proliferation of MG-63 cells with the EC50 values of 14.5, and 11.0 μM, respectively, meaning TM-1 and TM-2 could be promising leads for the discovery of potent PDK1 inhibitors. Graphical abstract image
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Introduction of 2-O-benzyl abasic nucleosides to the 3′-overhang regions of siRNAs greatly improves nuclease resistance ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Yuki Nagaya, Yoshiaki Kitamura, Aya Shibata, Masato Ikeda, Yukihiro Akao, Yukio Kitade Chemically modified siRNAs containing 2-O-benzyl-1-deoxy-d-ribofuranose (RH OBn) in their 3′-overhang region were significantly more resistant towards serum nucleases than siRNAs possessing the natural nucleoside in this region. The knockdown efficacies and binding affinities of these modified siRNAs to the recombinant human Argonaute protein 2 (hAgo2) PAZ domain were comparable with that of siRNA with a thymidine dimer at the 3′-end. Graphical abstract image
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Synthesis, biological activities and SAR studies of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases as ketol-acid reductoisomerase inhibitors ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Bao-Lei Wang, Li-Yuan Zhang, Xing-Hai Liu, Yi Ma, Yan Zhang, Zheng-Ming Li, Xiao Zhang A series of new 3-substitutedphenyl-4-substitutedbenzylideneamino-1,2,4-triazole Mannich bases and bis-Mannich bases were synthesized through Mannich reaction with high yields. Their structures were confirmed by means of IR, 1H NMR, 13C NMR and elemental analysis. The preliminary bioassay indicated that compounds 7g, 7h and 7l exhibited potent in vitro inhibitory activities against ketol-acid reductoisomerase (KARI) with K i value of (0.38 ± 0.25), (6.59 ± 2.75) and (8.46 ± 3.99) μmol/L, respectively, and were comparable with IpOHA. They could be new KARI inhibitors for follow-up research. Some of the title compounds also exhibited obvious herbicidal activities against Echinochloa crusgalli and remarkable in vitro fungicidal activities against Physalospora piricola and Rhizoctonia cerealis. The SAR of the compounds were analyzed, in which the molecular docking revealed the binding mode of 7g with the KARI, and the 3D-QSAR results provided useful information for guiding further optimization of this kind of structures to discover new fungicidal agents towards Rhizoctonia cerealis. Graphical abstract image
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Imidazo[1,2-a]pyridines linked with thiazoles/thiophene motif through keto spacer as potential cytotoxic agents and NF-κB inhibitors ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Kamala K. Vasu, Chander Singh Digwal, Amit N. Pandya, Dhaivat H. Pandya, Jayesh A. Sharma, Sneha Patel, Milee Agarwal A series of new imidazo[1,2-a]pyridine linked with thiazole/thiophene motif through a keto spacer were synthesized and tested for their cytotoxic potential against three human cancer cell lines including A549, HeLa and U87-MG using MTT assay. Compounds A2, A3, A4, C1 and C2 showed cytotoxicity against all the three cell lines. The selectivity index for compound A4 for A549 and HeLa cells was comparable to that of doxorubicin. Among the synthesized compounds, B5 showed the maximum inhibition of NF-κB activity as ascertained by NF-κB reporter assay (IC50 = 6.5 ± 0.6 µM). Treatment of NCI-H23 cells (EGFR overexpressed, KRAS G12V mutant) with erlotinib and gefitinib along with compounds A4 and B5 indicated synergistic and additive potential of combination therapy. Graphical abstract image
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Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2 ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Emily R. Hankosky, Shyam R. Joolakanti, Justin R. Nickell, Venumadhav Janganati, Linda P. Dwoskin, Peter A. Crooks A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [3H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [3H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [3H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [3H]DA uptake at VMAT2, Ki changes in the nanomolar range (Ki = 0.014–0.073 µM). Compound 15d exhibited the highest affinity (Ki = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (Ki = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2. Graphical abstract image
