Journal Sciences News
The Journal of Thoracic and Cardiovascular Surgery
Available online 16 January 2018
Discovery of Selective 2,4-Diaminoquinazoline Toll-like Receptor 7 (TLR 7) Agonists
Publication date: Available online 16 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Serge Pieters, David McGowan, Florence Herschke, Frederik Pauwels, Bart Stoops, Stefaan Last, Werner Embrechts, Annick Scholliers, Wendy Mostmans, Kris Van Dijck, Bertrand Van Schoubroeck, Tine Thon
Available online 16 January 2018
Novel SIRT1 activator MHY2233 improves glucose tolerance and reduces hepatic lipid accumulation in db/db mice
Publication date: Available online 16 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Min Jo Kim, Hye Jin An, Dae Hyun Kim, Bonggi Lee, Hye Jin Lee, Sultan Ullah, Su Jeong Kim, Hyoung Oh Jeong, Kyoung Mi Moon, Eun Kyeong Lee, Jungho Yang, Jinia Akter, Pusoon Chun, Hyung Ryong Moon, Hae Young Chung The NAD+-dependent deacetylase SIRT1, which is associated with the improvement of metabolic syndromes, such as type 2 diabetes, is a well-known longevity-related gene. Several in vitro and in vivo studies have shown the known protective effects of SIRT1 activators, such as resveratrol and SRT1720, on diabetes- or obesity-induced fatty liver and insulin resistance. Here, we newly synthesized 18 benzoxazole hydrochloride derivatives based on the structure of resveratrol and SRT1720. We performed an in vitro SIRT1 activity assay to identify the strongest SIRT1 activator. The assay confirmed MHY2233 to be the strongest SIRT1 activator (1.5-fold more potent than resveratrol), and docking simulation showed that the binding affinity of MHY2233 was higher than that of resveratrol and SRT1720. To investigate its beneficial effects, db/db mice were orally administered MHY2233 for 1 month, and various metabolic parameters were assessed in the serum and liver tissues. MHY2233 markedly ameliorated insulin signaling without affecting body weight in db/db mice. In particular, the mRNA expression of lipogenic genes, such as acetyl CoA carboxylase, fatty acid synthase, and sterol regulatory element-binding protein, which increased in db/db mice, decreased following oral treatment with MHY2233. In conclusion, the novel SIRT1 activator MHY2233 reduced lipid accumulation and improved insulin resistance. This finding may contribute toward therapeutic approaches for fatty liver disease and glucose tolerance.

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15 January 2018
Triptolide Derivatives as Potential Multifunctional Anti-Alzheimer Agents: Synthesis and StructureActivity Relationship Studies
Publication date: Available online 16 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Chengqing Ning, Liumei Mo, Xuwei Chen, Wentong Tu, Jun Wu, Shengtao Hou, Jing Xu Owning to the promising neuroprotective profile and the ability to cross the bloodbrain barrier, triptolide has attracted extensive attention. Although its limited solubility and toxicity have greatly hindered clinical translation, triptolide has nonetheless emerged as a promising candidate for structureactivity relationship studies for Alzheimers disease. In the present study, a series of triptolide analogs were designed and synthesized, and their neuroprotective and anti-neuroinflammatory effects were then tested using a cell culture model. Among the triptolide derivatives tested, a memantine conjugate, compound 8, showed a remarkable neuroprotective effect against A
15 January 2018
Editorial Board
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2

15 January 2018
Recent encounters with atropisomerism in drug discovery
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Peter W. Glunz Atropisomerism is stereochemistry arising from restricted bond rotation that creates a chiral axis. Atropisomers are subject to time-dependent inversion of chirality via bond rotation, a property which in drug molecules introduces complexity and challenges for drug discovery and development processes. Greater recognition of the occurrence of atropisomerism and improved characterization techniques have helped medicinal chemists successfully advance atropisomeric drug molecules. This review provides recent examples of atropisomerism encountered in medicinal chemistry efforts and the strategies used to address the accompanying challenges.

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15 January 2018
Breakthroughs in neuroactive steroid drug discovery
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Maria-Jesus Blanco, Daniel La, Quinn Coughlin, Caitlin A. Newman, Andrew M. Griffin, Boyd L. Harrison, Francesco G. Salituro Endogenous and synthetic neuroactive steroids (NASs) or neurosteroids are effective modulators of multiple signaling pathways including receptors for the
15 January 2018
Synthesis and biological evaluation of 4
15 January 2018
Facile conversion of ATP-binding RNA aptamer to quencher-free molecular aptamer beacon
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Yoojin Park, Duangrat Nim-anussornkul, Tirayut Vilaivan, Takashi Morii, Byeang Hyean Kim We have developed RNA-based quencher-free molecular aptamer beacons (RNA-based QF-MABs) for the detection of ATP, taking advantage of the conformational changes associated with ATP binding to the ATP-binding RNA aptamer. The RNA aptamer, with its well-defined structure, was readily converted to the fluorescence sensors by incorporating a fluorophore into the loop region of the hairpin structure. These RNA-based QF-MABs exhibited fluorescence signals in the presence of ATP relative to their low background signals in the absence of ATP. The fluorescence emission intensity increased upon formation of a RNA-based QF-MABATP complex.

