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• The discovery and development of selective 3-fluoro-4-aryloxyallylamine inhibitors of the amine oxidase activity of semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1).

  Authors: Jonathan S Foot, Mandar Deodhar, Craig I Turner, Ping Yin, Ellen M van Dam, Diego G Silva, Aldo Olivieri, Andrew Holt, Ian A McDonald

  Bioorganic & medicinal chemistry letters.

  A new class of 3-fluoroallyl amine-based SSAO/VAP-1 inhibitors is reported. These compounds have excellent selectivity over diamine oxidase, MAO-A and MAO-B. Synthesis and SAR studies leading toA new class of 3-fluoroallyl amine-based SSAO/VAP-1 inhibitors is reported. These compounds have excellent selectivity over diamine oxidase, MAO-A and MAO-B. Synthesis and SAR studies leading to compound 28 (PXS-4159A) are reported. The pharmacokinetic profile of 28 in the rat, together with activity in a murine model of lung inflammation are also disclosed.

• E297G mutated bile salt export pump (BSEP) function enhancers derived from GW4064: Structural development study and separation from farnesoid X receptor-agonistic activity.

  Authors: Takashi Misawa, Hisamitsu Hayashi, Makoto Makishima, Yuichi Sugiyama, Yuichi Hashimoto

  Bioorganic & medicinal chemistry letters.

  Bile salt export pump (BSEP) is a member of the ATP-binding cassette transmembrane transporter family and mediates biliary excretion of bile acids from hepatocytes. Several BSEP mutants, includingBile salt export pump (BSEP) is a member of the ATP-binding cassette transmembrane transporter family and mediates biliary excretion of bile acids from hepatocytes. Several BSEP mutants, including Glu297Gly (E297G) and Asp482Gly (D482G), cause progressive familial intrahepatic cholestasis type 2. We previously found that compounds based on GW4064, a representative farnesoid X receptor (FXR) agonist, enhanced E297G BSEP transport activity. Here, we conducted a structure-activity relationship analysis of GW4064 derivatives aimed at separating E297G BSEP-function-promoting activity and FXR-agonistic activity. Among newly synthesized reversed-amide derivatives of previously reported GW4064 analogs 2a-2f, we identified 7c as a selective BSEP function enhancer.

• Identification of benzoxazole analogs as novel, S1P(3) sparing S1P(1) agonists.

  Authors: Guanghui Deng, Qinghua Meng, Qian Liu, Xuesong Xu, Qiongfeng Xu, Feng Ren, Taylor B Guo, Hongtao Lu, Jia-Ning Xiang, John D Elliott, Xichen Lin

  Bioorganic & medicinal chemistry letters.

  A novel series of benzoxazole-derived S1P(1) agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to theA novel series of benzoxazole-derived S1P(1) agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P(1) agonist (over S1P(3)) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.

• Investigation of the nucleotide triphosphate substrate specificity of Homo sapiens UDP-N-acetylgalactosamine pyrophosphorylase (AGX1).

  Authors: Mengyang Xue, Wanyi Guan, Yang Zou, Junqiang Fang, Xian-Wei Liu, Peng George Wang, Fengshan Wang

  Bioorganic & medicinal chemistry letters.

  Nucleotide sugars are essential glycosyl donors for Leloir-type glycosyltransferases. The UDP-N-acetylgalactosamine pyrophosphorylase (UDP-GalNAc PP; AGX1) from Homo sapiens catalyzes the synthesisNucleotide sugars are essential glycosyl donors for Leloir-type glycosyltransferases. The UDP-N-acetylgalactosamine pyrophosphorylase (UDP-GalNAc PP; AGX1) from Homo sapiens catalyzes the synthesis of UDP-N-acetylgalactosamine from N-acetylgalactosamine 1-phosphate and UTP. In this Letter, we systematically studied nucleotide substrate specificity of AGX1 during its uridyltransfer reaction, and described the capability of AGX1 to catalyze dUTP and dTTP to their corresponding nucleotide sugars for the first time. Furthermore, using such a eukaryotic enzyme, we synthesized dUDP-GalNAc and dTDP-GalNAc in multiple mg scale in vitro efficiently and rapidly.