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Fragment-based design, synthesis, biological evaluation, and SAR of 1H-benzo[d]imidazol-2-yl)-1H-indazol derivatives as potent PDK1 inhibitors ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Ting Chen, Venkataswamy Sorna, Susie Choi, Lee Call, Jared Bearss, Kent Carpenter, Steven L. Warner, Sunil Sharma, David J. Bearss, Hariprasad Vankayalapati In this work, we describe the use of the rule of 3 fragment-based strategies from biochemical screening data of 1100 in-house, small, low molecular weight fragments. The sequential combination of in silico fragment hopping and fragment linking based on S160/Y161/A162 hinge residues hydrogen bonding interactions leads to the identification of novel 1H-benzo[d]imidazol-2-yl)-1H-indazol class of Phosphoinositide-Dependent Kinase-1 (PDK1) inhibitors. Consequent SAR and follow-up screening data led to the discovery of two potent PDK1 inhibitors: compound 32 and 35, with an IC50 of 80 nM and 94 nM, respectively. Further biological evaluation showed that, at the low nanomolar concentration, the drug had potent ability to inhibit phosphorylation of AKT and p70S6, and selectively kill the cancer cells with mutations in both PTEN and PI3K. The microarray data showed that DUSP6, DUSP4, and FOSL1 were down-regulated in the sensitive cell lines with the compound treatment. The in vivo test showed that 35 can significantly inhibit tumor growth without influencing body weight growth. Our results suggest that these compounds, especially 35, merit further pre-clinical evaluation. Graphical abstract image
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Potential anti-proliferative agents from 1,4-benzoxazinone-quinazolin-4(3H)-one templates ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Rajitha Bollu, Saleha Banu, Suresh Kasaboina, Rajashaker Bantu, Lingaiah Nagarapu, Sowjanya Polepalli, Nishant Jain A novel synthetic protocol has been developed for the synthesis of 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids 7a–n by employing Pd-catalyzed CH arylation in presence of 5–10% phosphine ligand in good to excellent yields and evaluated for their anti-proliferative activity against three cancer cell lines such as A549 (lung), HeLa (cervical), MDA-MB-231 (breast). Compounds 7d, 7f, 7l and 7n exhibited promising anti-proliferative activity with GI50 values ranging from 0.37 to 2.73 µM respectively against A549, HeLa, and MDA-MB-231, while compound 7f showed significant activity against MDA-MB-231 with GI50 value 0.58 µM, 7j showed significant activity against A549 with GI50 value 0.32 µM and 7l showed significant activity against HeLa with GI50 value 0.37 µM. This is the first report on the synthesis and in vitro anti-proliferative evaluation of 1,4-benzoxazinone-acetylphenylallyl quinazolin-4(3H)-one hybrids. Graphical abstract image
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Protective effect of Opuntia ficus-indica L. cladodes against UVA-induced oxidative stress in normal human keratinocytes ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): Ganna Petruk, Flaviana Di Lorenzo, Paola Imbimbo, Alba Silipo, Andrea Bonina, Luisa Rizza, Renata Piccoli, Daria Maria Monti, Rosa Lanzetta Opuntia ficus-indica L. is known for its beneficial effects on human health, but still little is known on cladodes as a potent source of antioxidants. Here, a direct, economic and safe method was set up to obtain water extracts from Opuntia ficus-indica cladodes rich in antioxidant compounds. When human keratinocytes were pre-treated with the extract before being exposed to UVA radiations, a clear protective effect against UVA-induced stress was evidenced, as indicated by the inhibition of stress-induced processes, such as free radicals production, lipid peroxidation and GSH depletion. Moreover, a clear protective effect against apoptosis in pre-treated irradiated cells was evidenced. We found that eucomic and piscidic acids were responsible for the anti-oxidative stress action of cladode extract. In conclusion, a bioactive, safe, low-cost and high value-added extract from Opuntia cladodes was obtained to be used for skin health/protection. Graphical abstract image
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PSMA-targeted bispecific Fab conjugates that engage T cells ()
Publication date: 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 24 Author(s): James T. Patterson, Jason Isaacson, Lisa Kerwin, Ghazi Atassi, Rohit Duggal, Damien Bresson, Tong Zhu, Heyue Zhou, Yanwen Fu, Gunnar F. Kaufmann Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an αCD3 Fab enabled installation of either the PSMA-targeting small molecule DUPA (SynFab) or the attachment of an αPSMA Fab (BisFab) by covalent linkage. Optimization of the reducing conditions was critical for selective interchain disulfide reduction and good bioconjugate yield. Activity of αPSMA/CD3 Fab conjugates was tested by in vitro cytotoxicity assays using prostate cancer cell lines. Both bispecific formats demonstrated excellent potency and antigen selectivity. Graphical abstract image