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15 January 2018
Investigation of copper-free alkyne/azide 1,3-dipolar cycloadditions using microwave irradiation
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Lindsay E. Chatkewitz, John F. Halonski, Marshall S. Padilla, Douglas D. Young The prevalence of 1,3-dipolar cycloadditions of azides and alkynes within both biology and chemistry highlights the utility of these reactions. However, the use of a copper catalyst can be prohibitive to some applications. Consequently, we have optimized a copper-free microwave-assisted reaction to alleviate the necessity for the copper catalyst. A small array of triazoles was prepared to examine the scope of this approach, and the methodology was translated to a protein context through the use of unnatural amino acids to demonstrate one of the first microwave-mediated bioconjugations involving a full length protein.

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15 January 2018
Identification of bicyclic hexafluoroisopropyl alcohol sulfonamides as retinoic acid receptor-related orphan receptor gamma (ROR
15 January 2018
Design, synthesis and structure-activity relationship evaluation of novel LpxC inhibitors as Gram-negative antibacterial agents
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Shi Ding, Rui-Yang Dai, Wen-Ke Wang, Qiao Cao, Le-Fu Lan, Xian-Li Zhou, Yu-She Yang LpxC inhibitors are new-type antibacterial agents developed in the last twenty years, mainly against Gram-negative bacteria infections. To develop novel LpxC inhibitors with good antibacterial activities and biological metabolism, we summarized the basic skeleton of reported LpxC inhibitors, designed and synthesized several series of compounds and tested their antibacterial activities against Escherichial coli and Pseudomonas aeruginosa in vitro. Structure-activity relationships have been discussed in this article. The metabolism stability of YDL-2, YDL-5, YDL-8, YDL-14, YDL-20YDL-23 have been evaluated in liver microsomes, which indicated that the 2-amino isopropyl group may be a preferred structure than the 2-hydroxy ethyl group in the design of LpxC inhibitors.

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15 January 2018
Cytotoxic quinazoline alkaloids from the seeds of Peganum harmala
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Sheng-Ge Li, Kai-Bo Wang, Chi Gong, Yu Bao, Ning-Bo Qin, Da-Hong Li, Zhan-Lin Li, Jiao Bai, Hui-Ming Hua Seventeen quinazoline alkaloids and derivatives, containing two pairs of new epimers, named as (S)- and (R)-1-(2-aminobenzyl)-3-hydroxypyrrolidin-2-one
15 January 2018
Protective effects of 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ols against 4-hydroxynonenal-induced cell death in adult retinal pigment epithelial-19 cells
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Dawon Bae, Jaya Gautam, Hyeonjin Jang, Suhrid Banskota, Sang Yeul Lee, Min-Ji Jeong, A-Sol Kim, Hong Chul Kim, Iyn-Hyang Lee, Tae-gyu Nam, Jung-Ae Kim, Byeong-Seon Jeong Dysfunction or progressive degeneration of retinal pigment epithelium (RPE) contributes in the initial pathogenesis of age-related macular degeneration (AMD) causing irreversible vision loss, which makes RPE the prime target of the disease. The present study aimed to identify compounds to protect 4-hydroxynonenal (4-HNE)-induced RPE cell death by inhibiting NADPH oxidase 4 (NOX4) activity, not just as free radical scavengers, using ARPE-19, a human adult retinal pigment epithelial cell line, as a RPE representative. Novel thirty-two 6-ureido/thioureido-2,4,5-trimethylpyridin-3-ol derivatives 17 were synthesized and tested. We found that there was a strong correlation between level of protective effect of compounds 17 against 4-HNE-induced APRE-19 cell death and that of inhibitory activity against 4-HNE-induced superoxide production, and that most of the compounds 17 showed minimal DPPH radical scavenging activity. Compound 1728 showed the best protective activity against 4-HNE-induced superoxide production (79.5% inhibition) and cell death (85.1% recovery) at 10
15 January 2018
Synthesis, in vitro
15 January 2018
Synthesis and evaluation of a class of 1,4,7-triazacyclononane derivatives as iron depletion antitumor agents
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Sheng Wang, Yongkang Gai, Shasha Zhang, Lei Ke, Xiang Ma, Guangya Xiang Iron depletion has been confirmed as an efficient strategy for cancer treatment. In the current study, a series of 1,4,7-triazacyclononane derivatives HE-NO2A, HP-NO2A and NE2P2A, as well as the bifunctional chelators p-NO2-PhPr-NE3TA and p-NH2-PhPr-NE3TA were synthesized and evaluated as iron-depleting agents for the potential anti-cancer therapy against human hepatocellular carcinoma. The cytotoxicity of these chelators was measured using hepatocellular cancer cells and compared with the clinically available iron depletion agent DFO and the universal metal chelator DTPA. All these 1,4,7-triazacyclononane-based chelators exhibited much stronger antiproliferative activity than DFO and DTPA. Among them, chelators with phenylpropyl side chains, represented by p-NO2-PhPr-NE3TA and p-NH2-PhPr-NE3TA, displayed the highest antiproliferative activity against HepG2 cells. Hence, these compounds are attractive candidates for the advanced study as iron depletion agents for the potential anti-cancer therapy, and could be further in conjugation with a targeting moiety for the future development in targeted iron depletion therapy.