• N-Acyl and N-sulfonyloxazolidine-2,4-diones are pseudo-irreversible inhibitors of serine proteases.

  Authors: Ana Bela Santana, Susana D Lucas, Lídia M Gonçalves, Henrique F Correia, Teresa A F Cardote, Rita C Guedes, Jim Iley, Rui Moreira

  Bioorganic & medicinal chemistry letters.

  The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature ofThe synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation. The title compounds were also shown to be potent inhibitors of human neutrophil elastase (HNE) and proteinase-3, and weak inhibitors of human cathepsin G. The results herein presented show that the oxazolidine-2,4-diones represent a new promising class of serine protease inhibitors.

• Discovery of novel EGFR tyrosine kinase inhibitors by structure-based virtual screening.

  Authors: Siyuan Li, Xianqiang Sun, Hongli Zhao, Yun Tang, Minbo Lan

  Bioorganic & medicinal chemistry letters.

  By using of structure-based virtual screening, 13 novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were discovered from 197,116 compounds in the SPECS database here. AmongBy using of structure-based virtual screening, 13 novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors were discovered from 197,116 compounds in the SPECS database here. Among them, 8 compounds significantly inhibited EGFR kinase activity with IC(50) values lower than 10μM. 3-{[1-(3-Chloro-4-fluorophenyl)-3,5-dioxo-4-pyrazolidinylidene]methyl}phenyl 2-thiophenecarboxylate (13), particularly, was the most potent inhibitor possessing the IC(50) value of 3.5μM. The docking studies also provide some useful information that the docking models of the 13 compounds are beneficial to find a new path for designing novel EGFR inhibitors.

• Thieno[3,2-d]pyrimidin-4(3H)-one derivatives as PDK1 inhibitors discovered by fragment-based screening.

  Authors: Angeline C-H Lee, Pondy Murugappan Ramanujulu, Anders Poulsen, Meredith Williams, Stéphanie Blanchard, Diana M Ma, Zahid Bonday, Kay Lin Goh, Kee Chuan Goh, Miah Kiat Goh, Jeanette Wood, Brian W Dymock

  Bioorganic & medicinal chemistry letters.

  Ligand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design andLigand efficient fragments binding to PDK1 were identified by an NMR fragment-based screening approach. Computational modeling of the fragments bound to the active site led to the design and synthesis of a series of novel 6,7-disubstituted thienopyrimidin-4-one compounds, with low micromolar inhibitory activity against PDK1 in a biochemical enzyme assay.

• Kappa agonist CovX-Bodies.

  Authors: Lee R Roberts, Kevin Brady, Amy Brown, Doreen Davey, Lijin Feng, Hanhua Huang, Dingguo Liu, Laia Malet, Gordon McMurray, Anne Phelan, Ken Saunders, Abhijit Bhat

  Bioorganic & medicinal chemistry letters.

  Small peptidic kappa agonists were covalently linked to the reactive lysine of the CovX antibody to create compounds having potent activity at the kappa receptor with greatly extended half-life whenSmall peptidic kappa agonists were covalently linked to the reactive lysine of the CovX antibody to create compounds having potent activity at the kappa receptor with greatly extended half-life when compared to the parent peptide as exemplified by compound 20.

• The antibacterial activity of 4,4'-bipyridinium amphiphiles with conventional, bicephalic and gemini architectures.

  Authors: Melissa C Grenier, Robert W Davis, Kelsey L Wilson-Henjum, Jade E Ladow, Jacob W Black, Kevin L Caran, Kyle Seifert, Kevin P C Minbiole

  Bioorganic & medicinal chemistry letters.

