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Bioorganic & Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/28438542/identification-of-low-micromolar-dual-inhibitors-for-aldose-reductase-alr2-and-poly-adp-ribose-polymerase-parp-1-using-structure-based-design-approach
#1
Navriti Chadha, Om Silakari
Clinical studies have revealed that diabetic retinopathy is a multifactorial disorder. Moreover, studies also suggest that ALR2 and PARP-1 co-occur in retinal cells, making them appropriate targets for the treatment of diabetic retinopathy. To find the dual inhibitors of ALR2 and PARP-1, the structure based design was carried out in parallel for both the target proteins. A series of novel thiazolidine-2,4-dione (TZD) derivatives were therefore rationally designed, synthesized and their in vitro inhibitory activities against ALR2 and PARP-1 were evaluated...
April 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28438541/synthesis-structural-characterization-and-biological-activity-of-novel-knoevenagel-condensates-on-dld-1-human-colon-carcinoma
#2
Lucia Rišiaňová, Eva Fischer-Fodor, Jindra Valentová, Corina Tatomir, Nicoleta Corina Decea, Piroska Virag, Iveta Pechová, Ferdinand Devínsky, Natalia Miklašová
Biologically active Knoevenagel condensates (1-14) of diarylheptanoids: 1,7-bis(3-methoxy-4-hydroxyphenyl)hepta-1,7-diene-3,5-dione and 1,7-bis(3-ethoxy-4-hydroxyphenyl)hepta-1,7-diene-3,5-dione, were synthesized and structurally characterized. Compounds 1-14 exhibited cytotoxicity against colon carcinoma cells, and their antiproliferative effect was associated with a significant decrease of multidrug resistance proteins. One of the underlying mechanisms of these effects is the reduction of intracellular and extracellular SOD enzymes by compounds 1, 12 and 14, which render the tumor cells more vulnerable to oxidative stress...
April 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28434766/stereoselective-synthesis-of-enantiopure-n-substituted-pyrrolidin-2-5-dione-derivatives-by-1-3-dipolar-cycloaddition-and-assessment-of-their-in-vitro-antioxidant-and-antibacterial-activities
#3
Siwar Ghannay, Sana Bakari, Ameni Ghabi, Adel Kadri, Moncef Msaddek, Kaïss Aouadi
1,3-Dipolar cycloaddition between a chiral nitrone and N-substituted maleimides afforded unprecedented enantiopure spiro-fused heterocycles in good yields with a high enantio- and diastereoselectivity. The reaction was taking place on the less hindered face of the nitrone. The obtaining heterocycles were screened for their in vitro antioxidant properties and the results revealed that the potent antioxidant activity was generally recorded to compounds (3g) and (3e). The in vitro antibacterial activities of these two compounds were also investigated and the results demonstrated the strongest potential of compound (3g) against all the tested bacteria...
April 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28434765/4-connected-azabicyclo-5-3-0-decane-smac-mimetics-zn-2-chelators-as-dual-action-antitumoral-agents
#4
Leonardo Manzoni, Alessandro Samela, Stefano Barbini, Silvia Cairati, Marta Penconi, Daniela Arosio, Daniele Lecis, Pierfausto Seneci
Putative dual action compounds (DACs 3a-d) based on azabicyclo[5.3.0]decane (ABD) Smac mimetic scaffolds linked to Zn(2+)-chelating 2,2'-dipicolylamine (DPA) through their 4 position are reported and characterized. Their synthesis, their target affinity (cIAP1 BIR3, Zn(2+)) in cell-free assays, their pro-apoptotic effects, and their cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. A limited influence of Zn(2+) chelation on in vitro activity of DPA-substituted DACs 3a-d was sometimes perceivable, but did not lead to strong cellular synergistic effects...