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15 January 2018
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15 January 2018
Rational modification of semaxanib and sunitinib for developing a tumor growth inhibitor targeting ATP binding site of tyrosine kinase
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Jagroop Kaur, Baljit Kaur, Palwinder Singh Analysis of the crystal structure of tyrosine kinase in complexation with an ATP analogue, supplemented with the molecular docking studies of semaxanib and sunitinib in the ATP binding site of the enzyme enabled us to make design of a series of tyrosine kinase inhibitors. The combination of pyrrole and indolinone in one molecule and placement of appropriate substituent thereof made the molecule compatible for the hydrophobic sub-pocket of the enzyme. Screening of the compounds over 60 cell line panel of human tumor cell lines identified compound 3a that exhibited GI50 35
15 January 2018
Small molecule inhibitors of anthrax edema factor
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Guan-Sheng Jiao, Seongjin Kim, Mahtab Moayeri, April Thai, Lynne Cregar-Hernandez, Linda McKasson, Sean O'Malley, Stephen H. Leppla, Alan T. Johnson Anthrax is a highly lethal disease caused by the Gram-(+) bacteria Bacillus anthracis. Edema toxin (ET) is a major contributor to the pathogenesis of disease in humans exposed to B. anthracis. ET is a bipartite toxin composed of two proteins secreted by the vegetative bacteria, edema factor (EF) and protective antigen (PA). Our work towards identifying a small molecule inhibitor of anthrax edema factor is the subject of this letter. First we demonstrate that the small molecule probe 5
15 January 2018
Anti-neuroinflammatory effects of sesquiterpenoids isolated from Nardostachys jatamansi
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Chi-Su Yoon, Kwan-Woo Kim, Sang-Chan Lee, Youn-Chul Kim, Hyuncheol Oh Two new nardosinone-type sesquiterpenoids, namely kanshone J (1) and kanshone K (2) along with seven known terpenoids (39) were isolated from the rhizomes and roots of Nardostachys jatamansi DC (Valerianaceae). The structures of these compounds were determined mainly by analysis of 1D-, 2D-NMR and MS data. In addition, the absolute configuration of compound 1 was assigned by application of the modified Moshers method. In an initial assay to evaluate their anti-neuroinflammatory effects, compounds 15 and 9 exhibited dose-dependent inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV2 cells, with IC50 values ranging from 2.43 to 46.54
15 January 2018
Design and synthesis of novel pyrimidine analogs as highly selective, non-covalent BTK inhibitors
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Wataru Kawahata, Tokiko Asami, Takayuki Irie, Masaaki Sawa BTK is a promising target for the treatment of multiple diseases such as B cell malignances, asthma, and rheumatoid arthritis. Here, we report the discovery of a series of novel pyrimidine analogs as potent, highly selective, non-covalent inhibitors of BTK. Compound 25d demonstrated higher affinity to an unactivated conformation of BTK that resulted in an excellent kinase selectivity. Compound 25d showed a good oral bioavailability in mice, and significantly inhibits the PCA reaction in mice.

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15 January 2018
Synthesis, antitumor activity, and cytotoxicity of 4-substituted 1-benzyl-5-diphenylstibano-1H-1,2,3-triazoles
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Mizuki Yamada, Tsutomu Takahashi, Mai Hasegawa, Mio Matsumura, Kanna Ono, Ryota Fujimoto, Yuki Kitamura, Yuki Murata, Naoki Kakusawa, Motohiro Tanaka, Tohru Obata, Yasuyuki Fujiwara, Shuji Yasuike Trisubstituted 5-organostibano-1H-1,2,3-triazoles (3af) were synthesized by the Cu-catalyzed azide-alkyne cycloaddition of various ethynylstibanes (1) with benzylazide (2) in the presence of CuBr (5 mol%) under aerobic conditions. The reaction of 5-stibanotriazoles with HCl afforded C5-unsubstituted 1,2,3-triazoles (4af). The antitumor activity of trisubstituted 5-organostibano-1H-1,2,3-triazoles (3af) and their 5-unsubstituted 1,2,3-triazoles (4af) were evaluated in several tumor cell lines. All 5-stibanotriazoles (3af) exerted an excellent antitumor activity. On the contrary, 5-unsubstituted 1,2,3-triazoles (4af) without a diphenylantimony group in the molecule exhibited very low antitumor activity compared with 5-stibanotriazoles (3af). In compounds of both the series, the substituted 4-butyl group appeared to decrease antitumor activity. However, results suggested that organometal (antimony) in the molecule was required for greater antitumor activity. In addition, all 5-stibanotriazoles (3af), but not all 5-unsubstituted 1,2,3-triazoles (4af), exhibited cytotoxicity in normal vascular endothelial cells derived from bovine aorta. Among the compounds (3be) that exhibited excellent antitumor activity, those with 4-methylphenyl (3b) and 1-cyclohexenyl (3e) showed relatively low cytotoxicity to vascular endothelial cells. Together, these results suggest that trisubstituted 5-organostibano-1H-1,2,3-triazoles, including compounds 3b and 3e, may serve as potential anticancer therapeutic drugs in the future.