  Dialkyl 4,4'-bipyridinium compounds are widely employed for their useful redox properties, and are commonly known as viologens due to their intense coloration upon reduction. Despite their prevalenceDialkyl 4,4'-bipyridinium compounds are widely employed for their useful redox properties, and are commonly known as viologens due to their intense coloration upon reduction. Despite their prevalence and amphiphilic nature, the antibacterial activity of these compounds remains largely unreported. We have thus prepared a series of mono- and bis-alkylated analogs of 4,4'-bipyridine to investigate structure-activity relationships in their inhibition of a battery of Gram positive and Gram negative bacteria. The prepared cationic compounds were conventional (one cationic head, one non-polar tail), bicephalic (two heads, one tail), or gemini (two heads, two tails) in their amphiphilic structure. Additionally, an isomeric series of six bis-alkylated compounds ranging from symmetric (PQ-11,11) to highly asymmetric (PQ-20,2) were prepared. Four themes of bioactivity emerged: (1) the most bioactive compounds were gemini in structure; (2) 22 carbons in the alkyl chains, with little to modest asymmetry, led to optimal activity; (3) bicephalic compounds were generally comparable to conventional amphiphiles, though only about 12 carbons in the alkyl chains were solubilized in water by each cationic nitrogen; (4) the effects of counterion identity were not evident between chlorides and bromides; however, the presence of the iodide counterion inhibited dissolution in all compounds tested. Three isomeric compounds with little to no asymmetry in tail length, PQ-11,11, PQ-12,10, and PQ-14,8, prepared as the bromide salts, showed comparable and highly potent activity, with MIC levels around 2μM against 3 of 4 bacteria tested. The simple (one- to two-step) syntheses of potent antimicrobials portend well for future optimization.

• Anion-selective transport activities of tetrameric sterol-spermine conjugates.

  Authors: Wen-Hua Chen, Jia Zhou, Yong-Min Wang

  Bioorganic & medicinal chemistry letters.

  Three tetrameric sterol-spermine conjugates were shown to be capable of mediating chloride transport across 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC)-based liposomal membranes viaThree tetrameric sterol-spermine conjugates were shown to be capable of mediating chloride transport across 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC)-based liposomal membranes via an anion-exchange mechanism. Of the three conjugates, the one that was derived from deoxycholic acid showed the highest activity. Such anion transporting properties may provide molecular basis for the antibacterial activities of these sterol-spermine tetramers. In other words, they function as antibiotics, most probably via the formation of anion-selective pores or channels.

• Synthesis of a ratiometric fluorescent peptide sensor for the highly selective detection of Cd(2+).

  Authors: Yan Li, Lianzhi Li, Xuewei Pu, Guolin Ma, Erqiong Wang, Jinming Kong, Zhipeng Liu, Yangzhong Liu

  Bioorganic & medicinal chemistry letters.

  A novel ratiometric fluorescent peptidyl chemosensor (Dansyl-Cys-Pro-Gly-Cys-Trp-NH(2), D-P5) for metal ions detection has been synthesized via Fmoc solid-phase peptide synthesis. The chemosensorA novel ratiometric fluorescent peptidyl chemosensor (Dansyl-Cys-Pro-Gly-Cys-Trp-NH(2), D-P5) for metal ions detection has been synthesized via Fmoc solid-phase peptide synthesis. The chemosensor exhibited a high selectivity for Cd(2+) over other metal ions including competitive transition and Group I and II metal ions in neutral pH. The fluorescence emission intensity of D-P5 was significantly enhanced in the presence of Cd(2+) by fluorescent resonance energy transfer (FRET) and chelation enhanced fluorescence (CHEF) effects. The binding stoichiometry, detection limit, binding affinity, reversibility and pH sensitivity of the sensor for Cd(2+) were investigated.

• Synthesis and structure-activity relationship of aminopyridines with substituted benzoxazoles as c-Met kinase inhibitors.