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Enhanced intracellular peptide delivery by multivalent cell-penetrating peptide with bioreducible linkage ()
Publication date: Available online 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Hyungjin Kim, Mizuki Kitamatsu, Takashi Ohtsuki Multivalent cell-penetrating peptides (CPPs) have been reported to show enhancement in cellular uptake and endosomolytic activity. However, its application was limited to trans-delivery of cargo which is lower in cellular uptake efficiency of cargo than cis-delivery. Here, we tried the cis-delivery of cargo with multivalent CPP by preparing bioreducible dimeric CPP−cargo with apoptotic activity using TatBim peptide, a fusion of Tat CPP and Bim peptide derived from Bim apoptosis-inducing protein. Dimeric TatBim was almost twice as highly internalized by cells and significantly induced apoptosis compared to monomeric TatBim. Contribution of bioreducible linkage of dimeric TatBim towards apoptotic activity was also confirmed. Graphical abstract image
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Molecular determinants of loperamide and N-desmethyl loperamide binding in the hERG cardiac K+ channel ()
Publication date: Available online 15 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Roy J Vaz, Jiesheng Kang, Yongyi Luo, David Rampe Abuse of the common anti-diarrheal loperamide is associated with QT interval prolongation as well as development of the potentially fatal arrhythmia torsades de pointes. The mechanism underlying this cardiotoxicity is high affinity inhibition of the human ether-a-go-go-related gene (hERG) cardiac K+ channel. N-desmethyl loperamide is the major metabolite of loperamide and is a close structural relative of the parent molecule. To date no information is available regarding the affinity of N-desmethyl loperamide for human cardiac ion channels. The effects of N-desmethyl loperamide on various cloned human cardiac ion channels including hERG, KvLQT1/mink and Nav1.5 were studied and compared to that of the parent. N-desmethyl loperamide was a much weaker (7.5-fold) inhibitor of hERG compared to loperamide. However, given the higher plasma levels of the metabolite relative to the parent, it is likely that N-desmethyl loperamide can contribute, at least secondarily, to the cardiotoxicity observed with loperamide abuse. We used the recently solved cryo-EM structure of the hERG channel together with previously published inhibitors, to understand the basis of the interactions as well as the difference that a single methyl plays in the hERG channel blocking affinities of these two compounds. Graphical abstract image
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Downregulation of Akt2 attenuates ER stress-induced cytotoxicity through JNK-Wnt pathway in cardiomyocytes ()
Publication date: Available online 14 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Yan-Xia Gao, Wen-Ting He, Long-Fei Pan, Hui Feng, Jiang-Li Sun, Bin Zhang, Lei Yu, Li-Jun Li Akt, also known as protein kinase B (PKB), is a serine/threonine kinase that promotes survival and growth in response to extracellular signals. Akt1 has been demonstrated to play vital roles in cardiovascular diseases, but the role of Akt2 in cardiomyocytes is not fully understood. This study investigated the effect of Akt2 knockdown on tunicamycin (TM)-induced cytotoxicity in cardiomyocytes and the underlying mechanisms with a focus on the JNK-Wnt pathway. TM treatment significantly increased the expression of Akt2 at both mRNA and protein levels, which was shown to be mediated by the induction of reactive oxygen species (ROS). Knockdown of Akt2 expression via siRNA transfection markedly increased cell viability, decreased lactate dehydrogenase (LDH) release and reduced cell apoptosis after TM exposure. The results of western blot showed that downregulation of Akt2 also attenuated the TM-induced activation of the unfolded protein response (UPR) factors and ER stress associated pro-apoptotic proteins. In addition, Si-Akt2 transfection partially prevented the TM-induced decrease in nuclear localization of β-catenin. By using the selective inhibitor SP-600125 to inhibit JNK phosphorylation, we found that knockdown of Akt2-induced protection and inhibition of ER stress was mediated by reversing TM-induced decrease of Wnt through the JNK pathway. In summary, these data suggested that Akt2 play a pivotal role in regulating cardiomyocyte survival during ER stress by modulating the JNK-Wnt pathway. Graphical abstract image