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15 January 2018
Towards smart biocide-free anti-biofilm strategies: Click-based synthesis of cinnamide analogues as anti-biofilm compounds against marine bacteria
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): C. Sall, M. Ay
15 January 2018
Discovery of new GSK-3
15 January 2018
Histone H3 peptides incorporating modified lysine residues as lysine-specific demethylase 1 inhibitors
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Taeko Kakizawa, Yosuke Ota, Yukihiro Itoh, Takayoshi Suzuki Lysine-specific demethylase 1 (LSD1) is a flavin-dependent enzyme that removes methyl groups from mono- or dimethylated lysine residues at the fourth position of histone H3. We have previously reported several histone H3 peptides containing an LSD1 inactivator motif at Lys-4. In this study, histone H3 peptides having a trans-2-phenylcyclopropylamine (PCPA), a 2,5-dihydro-1H-pyrrole, and a 1,2,3,6-tetrahydropyridine moiety at Lys-4 were prepared along with related compounds possessing a shorter side chain at the fourth position. Enzymatic assays showed that PCPA peptides containing a longer side chain, which can react with FAD in the active site, are potent LSD1-selective inhibitors.

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15 January 2018
Effect of side chain hydrophobicity and cationic charge on antimicrobial activity and cytotoxicity of helical peptoids
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Jiyoun Lee, Dahyun Kang, Jieun Choi, Wei Huang, Mayken Wadman, Annelise E. Barron, Jiwon Seo Peptoids are peptidomimetic polymers that are resistant to proteolysis and less prone to immune responses; thus, they can provide a practical alternative to peptides. Among the various therapeutic applications that have been explored, cationic amphipathic peptoids have demonstrated broad-spectrum antibacterial activity, including activity towards drug-resistant bacterial strains. While their potency and activity spectrum can be manipulated by sequence variations, bacterial selectivity and systemic toxicity need to be improved for further clinical development. To this aim, we incorporated various hydrophobic or cationic residues to improve the selectivity of the previously developed antibacterial peptoid 1. The analogs with hydrophobic residues demonstrated non-specific cytotoxicity, while those with an additional cationic residue showed improved selectivity and comparable antibacterial activity. Specifically, compared to 1, peptoid 7 showed much lower hemolysis and cytotoxicity, while maintaining the antibacterial activity. Therefore, we believe that peptoid 7
15 January 2018
Discovery of molecular mechanism of a clinical herbal formula upregulating serum HDL-c levels in treatment of metabolic syndrome by in vivo and computational studies
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Meimei Chen, Fafu Yang, Jie Kang, Huijuan Gan, Xinmei Lai, Yuxing Gao Decreased HDL cholesterol (HDL-c) is considered as an independent risk factor of cardiovascular disease in metabolic syndrome (Mets). Wendan decoction (WDD), a famous clinical traditional Chinese medicine formula in Mets in China, which can obviously up-regulate serum HDL-c levels in Mets. However, till now, the molecular mechanism of up-regulation still remained unclear. In this study, an integrated approach that combined serum ABCA1 in vivo assay, QSAR modeling and molecular docking was developed to explore the molecular mechanism and chemical substance basis of WDD upregulating HDL-c levels. Compared with Mets model group, serum ABCA1 and HDL-c levels intervened by two different doses of WDD for two weeks were significantly up-regulated. Then, kohonen and LDA were applied to develop QSAR models for ABCA1 up-regulators based flavonoids. The derived QSAR model produced the overall accuracy of 100%, a very powerful tool for screening ABCA1 up-regulators. The QSAR model prediction revealed 67 flavonoids in WDD were ABCA1 up-regulators. Finally, they were subjected to the molecular docking to understand their roles in up-regulating ABCA1 expression, which led to discovery of 23 ABCA1 up-regulators targeting LXR beta. Overall, QSAR modeling and docking studies well accounted for the observed in vivo activities of ABCA1 affected by WDD.