  Authors: Jongkook Lee, Sun-Young Han, Heejung Jung, Jeon Yang, Jie-Won Choi, Chong Hack Chae, Chi Hoon Park, Sang Un Choi, Kwangho Lee, Jae Du Ha, Chong Ock Lee, Jae Wook Ryu, Hyoung Rae Kim, Jong Sung Koh, Sung Yun Cho

  Bioorganic & medicinal chemistry letters.

  A series of hydroxybenzoxazole derivatives was synthesized, and their c-Met kinase inhibitory activity was evaluated. Described herein is a potent c-Met inhibitor by structural modification of theA series of hydroxybenzoxazole derivatives was synthesized, and their c-Met kinase inhibitory activity was evaluated. Described herein is a potent c-Met inhibitor by structural modification of the parent benzoxazole scaffold, with particular focus on the hydroxyl substituent of the benzoxazole moiety.

• Discovery and optimization of a potent and selective triazolopyridinone series of c-Met inhibitors.

  Authors: Christiane M Bode, Alessandro A Boezio, Brian K Albrecht, Steven F Bellon, Loren Berry, Martin A Broome, Deborah Choquette, Isabelle Dussault, Richard T Lewis, Min-Hwa Jasmine Lin, Karen Rex, Douglas A Whittington, Yajing Yang, Jean-Christophe Harmange

  Bioorganic & medicinal chemistry letters.

  Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of aDeregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, we report the discovery of a structurally diverse series of carbon-linked quinoline triazolopyridinones, which demonstrates nanomolar inhibition of c-Met kinase activity. This novel series of inhibitors exhibits favorable pharmacokinetics as well as potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver pharmacodynamic model.

• Design and synthesis of gambogic acid analogs as potent cytotoxic and anti-inflammatory agents.

  Authors: Chiao-Ting Yen, Kyoko Nakagawa-Goto, Tsong-Long Hwang, Susan L Morris-Natschke, Kenneth F Bastow, Yang-Chang Wu, Kuo-Hsiung Lee

  Bioorganic & medicinal chemistry letters.

  Prenyl- and pyrano-xanthones derived from 1,3,6-trihydroxy-9H-xanthen-9-one, a basic backbone of gambogic acid (GA), were synthesized and evaluated for in vitro cytotoxic effects against four humanPrenyl- and pyrano-xanthones derived from 1,3,6-trihydroxy-9H-xanthen-9-one, a basic backbone of gambogic acid (GA), were synthesized and evaluated for in vitro cytotoxic effects against four human cancer cell lines (KB, KBvin, A549, and DU-145) and anti-inflammatory activity toward superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. Among them, prenylxanthones 7-13 were generally less active than pyranoxanthones 14-21 in both anticancer and anti-inflammatory assays. Furthermore, two angular 3,3-dimethypyranoxanthones (16 and 20) showed the greatest and selective activity against the KBvin multidrug resistant (MDR) cell line with IC(50) values of 0.9 and 0.8μg/mL, respectively. An angular 3-methyl-3-prenylpyranoxanthone (17) selectively inhibited elastase release with 200 times more potency than phenylmethylsulfonyl fluoride (PMSF), the positive control.

• Acylprolinamides: A new class of peptide deformylase inhibitors with in vivo antibacterial activity.

  Authors: Jeffrey M Axten, Jesús R Medina, Charles W Blackledge, Céline Duquenne, Seth W Grant, Mark A Bobko, Tony Peng, William H Miller, Theresa Pinckney, Timothy F Gallagher, Swarupa Kulkarni, Thomas Lewandowski, Glenn S Van Aller, Rimma Zonis, Paris Ward, Nino Campobasso

  Bioorganic & medicinal chemistry letters.

  A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that wereA new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.

• Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13.

  Authors: Mi-Sun Yu, June Lee, Jin Moo Lee, Younggyu Kim, Young-Won Chin, Jun-Goo Jee, Young-Sam Keum, Yong-Joo Jeong

  Bioorganic & medicinal chemistry letters.