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Synthesis and Biological Evaluation of Novel Mono- and Bivalent ASGP-R-targeted Drug-conjugates ()
Publication date: Available online 14 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Rostislav A. Petrov, Svetlana Yu. Maklakova, Yan A. Ivanenkov, Stanislav A. Petrov, Olga V. Sergeeva, Emil Yu. Yamansarov, Irina V. Saltykova, Igor I. Kireev, Irina B. Alieva, Ekaterina V. Deyneka, Alina A. Sofronova, Anastasiia V. Aladinskaia, Alexandre V. Trofimenko, Renat S. Yamidanov, Sergey V. Kovalev, Victor E. Kotelianski, Timofey S. Zatsepin, Elena K. Beloglazkina, Alexander G. Majouga Asialoglycoprotein receptor (ASGP-R) is a promising biological target for drug delivery into hepatoma cells. Nevertheless, there are only few examples of small-molecule conjugates of ASGP-R selective ligand equipped by a therapeutic agent for the treatment of hepatocellular carcinoma (HCC). In the present work, we describe a convenient and versatile synthetic approach to novel mono- and multivalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose and anticancer drug – paclitaxel (PTX). Several molecules have demonstrated high affinity towards ASGP-R and good stability under physiological conditions, significant in vitro anticancer activity comparable to PTX, as well as good internalization via ASGP-R-mediated endocytosis. Therefore, the conjugates with the highest potency can be regarded as a promising therapeutic option against HCC. Graphical abstract image
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Hybrid Peptide-Small Molecule Oxytocin Analogs are Potent and Selective Agonists of the Oxytocin Receptor ()
Publication date: Available online 13 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Natasha Kablaoui, Michelle Vanase-Frawley, Simone Sciabola Oxytocin (OT) is a peptide hormone agonist of the oxytocin receptor (OTR) that has been proposed as a therapeutic to treat a number of social and emotional disorders in addition to its current clinical use to induce labor and treat postpartum bleeding. OT is administered intravenously and intranasally rather than orally, in part because its low passive permeability causes low oral bioavailability. Non-peptidic OTR agonists have also been reported, but none with the exquisite potency of the peptide based agonists. In this report, we describe the OTR agonist activity and exposed polarity of a set of truncated OT analogs as well as hybrid peptide-small molecule analogs of OT. Examples of both truncated analogs and peptide-small molecule hybrid analogs are potent and selective OTR agonists. Hybrid agonist 13, which is 232 daltons smaller than OT, still retains subnanomolar potency, full agonist activity, and selectivity over V1a. While these compounds were designed to address the low permeability of OT and other full length analogs, we found that reduction in molecular weight and the removal or replacement of the three amino acid tail of OT did not have a significant effect on passive permeability. Graphical abstract image
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Design, synthesis, and evaluation of novelinhibitors for wild-type human serine racemase ()
Publication date: Available online 13 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Satoyuki Takahara, Kiyomi Nakagawa, Tsugumi Uchiyama, Tomoyuki Yoshida, Kazunori Matsumoto, Yasuo Kawasumi, Mineyuki Mizuguchi, Takayuki Obita, Yurie Watanabe, Daichi Hayakawa, Hiroaki Gouda, Hisashi Mori, Naoki Toyooka Most of the endogenous free D-serine (about 90%) in the brain is produced by serine racemase (SR). D-Serine in the brain is involved in neurodegenerative disorders and epileptic states as an endogenous co-agonist of the NMDA-type glutamate receptor. Thus, SR inhibitors are expected to be novel therapeutic candidates for the treatment of these disorders. In this study, we solved the crystal structure of wild-type SR, and tried to identify a new inhibitor of SR by in silico screening using the structural information. As a result, we identified two hit compounds by their in vitro evaluations using wild-type SR. Based on the structure of the more potent hit compound 1, we synthesized 15 derivatives and evaluated their inhibitory activities against wild-type SR. Among them, the compound 9C showed relatively high inhibitory potency for wild-type SR. Compound 9C was a more potent inhibitor than compound 24, which was synthesized by our group based upon the structural information of the mutant-type SR. Graphical abstract image