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15 January 2018
Discovery of benzotriazole-azo-phenol/aniline derivatives as antifungal agents
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Min Lv, Jingchun Ma, Qin Li, Hui Xu A series of benzotriazole-azo-phenol/aniline derivatives were prepared and evaluated for their antifungal activities against six phytopathogenic fungi such as Fusarium graminearum, Fusarium solani, Alternaria alternate, Valsa mali, Botrytis cinerea, and Curvularia lunata. Among them, compounds IIf, IIn, and IIr showed a broad-spectrum of potent antifungal activities. Especially some compounds displayed 3.510.8 folds more potent activities than carbendazim against A. alternata and C. lunata. Notably, compounds IIc, IIm, and IIr exhibited good protective and therapeutic effects against B. cinerea at 200
15 January 2018
Structure-based design, synthesis, and binding mode analysis of novel and potent chymase inhibitors
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Junko Futamura-Takahashi, Taisaku Tanaka, Hajime Sugawara, Shinzo Iwashita, Seiichi Imajo, Yoshiaki Oyama, Tsuyoshi Muto Based on insight from the X-ray crystal structure of human chymase in complex with compound 1, a lactam carbonyl of the diazepane core was exchanged with O-substituted oxyimino group, leading to amidoxime derivatives. This modification resulted in highly potent chymase inhibitors, such as O-phenylamidoxime 5f. X-ray crystal structure analysis indicated that compound 5f induced movement of the Leu99 and Tyr94 side chains at the S2 site, and the increase in inhibitory activity of O-phenyl amidoxime derivatives suggested that the O-phenyl moiety interacted with the Tyr94 residue. Surface plasmon resonance experiments showed that compound 5f had slower association and dissociation kinetics and the calculated residence time of compound 5f to human chymase was extended compared to that of amide compound 1.

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15 January 2018
Synthesis of radioiodinated probes targeted toward matrix metalloproteinase-12
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Masayori Hagimori, Takashi Temma, Shinji Kudo, Kohei Sano, Naoya Kondo, Takahiro Mukai Matrix metalloproteinase-12 (MMP-12, macrophage elastase) is a member of the MMP family that is responsible for the degradation of extracellular matrix, and is associated with the inflammatory process of chronic obstructive pulmonary disease (COPD). COPD, characterized by progressive and irreversible airflow obstruction, is recently a major cause of mortality and morbidity worldwide. Herein, to develop radioiodinated probes for the early diagnosis of COPD, we designed and synthesized novel MMP-12-targeted dibenzofuran compounds (13) with a variety of linker structures (carbamate, amide, and sulfonamide). In competitive enzyme activity assays, it was revealed that the linker structures significantly affected the inhibitory activity against and selectivity for MMP-12. Compound 1, with carbamate linker, demonstrated potent MMP-12 inhibitory activity (IC50
15 January 2018
Synthesis and biological evaluation of 1-amino isochromans from 2-bromoethyl benzaldehyde and amines in acid medium
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Narjis Fatima, B.V. Subba Reddy, Sabitha Gowravaram, J.S. Yadav, Sudhakar Kadari, Chandra Shekar Putta We have developed a facile and efficient synthetic route to substituted isochromans for the first time by reacting 2-(2-bromoethyl)benzaldehyde with a variety of aryl, heteroaryl amines in AcOH. The reaction is catalyst/additive free and takes place at reflux conditions with short reaction time to furnish products in good to excellent yields. All the compounds have been characterized by spectral techniques such as IR, 1H NMR and Mass etc. Synthesized compounds were evaluated for antimicrobial activity against specific bacterial like 1) Staphylococcus strains aureus 2) Bacillus subtilis 3) Escherichia coli 4) Pseudomonas aeruginosa. Compounds 3e, 3n, 3
15 January 2018
AMP and adenosine are both ligands for adenosine 2B receptor signaling
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Jessica K. Holien, Benjamin Seibt, Veena Roberts, Evelyn Salvaris, Michael W. Parker, Peter J. Cowan, Karen M. Dwyer Adenosine is considered the canonical ligand for the adenosine 2B receptor (A2BR). A2BR is upregulated following kidney ischemia augmenting post ischemic blood flow and limiting tubular injury. In this context the beneficial effect of A2BR signaling has been attributed to an increase in the pericellular concentration of adenosine. However, following renal ischemia both kidney adenosine monophosphate (AMP) and adenosine levels are substantially increased. Using computational modeling and calcium mobilization assays, we investigated whether AMP could also be a ligand for A2BR. The computational modeling suggested that AMP interacts with more favorable energy to A2BR compared with adenosine. Furthermore, AMP
15 January 2018
Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Andrew M. Thompson, Andrew J. Marshall, Louis Maes, Nigel Yarlett, Cyrus J. Bacchi, Eric Gaukel, Stephen A. Wring, Delphine Launay, Stephanie Braillard, Eric Chatelain, Charles E. Mowbray, William A. Denny A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.