  Severe acute respiratory syndrome (SARS) is an infectious disease with a strong potential for transmission upon close personal contact and is caused by the SARS-coronavirus (CoV). However, there areSevere acute respiratory syndrome (SARS) is an infectious disease with a strong potential for transmission upon close personal contact and is caused by the SARS-coronavirus (CoV). However, there are no natural or synthetic compounds currently available that can inhibit SARS-CoV. We examined the inhibitory effects of 64 purified natural compounds against the activity of SARS helicase, nsP13, and the hepatitis C virus (HCV) helicase, NS3h, by conducting fluorescence resonance energy transfer (FRET)-based double-strand (ds) DNA unwinding assay or by using a colorimetry-based ATP hydrolysis assay. While none of the compounds, examined in our study inhibited the DNA unwinding activity or ATPase activity of human HCV helicase protein, we found that myricetin and scutellarein potently inhibit the SARS-CoV helicase protein in vitro by affecting the ATPase activity, but not the unwinding activity, nsP13. In addition, we observed that myricetin and scutellarein did not exhibit cytotoxicity against normal breast epithelial MCF10A cells. Our study demonstrates for the first time that selected naturally-occurring flavonoids, including myricetin and scultellarein might serve as SARS-CoV chemical inhibitors.

• Synthesis, characterization and in vitro anti-tumor activities of matrine derivatives.

  Authors: Lisheng Wang, Yejun You, Songqing Wang, Xu Liu, Buming Liu, Jinni Wang, Xiao Lin, Mingsheng Chen, Gang Liang, Hua Yang

  Bioorganic & medicinal chemistry letters.

  Nineteen previously unreported matrine derivatives were synthesized and characterized using elemental analysis, infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and massNineteen previously unreported matrine derivatives were synthesized and characterized using elemental analysis, infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and mass spectrometry. Target compounds 6a-6l and 7a-7c showed stronger inhibitory activities than matrine in the in vitro antitumor tests and inhibited the growth of the Hep7402, B16-F10, A549, and TW03 cell lines. In addition, compound 6i exhibited a potent antitumor activity similar to that of colchicine.

• Anticonvulsant activity of artificial sweeteners: A structural link between sweet-taste receptor T1R3 and brain glutamate receptors.

  Authors: Alan Talevi, Andrea V Enrique, Luis E Bruno-Blanch

  Bioorganic & medicinal chemistry letters.

  A virtual screening campaign based on application of a topological discriminant function capable of identifying novel anticonvulsant agents indicated several widely-used artificial sweeteners asA virtual screening campaign based on application of a topological discriminant function capable of identifying novel anticonvulsant agents indicated several widely-used artificial sweeteners as potential anticonvulsant candidates. Acesulfame potassium, cyclamate and saccharin were tested in the Maximal Electroshock Seizure model (mice, ip), showing moderate anticonvulsant activity. We hypothesized a probable structural link between the receptor responsible of sweet taste and anticonvulsant molecular targets. Bioinformatic tools confirmed a highly significant sequence-similarity between taste-related protein T1R3 and several metabotropic glutamate receptors from different species, including glutamate receptors upregulated in epileptogenesis and certain types of epilepsy.

• Role of the C(8)gem-dimethyl group of bryostatin 1 on its unique pattern of biological activity.

  Authors: Gary E Keck, Yam B Poudel, Arnab Rudra, Jeffrey C Stephens, Noemi Kedei, Nancy E Lewin, Peter M Blumberg

  Bioorganic & medicinal chemistry letters.

  The role of the C(8)gem-dimethyl group in the A-ring of bryostatin 1 has been examined through chemical synthesis and biological evaluation of a new analogue. Assays for biological function usingThe role of the C(8)gem-dimethyl group in the A-ring of bryostatin 1 has been examined through chemical synthesis and biological evaluation of a new analogue. Assays for biological function using U937, K562, and MV4-11 cells as well as the profiles for downregulation of PKC isozymes revealed that the presence of this group is not a critical determinant for the unique pattern of biological activity of bryostatin.