April 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28434764/novel-non-trimethoxylphenyl-piperlongumine-derivatives-selectively-kill-cancer-cells
#5
Youjun Zhang, Hao Ma, Yuelin Wu, Zhongli Wu, Zhengguang Yao, Wannian Zhang, Chunlin Zhuang, Zhenyuan Miao
Piperlongumine (PL) is a natural alkaloid with broad biological activities. Twelve analogues have been designed and synthesized with non-substituted benzyl rings or heterocycles in this work. Most of the compounds showed better anticancer activities than the parent PL without apparent toxicity in normal cells. Elevation of cellular ROS levels was one of the main anticancer mechanisms of these compounds. Cell apoptosis and cell cycle arrest for the best compound ZM90 were evaluated and similar mechanism of action with PL was demonstrated...
April 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28438540/potent-and-selective-oxytocin-receptor-agonists-without-disulfide-bridges
#6
Yusuke Adachi, Katsuya Sakimura, Yuji Shimizu, Masaharu Nakayama, Yasuko Terao, Takahiko Yano, Taiji Asami
Oxytocin (OT) is a neuropeptide involved in a wide variety of physiological actions, both peripherally and centrally. Many human studies have revealed the potential of OT to treat autism spectrum disorders and schizophrenia. OT interacts with the OT receptor (OTR) as well as vasopressin 1a and 1b receptors (V1aR, V1bR) as an agonist, and agonistic activity for V1aR and V1bR may have a negative impact on the therapeutic effects of OTR agonism in the CNS. An OTR-selective agonistic peptide, FE 202767, in which the structural differences from OT are a sulfide bond instead of a disulfide bond, and N-alkylglycine replacement for Pro at position 7, was reported...
April 12, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28431878/design-synthesis-and-anticancer-activity-of-novel-nopinone-based-thiosemicarbazone-derivatives
#7
Yunyun Wang, Wen Gu, Yu Shan, Fei Liu, Xu Xu, Yiqin Yang, Qiangjian Zhang, Yan Zhang, Hongbo Kuang, Zhonglong Wang, Shifa Wang
A series of new nopinone-based thiosemicarbazone derivatives were designed and synthesized as potent anticancer agents. All these compounds were identified by (1)H NMR, (13)C NMR, HR-MS spectra analyses. In the in vitro anticancer activity, most derivatives showed considerable cytotoxic activity against three human cancer cell lines (MDA-MB-231, SMMC-7721 and Hela). Among them, compound 4i exhibited most potent antitumor activity against three cancer cell lines with the IC50 values of 2.79±0.38, 2.64±0.17 and 3...
April 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28427808/rapid-microwave-accelerated-synthesis-and-anti-osteoporosis-activities-evaluation-of-morusin-scaffolds-and-morusignin-l-scaffolds
#8
Bing Lin, Jun-Fei Huang, Xiong-Wei Liu, Xi-Tao Ma, Xiong-Li Liu, Yi Lu, Ying Zhou, Feng-Min Guo, Ting-Ting Feng
Described herein is a facile and efficient methodology toward the synthesis of Morusin scaffolds and Morusignin L scaffolds 4-9 and 12via a novel three-step approach (Michael addition or prenylation, cyclization and cyclization) and use a rapid, microwave-accelerated cyclization as the key step. Furthermore, their biological activities have been preliminarily demonstrated by in vitro evaluation for anti-osteoporosis activity. These Morusin, Morusignin L and newly synthesized compounds 5b, 6a, 8e, 8f greatly exhibited the highest potency, especially at the 10(-5)mol/L (P<0...
April 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28431877/synthesis-and-evaluation-of-pyridinium-polyoxometalates-as-anti-hiv-1-agents
#9
Shunyi Wang, Wuji Sun, Qin Hu, Hong Yan, Yi Zeng
The unique properties of polyoxometalates, such as molecular polarity, redox potential, surface charge distribution, shape and acidity, influence their response of recognition to targeted biological macromolecules. By using PM-19 (K7PTi2W10O40) as a lead-compound, a series of novel pyridinium polyoxometalates (A7PTi2W10O40), which hadn't been reported in literatures, were designed and synthesized. The evaluation was conducted using the single-cycle pseudovirus infection assay (TZM-bl assay), CCK-8 method was used for determining the cytotoxicity...