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15 January 2018
NOTA analogue: A first dithiocarbamate inhibitor of metallo-
15 January 2018
Discovery of 1-(4-((3-(4-methylpiperazin-1-yl)propyl)amino)benzyl)-5-(trifluoromethyl)pyridin-2(1H)-one, an orally active multi-target agent for the treatment of diabetic nephropathy
Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2 Author(s): Jun Chen, Zhangzhe Peng, Miaomiao Lu, Xuan Xiong, Zhuo Chen, Qianbin Li, Zeneng Cheng, Dejian Jiang, Lijian Tao, Gaoyun Hu Oxidative stress, inflammation and fibrosis can cause irreversible damage on cell structure and function of kidney and are key pathological factors in Diabetic Nephropathy (DN). Therefore, multi-target agents are urgently need for the clinical treatment of DN. Using Pirfenidone as a lead compound and based on the previous research, two novel series (5-trifluoromethyl)-2(1H)-pyridone analogs were designed and synthesized. SAR of (5-trifluoromethyl)-2(1H)-pyridone derivatives containing nitrogen heterocyclic ring have been established for in vitro potency. In addition, compound 8, a novel agent that act on multiple targets of anti-DN with IC50 of 90
15 January 2018
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Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2

15 January 2018
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Publication date: 15 January 2018
Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2

Available online 12 January 2018
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Source:Bioorganic & Medicinal Chemistry Letters, Volume 28, Issue 2

Available online 12 January 2018
Degradation of huntingtin mediated by a hybrid molecule composed of IAP antagonist linked to phenyldiazenyl benzothiazole derivative
Publication date: Available online 12 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Shusuke Tomoshige, Sayaka Nomura, Kenji Ohgane, Yuichi Hashimoto, Minoru Ishikawa Huntingtons disease (HD) is an autosomal dominant neurodegenerative disorder caused by aggregation of mutant huntingtin (mHtt), and removal of mHtt is expected as a potential therapeutic option. We previously reported protein knockdown of Htt by using hybrid small molecules (Htt degraders) consisting of BE04, a ligand of ubiquitin ligase (E3), linked to probes for protein aggregates. Here, in order to examine the effect of changing the ligand, we synthesized a similar Htt degrader utilizing MV1, an antagonist of the inhibitor of apoptosis protein (IAP) family (a subgroup of ubiquitin E3 ligases), which is expected to have a higher affinity and specificity for IAP, as compared with BE04. The MV1-based hybrid successfully induced interaction between Htt aggregates and IAP, and reduced mHtt levels in living cells. Its mode of action was confirmed to be the same as that of the BE04-based hybrid. However, although the affinity of MV1 for IAP is greater than that of BE04, the efficacy of Htt degradation by the MV1-based molecule was lower, suggesting that linker length between the ligand and probe might be an important determinant of efficacy.

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Available online 12 January 2018
Discovery of a Novel Potent GPR40 Full Agonist
Publication date: Available online 12 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Sanath K. Meegalla, Hui Huang, Tonya Martin, June Xu, Shuyuan Zhao, Jianying Liu, Meghan Hall, Joe Gunnet, Yuanping Wang, Brian Rady, Jose Silva, Monicah Otieno, Eric Arnoult, S. Paul Lee, Alessandro Pocai, Mark R. Player Compound 12 is a GPR40 agonist that realizes the full magnitude of efficacy possible via GPR40 receptor agonism. In vitro and in vivo studies demonstrated superior glucose lowering by 12 compared to fasiglifam (TAK-875), in a glucose dependent manner. The enhanced efficacy observed with the full agonist 12 was associated with both direct and indirect stimulation of insulin secretion.

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Available online 12 January 2018
Synthesis and evaluation of radiolabeled AGI-5198 analogues as candidate radiotracers for imaging mutant IDH1 expression in tumors
Publication date: Available online 12 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Satish K. Chitneni, Zachary J. Reitman, Rebecca Spicehandler, David M. Gooden, Hai Yan, Michael R. Zalutsky Mutations in the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) are commonly found in gliomas. AGI-5198, a potent and selective inhibitor of the mutant IDH1 enzyme, was radiolabeled with radioiodine and fluorine-18. These radiotracers were evaluated as potential probes for imaging mutant IDH1 expression in tumors with positron emission tomography (PET). Radioiodination of AGI-5198 was achieved using a tin precursor in 79 6% yield (n=9), and 18F-labeling was accomplished by the Ugi reaction in a decay-corrected radiochemical yield of 2.6 1.6% (n=5). The inhibitory potency of the analogous nonradioactive compounds against mutant IDH1 (IDH1-R132H) was determined in enzymatic assays. Cell uptake studies using radiolabeled AGI-5198 analogues revealed somewhat higher uptake in IDH1-mutated cells than that in wild-type IDH1 cells. The radiolabeled compounds displayed favorable tissue distribution characteristics in vivo, and good initial uptake in IDH1-mutated tumor xenografts; however, tumor uptake decreased with time. Radioiodinated AGI-5198 exhibited higher tumor-to-background ratios compared with 18F-labeled AGI-5198; unfortunately, similar results were observed in wild-type IDH1 tumor xenografts as well, indicating lack of selectivity for mutant IDH1 for this tracer. These results suggest that AGI-5198 analogues are not a promising platform for radiotracer development. Nonetheless, insights gained from this study may help in design and optimization of novel chemical scaffolds for developing radiotracers for imaging the mutant IDH1 enzyme.