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Effects of newly synthetized isoquinoline derivatives on rat uterine contractility and ROCK II activity ()
Publication date: Available online 13 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): D. Domokos, F. Fülöp, G. Falkay, R. Gáspár Protein kinases have an important role in signal transduction in the cellular system via protein phosphorylation. RhoA activated Rho-kinases have a pivotal role in the regulation of smooth muscle contraction. ROCK I and ROCK II phosphorylate myosin-phosphatase and myosin-kinase, which induces contraction in the myometrium. Several studies have investigated the affinity of isoquinoline alkaloids (HA-1077, H1152P) to Rho-kinases, and these compounds notably inhibited the Ca2+ -independent process. We measured the efficiency of 25 original, newly synthesized isoquinoline derivatives for the Rho-kinase activity using Rho-associated kinase activity assay and determined their effects on the non-pregnant, 20-day pregnant and parturient rat myometrial contraction in vitro. The IC50 values of 11 from among the 25 derivatives were significantly lower on the oxytocin-induced non-pregnant rat uterine contraction compared with Y-27632 and fasudil, although their maximal inhibitory effects were weaker than those of Y-27632 and fasudil. We measured the effects of 11 isoquinoline molecules with significant IC50 values on ROCK II activity. We found two isoquinolines out of 11 compounds (218 and 852) which decreased the active ROCK II level similarly as Y-27632. Then we found that 218 and 852 relaxed the 20th-day pregnant and parturient rat uterus with greater potency as compared with fasudil. The majority of the synthesized isoquinoline derivatives have uterus relaxant effects and two of them significantly suppress the Rho-kinase mediated myosin light chain phosphorylation. Our results may suggest that the isoquinoline structure has a promising prospect for the development of new and effective inhibitors of uterine contractions in preterm birth. Graphical abstract image
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Synthesis of pentacyclic iminosugars with constrained butterfly-like conformation and their HIV-RT inhibitory activity ()
Publication date: Available online 13 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Lianhai Yan, Zhuqing Yin, Liping Niu, Jie Shao, Hua Chen, Xiaoliu Li Novel pentacyclic iminosugars 1 and 2 with the constrained butterfly-like conformation were first synthesized by the key intramolecular click reaction from the tricyclic iminosugars fused benzo[e][1,3]thiazin-4-one 3 and 4. The pentacyclic iminosugar was constructed by fusing both benzo[e][1,3]thiazin-4-one and triazolo[5,1-c][1,4]oxazepine scaffolds. Their structures were determined by their 1H, 13C NMR, and HRMS (ESI) spectra and X-Ray. The pentacyclic iminosugars 1(a-c), 2(a-b) and their corresponding protected precursors 13(a-c) and 14(a-b) were examined for their HIV reverse transcriptase (RT) inhibitory activities. The result showed that all compounds could effectively inhibit RT activity. Among them, compound 13c was the best one with the IC50 value of RT inhibitory activity of 0.69 μM. Structure-activity relationship analysis suggested that the improvement of the hydrophilicity of the pentacycles was of benefit to their anti-HIV RT activity. Graphical abstract image
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Cytotoxicity and inhibition of leukemic cell proliferation by sesquiterpenes from rhizomes of Mah-Lueang (Curcuma cf. viridiflora Roxb.) ()
Publication date: Available online 13 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Songyot Anuchapreeda, Nattakanwadee Khumpirapang, Kawinnat Rupitiwiriya, Leelawat Tho-iam, Aroonchai Saiai, Siriporn Okonogi, Toyonobu Usuki Curcuma cf. viridiflora Roxb., also known as Mah-Lueang in Thai, belongs to the Zingiberaceae family and is grown from rhizomes. The rhizome of the plant has been used for medicinal purposes, in particular, to treat paralysis in Thai traditional medicine. However, no biologically active compounds have been reported from Mah-Lueang yet. In this study, natural compounds were isolated from Mah-Lueang and structurally determined by spectroscopic methods, including electrospray ionization mass spectrometry and nuclear magnetic resonance. The four isolated compounds were identified as furanodiene (1), dehydrocurdione (2), germacrone-4,5-epoxide (3), and zedoarondiol (4). These sesquiterpenes were investigated for antileukemic activities against KG1a and Molt4 cells. Leukemic cell proliferation is regulated by the Wilms’ tumor 1 (WT1) transcription factor. Compound 1 showed the strongest cytotoxicity against both KG1a and Molt4 cells. Noncytotoxic concentrations (20% inhibitory concentration values) of all compounds were able to decrease the WT1 protein expression and total cell numbers in both cell lines. The four compounds showed good inhibitory activities for WT1 protein expression. Compounds 3 and 4 showed excellent antileukemic activities for both cell lines. In summary, four sesquiterpene compounds with antileukemic activities against the KG1a and Molt4 cell lines were identified in Mah-Lueang extracts. Graphical abstract image