• Pre-steady state kinetic analysis of cyclobutyl derivatives of 2'-deoxyadenosine 5'-triphosphate as inhibitors of HIV-1 reverse transcriptase.

  Authors: Jiae Kim, Ligong Wang, Yongfeng Li, Kimberlynne D Becnel, Kathleen M Frey, Scott J Garforth, Vinayaka R Prasad, Raymond F Schinazi, Dennis C Liotta, Karen S Anderson

  Bioorganic & medicinal chemistry letters.

  Pre-steady state kinetic analysis was utilized for biochemical evaluation of a series of cyclobutyl adenosine nucleotide analogs with HIV-1 RT(WT). The phosphonyl-diphosphate form of the cyclobutylPre-steady state kinetic analysis was utilized for biochemical evaluation of a series of cyclobutyl adenosine nucleotide analogs with HIV-1 RT(WT). The phosphonyl-diphosphate form of the cyclobutyl nucleotide, 5, was the most efficiently incorporated of the series. Nucleotide 5 was fourfold more efficiently incorporated than the FDA approved TFV-DP by RT(WT). The kinetics of incorporation for 5 using the drug resistant mutant enzyme K65R was also determined. Compound 5 was threefold more efficiently incorporated compared to TFV-DP with RT(K65R). These results demonstrate cyclobutyl adenosine analogs can act as substrates for incorporation by HIV-1 RT and be a potential scaffold for HIV inhibitors.

• Ethyl 2,4,6-trihydroxybenzoate is an agonistic ligand for liver X receptor that induces cholesterol efflux from macrophages without affecting lipid accumulation in HepG2 cells.

  Authors: Minh-Hien Hoang, Yaoyao Jia, Hee-Jin Jun, Ji-Hae Lee, Dong-Ho Lee, Bang-Yeon Hwang, Woo-Jin Kim, Hak-Ju Lee, Sung-Joon Lee

  Bioorganic & medicinal chemistry letters.

  The present study reports a novel liver X receptor (LXR) activator, ethyl 2,4,6-trihydroxybenzoate (ETB), isolated from Celtis biondii. Using a reporter gene assay, time-resolved fluorescenceThe present study reports a novel liver X receptor (LXR) activator, ethyl 2,4,6-trihydroxybenzoate (ETB), isolated from Celtis biondii. Using a reporter gene assay, time-resolved fluorescence resonance energy transfer (TR-FRET), and surface plasmon resonance (SPR) analysis, we showed that ETB directly bound to and stimulated the transcriptional activity of LXR-α and LXR-β. In macrophages, hepatocytes, and intestinal cells, ETB suppressed cellular cholesterol accumulation in a dose-dependent manner and induced the transcriptional activation of LXR-α/-β-responsive genes. Notably, ETB did not induce lipogenic gene expression or cellular triglyceride accumulation in hepatocytes. These results suggest that ETB is a dual-LXR modulator that regulates the expression of key genes in cholesterol homeostasis in multiple cells without inducing lipid accumulation in HepG2 cells.

• Thieno[3,2-b]thiophene-2-carboxylic acid derivatives as GPR35 agonists.

  Authors: Huayun Deng, Jieyu Hu, Haibei Hu, Mingqian He, Ye Fang

  Bioorganic & medicinal chemistry letters.

  The optimization of a series of thieno[3,2-b]thiophene-2-carboxylic acid derivatives for agonist activity against the GPR35 is reported. Compounds were optimized to achieve β-arrestin-biased agonismThe optimization of a series of thieno[3,2-b]thiophene-2-carboxylic acid derivatives for agonist activity against the GPR35 is reported. Compounds were optimized to achieve β-arrestin-biased agonism for developing probe molecules that may be useful for elucidating the biology and physiology of GPR35. Compound 13 was identified to the most potent GPR35 agonist, and compounds 30 and 36 exhibited the highest efficacy to cause β-arrestin translocation.