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Available online 12 January 2018
Synthesis and biological evaluation of anti-cancer agents that selectively inhibit Her2 over-expressed breast cancer cell growth via down-regulation of Her2 protein
Publication date: Available online 12 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Anran Zhao, Qiaoyun Zheng, Cody M. Orahoske, Nethrie D. Idippily, Morgan M. Ashcraft, Aicha Quamine, Bin Su Compound JCC76 selectively inhibited the proliferation of human epidermal growth factor 2 (Her2) over-expressed breast cancer cells. In the current study, a ligand based structural optimization was performed to generate new analogs, and we identified derivatives 16 and 17 that showed improved activity and selectivity against Her2 positive breast cancer cells. A structure activity relationship (SAR) was summarized. Compounds 16 and 17 were also examined by western blot assay to check their effect on Her2 protein. The results reveal that the compounds could decrease the Her2 protein, which explains their selectivity to Her2 over-expressed breast cancer cells. Furthermore, the compounds inhibited the chaperone activity of small chaperone protein that could stabilize Her2 protein.

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Available online 12 January 2018
Design and synthesis of novel senkyunolide analogues as neuroprotective agents
Publication date: Available online 12 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Yuanying Fang, Rikang Wang, Qi Wang, Yongbing Sun, Saisai Xie, Zunhua Yang, Min Li, Yi Jin, Shilin Yang A class of senkyunolide analogues bearing benzofuranone fragment were designed, synthesized and evaluated for their neuroprotective effect in models of oxygen glucose deprivation (OGD) and oxidative stress. All tested compounds showed neuroprotection profile based on the cell viability assay. In particular, derivatives 1f1i possessing furoxan-based nitric oxide releasing functionality exhibited significant biological activities in OGD models. More importantly, compound 1g containing short linker with furoxan displayed the most potent neuroprotection at the concentration of 100
Available online 12 January 2018
Design and Synthesis of Novel Dasatinib Derivatives as Inhibitors of Leukemia Stem Cells
Publication date: Available online 12 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Hui-ying Li, Ding-Di He, Xiu-Juan Zhao, Tong-Yan Sun, Quan Zhang, Cui-Gai Bai, Yue Chen We used the concept of bioisosteres to design and synthesize a novel series of dasatinib derivatives for the treatment of leukemia. Unfortunately, most of the dasatinib derivatives did not show appreciable inhibition against leukemia cell lines K562 and HL60. However, acrylamide compound 2c had comparable inhibitory activity with dasatinib against K562 cells (IC50 = 0.039 nM vs 0.069 nM). And amide compound 2a and acrylamide compound 2c also had comparable inhibitory activity with dasatinib against the leukemia cell line HL60 (IC50 = 0.25 nM and 0.26 nM vs. 0.11 nM). Against the leukemia progenitor cell line KG1a, triazole compounds 15a and 15d15f and oxadiazole compounds 24a24d were more potent than dasatinib. In particular, the hydroxyl compounds 15a and 24a were about 64 and 180 fold more potent than dasatinib against KG1a cells (IC50 = 0.14
Available online 11 January 2018
Synthesis and biological evaluation of longanlactone analogues as neurotrophic agents
Publication date: Available online 12 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Chada Raji Reddy, Amol Gorgile Tukaram, Siddique Z. Mohammed, Uredi Dilipkumar, Bathini Nagendra Babu, Sumana Chakravarty, Dwaipayan Bhattacharya, Pranav C. Joshi, Ren
Available online 9 January 2018
Development of a Series of Novel o-Phenylenediamine-based Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors
Publication date: Available online 11 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): David K. Williams, Jay A. Markwalder, Aaron J. Balog, Bin Chen, Libing Chen, Jennifer Donnell, Lauren Haque, Amy C. Hart, Sunil K. Mandal, Andrew Nation, Weifang Shan, Gregory D. Vite, Kelly Covello, John T. Hunt, Maria N. Jure-Kunkel, Steven P. Seitz A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. .