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Identification of Novel Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 by Cross Docking-based Virtual Screening ()
Publication date: Available online 13 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Fangxia Zou, Stefan Pusch, Jie Hua, Tianfang Ma, Lijun Yang, Qihua Zhu, Yungen Xu, Yueqing Gu, Andreas von Deimling, Xiaoming Zha IDH1 mutation (mIDH1) occurs in 20-30% of gliomas and is a promising target for the cancer therapy. In this article, a cross docking-based virtual screening was employed to identify seven small molecules for the allosteric site of mIDH1. Compounds ZX01, ZX05 and ZX06 exhibited the potent inhibitory activity and the high selectivity against WT-IDH1, providing a good starting point for the further development of highly selective mIDH1 inhibitors. Importantly, the parallel artificial membrane permeation assay of the blood-brain barrier (PAMPA-BBB) identified ZX06 with a good ability to penetrate BBB. These findings indicate that ZX06 deserves further optimization as a lead compound for the treatment of patients with IDH1 mutated brain cancers. Graphical abstract image
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Small molecule SUMOylation activators are novel neuroprotective agents ()
Publication date: Available online 13 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Katherine Krajnak, Russell Dahl Neuronal loss characterizes many of the most intractable nervous system diseases that deprive our ageing population of their quality of life. Neuroprotective pharmacological modalities are urgently needed to address this burgeoning population. Small ubiquitin-like modifier (SUMO) conjugation has been established as an endogenous neuroprotective response, and we have discovered several classes of small molecules that enhance SUMO conjugation. Herein we describe the hit to lead campaign that enabled the discovery of 3 diverse classes of drug-like SUMOylation activators. Optimized compounds were ultimately validated in cell-based models of neuronal loss and provide a foundation for establishing systemically active SUMO activators to treat degenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and stroke. Graphical abstract image
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Discovery of 2-arylquinazoline derivatives as a new class of ASK1 inhibitors ()
Publication date: Available online 13 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Andrii Monastyrskyi, Simon Bayle, Victor Quereda, Wayne Grant, Michael Cameron, Derek Duckett, William Roush The development of a new series of apoptosis signal-regulating kinase 1 (ASK1) inhibitors is described. Starting from purine, pyrimidine and quinazoline scaffolds identified by high throughput screening, we used tools of structure-based drug design to develop a series of potent kinase inhibitors, including 2-arylquinazoline derivatives 12 and 23, with submicromolar inhibitory activities against ASK1. Kinetic analysis demonstrated that the 2-arylquinazoline scaffold ASK1 inhibitors described herein are ATP competitive. Graphical abstract image
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Structural Development of Tetrachlorophthalimides as Liver X Receptor β (LXRβ)-Selective Agonists with Improved Aqueous Solubility ()
Publication date: Available online 13 December 2017 Source:Bioorganic & Medicinal Chemistry Letters Author(s): Sayaka Nomura, Kaori Endo-Umeda, Shinya Fujii, Makoto Makishima, Yuichi Hashimoto, Minoru Ishikawa LXRβ-selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. We have reported a series of tetrachlorophthalimide analogs as an LXRβ-selective agonist. However, they exhibited poor aqueous solubility probably due to its high hydrophobicity and highly rigid and plane structure. In this report, we present further structural development of tetrachloro(styrylphenyl)phthalimides as the LXRβ-selective agonists with improved aqueous solubility. Graphical abstract image
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