• Structure and property based design, synthesis and biological evaluation of γ-lactam based HDAC inhibitors: Part II.

  Authors: Chulho Lee, Eunhyun Choi, Misun Cho, Boah Lee, Soo Jin Oh, Song-Kyu Park, Kiho Lee, Hwan Mook Kim, Gyoonhee Han

  Bioorganic & medicinal chemistry letters.

  Histone deacetylases (HDACs) are involved in post-translational modification and epi-genetic expression, and have been the intriguing targets for treatment of cancer. In previous study, we reportedHistone deacetylases (HDACs) are involved in post-translational modification and epi-genetic expression, and have been the intriguing targets for treatment of cancer. In previous study, we reported synthesis and the biological preliminary results of γ-lactam based HDAC inhibitors. Based on the previous results, smaller γ-lactam core HDAC inhibitors are more active than the corresponding series of larger δ-lactam based analogues and the hydrophobic and bulky cap groups are required for better potency which decreased microsomal stability. Thus, γ-lactam analogues with methoxy, trifluoromethyl groups of ortho-, meta-, para-positions of cap group were prepared and evaluated their biological potency. Among them, trifluoromethyl analogues, which have larger lipophilicity, showed better HDAC inhibitory activity than other analogues. In overall, lipophilicity leads to increase hydrophobic interaction between surface of HDAC active site and HDAC inhibitor, improves HDAC inhibitory activity.

• S-Adenosylhomocysteine hydrolase of the protozoan parasite Trichomonas vaginalis: Potent inhibitory activity of 9-(2-deoxy-2-fluoro-β,d-arabinofuranosyl)adenine.

  Authors: Ajit Shokar, Aaron Au, Seung Hwan An, Elsie Tong, Gabriel Garza, Jessica Zayas, Stanislaw F Wnuk, Kirkwood M Land

  Bioorganic & medicinal chemistry letters.

  In the present study, we carried out a structure-activity analysis in Trichomonas vaginalis of a series of adenosine and uridine analogues. The most potent compounds were found to be 2' and 3'In the present study, we carried out a structure-activity analysis in Trichomonas vaginalis of a series of adenosine and uridine analogues. The most potent compounds were found to be 2' and 3' modified adenosine analogues some of which are potent inhibitors of S-adenosylhomocysteine hydrolase. The 9-(2-deoxy-2-fluoro-β,d-arabinofuranosyl)adenine compound was more potent than metronidazole, a current FDA approved and commonly prescribed drug for treatment of trichomoniasis. Its IC(50) was 0.09μM compared to 0.72μM for metronidazole.

• Structure-activity relationship of a series of non peptidic RGD integrin antagonists targeting α(5)β(1): Part 1.

  Authors: Bénédicte Delouvrié, Katherine Al-Kadhimi, Jean-Claude Arnould, Simon T Barry, Darren A E Cross, Myriam Didelot, Paul R Gavine, Hervé Germain, Craig S Harris, Adina M Hughes [......] Jane Kendrew, Christine Lambert-van der Brempt, Jean-Jacques Lohmann, Morgan Ménard, Andrew A Mortlock, Martin Pass, Claire Rooney, Michel Vautier, Jennifer L Vincent, Nicolas Warin

  Bioorganic & medicinal chemistry letters.

  Potent antagonists of the integrin α(5)β(1), which are RGD mimetics built from tyrosine are described. This letter describes the optimization of in vitro potency obtained by variation of two parts ofPotent antagonists of the integrin α(5)β(1), which are RGD mimetics built from tyrosine are described. This letter describes the optimization of in vitro potency obtained by variation of two parts of the molecule, the basic group and the linker between the basic group and the phenyl central core.

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