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Available online 9 January 2018
Regioselective and Efficient Enzymatic Synthesis of Antimicrobial Andrographolide Derivatives
Publication date: Available online 9 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Harshal S. Patil, Dipesh D. Jadhav, Ajay Paul, Fayaj A. Mulani, Shrikant J. Karegaonkar, Hirekodathakallu V. Thulasiram Labdane diterpene andrographolide (1) is a major constituent of Andrographis paniculata and known to exhibit wide spectrum of biological activities. In this study, regioselective monoesters of (1) have been synthesized by using Amano lipase AK (Pseudomonas fluorescens) as a biocatalyst. Amano lipase AK was able to execute highly efficient esterification of hydroxyl group attached to C-14 carbon of (1) in presence of acyl donors. Among the various synthesized derivatives including two novel compounds such as andrographolide-14-propionate (3) and andrographolide-14-caproate (5) displayed antimicrobial activity against Staphylococcusaureus with low minimal inhibitory concentration (MIC) 4 g/mL and 16 g/mL respectively. Furthermore, they have shown low hemolysis activity at their respective MIC and increase in the permeability of the bacterial cell membrane as delineated by FITC uptake and SEM imaging studies.

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Available online 8 January 2018
Lysosomes-targeting imaging and anticancer properties of novel bis-naphthalimide derivatives
Publication date: Available online 9 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Rui-Xue Rong, Shan-Shan Wang, Xuan Liu, Ren-Feng Li, Ke-Rang Wang, Zhi-Ran Cao, Xiao-Liu Li A series of novel N,N-bis(3-aminopropyl)methylamine bridged bis-naphthalimide derivatives NI1NI8 containing saturated nitrogenous heterocycles were designed and synthesized, their cytotoxic activities against Hela, MCF-7, A549 and MGC-803 cells were investigated, Compounds NI1NI4 modified with piperidine and piperazine exhibited good and selective cytotoxic activity, for instance, compounds NI1 and NI4 showed potent cytotoxic activity against Hela cells and MGC-803 cells with the IC50 values of 2.89, 060, 2.73 and 1.60
Available online 6 January 2018
Therapeutic Effects of Isothiocyanate Prodrugs on Rheumatoid Arthritis
Publication date: Available online 8 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Yin Jiang, Hui-Ying Li, Xiao-Hui Li, Jun Lu, Quan Zhang, Cui-Gai Bai, Yue Chen Isothiocyanates 7a and 7b have poor stability and aqueous solubility. To address these problems, prodrugs 8a and 8b were synthesized. Prodrugs 8a and 8b were stable in HEPES buffer at pH 4.4, but released the active compounds 7a and 7b in HEPES buffer at pH 7.4 and in mouse plasma, respectively. Compound 8a and especially compound 8b showed anti-inflammatory effects. Compound 8b demonstrated significant efficacy in animal models of traumatic inflammation, acute inflammation and rheumatoid arthritis. Compound 8b also did not cause appreciable toxicity in mice after 5 weeks at a daily dose of 200 mg/kg.

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Available online 6 January 2018
Diversity oriented synthesis of chromene-xanthene hybrids as anti-breast cancer agents
Publication date: Available online 6 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): M. Srinivas Lavanya Kumar, Jyotsana Singh, Sudipta Kumar Manna, Saroj Maji, Rituraj Konwar, Gautam Panda A diverse library of chromene-xanthene hybrids were synthesized through intramolecular Friedel-Crafts reaction of the arenoxy carbinols. Examples include first incorporation of amino acid tyrosine into xanthene skeletons with polar functionalities. A careful structural evaluation revealed that tyrosine crafted chromene-xanthene hybrids exhibited good activities against breast cancer cell lines MCF-7, MDA-MB-231. The lead compound 16 displays significant cell cycle arrest at G1 phase and induces apoptosis in MDA-MB-231 cells.

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Identification of novel plasminogen activator inhibitor-1 inhibitors with improved oral bioavailability: Structure optimization of N-acylanthranilic acid derivatives
Publication date: Available online 6 January 2018
Source:Bioorganic & Medicinal Chemistry Letters Author(s): Nagahisa Yamaoka, Kenji Murano, Hidehiko Kodama, Akihisa Maeda, Takashi Dan, Tetsuo Nakabayashi, Toshio Miyata, Kanji Meguro Novel plasminogen activator inhibitor-1 (PAI-1) inhibitors with highly improved oral bioavailability were discovered by structure-activity relationship studies on N-acyl-5-chloroanthranilic acid derivatives. Because lipophilic N-acyl groups seemed to be important for the anthranilic acid derivatives to strongly inhibit PAI-1, synthesis of compounds in which 5-chloroanthranilic acid was bound to a variety of highly lipophilic moieties with appropriate linkers was investigated. As the result it appeared that some of the derivatives possessing aryl- or heteroaryl-substituted phenyl groups in the acyl chain had potent in vitro PAI-1 inhibitory activity. Oral absorbability of typical compounds was also evaluated in rats, and compounds 40, 55, 60 and 76 which have diverse chemical structure with each other were selected for further pharmacological evaluation.

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