April 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28427814/design-synthesis-and-x-ray-structural-studies-of-bace-1-inhibitors-containing-substituted-2-oxopiperazines-as-p1-p2-ligands
#10
Arun K Ghosh, Margherita Brindisi, Yu-Chen Yen, Emilio L Cárdenas, Jean-Rene Ella-Menye, Nagaswamy Kumaragurubaran, Xiangping Huang, Jordan Tang, Andrew D Mesecar
We report the design and synthesis of a series of BACE1 inhibitors incorporating mono- and bicyclic 6-substituted 2-oxopiperazines as novel P1' and P2' ligands and isophthalamide derivative as P2-P3 ligands. Among mono-substituted 2-oxopiperazines, inhibitor 5a with N-benzyl-2-oxopiperazine and isophthalamide showed potent BACE1 inhibitory activity (Ki=2nM). Inhibitor 5g, with N-benzyl-2-oxopiperazine and substituted indole-derived P2-ligand showed a reduction in potency. The X-ray crystal structure of 5g-bound BACE1 was determined and used to design a set of disubstituted 2-oxopiperazines and bicyclic derivatives that were subsequently investigated...
April 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28427813/novel-pyrazoles-and-pyrazolo-1-2-a-pyridazines-as-selective-cox-2-inhibitors-ultrasound-assisted-synthesis-biological-evaluation-and-dft-calculations
#11
Nagat Ghareb, Hosam A Elshihawy, Mohamed M Abdel-Daim, Mohamed A Helal
COX-2 is an inducible enzyme mediating inflammatory responses. Selective targeting of COX-2 is useful for developing anti-inflammatory agents devoid of ulcerogenic activity. Herein, we report the design and synthesis of a series of pyrazoles and pyrazolo[1,2-a]pyridazines with selective COX-2 inhibitory activity and in vivo anti-inflammatory effect. Both series were accessed through acid-catalyzed ultrasound-assisted reactions. The most active compounds in this study are two novel molecules, 11 and 16, showing promising selectivity and decent IC50 of 16...
April 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28416132/discovery-of-indazole-aldosterone-synthase-cyp11b2-inhibitors-as-potential-treatments-for-hypertension
#12
Scott B Hoyt, Jerry Taylor, Clare London, Amjad Ali, Feroze Ujjainwalla, Jim Tata, Mary Struthers, Doris Cully, Tom Wisniewski, Ning Ren, Charlene Bopp, Andrea Sok, Andreas Verras, Daniel McMasters, Qing Chen, Elaine Tung, Wei Tang, Gino Salituro, Joe Clemas, Gaochao Zhou, Douglas MacNeil, Ruth Duffy, Yusheng Xiong
We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.
April 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28431881/design-and-synthesis-of-1-2-3-triazolo-phenanthrene-hybrids-as-cytotoxic-agents
#13
Niggula Praveen Kumar, Shalini Nekkanti, S Sujana Kumari, Pankaj Sharma, Nagula Shankaraiah
A series of new 1,2,3-triazolo-phenanthrene hybrids has been synthesized by employing Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. These compounds were evaluated for their in vitro cytotoxic potential against various human cancer cell lines viz. lung (A549), prostate (PC-3 and DU145), gastric (HGC-27), cervical (HeLa), triple negative breast (MDA-MB-231, MDA-MB-453) and breast (BT-549, 4T1) cells. Among the tested compounds, 7d displayed highest cytotoxicity against DU145 cells with IC50 value of 1...
April 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28416134/syntheses-of-benzophenone-xanthone-hybrid-polyketides-and-their-antibacterial-activities
#14
Takeshi Kodama, Takuya Ito, Dya Fita Dibwe, So-Yeun Woo, Hiroyuki Morita
Muchimangins are benzophenone-xanthone hybrid polyketides produced by Securidaca longepedunculata. However, their biological activities have not been fully investigated, since they are minor constituents in this plant. To evaluate the possibility of muchimangins as antibacterial agent candidates, five muchimangin analogs were synthesized from 2,4,5-trimethoxydiphenyl methanol and the corresponding xanthones, by utilizing p-toluenesulfonic acid monohydrate for the Brønsted acid-catalysis. The antibacterial assays against Gram-positive bacteria, Staphylococcus aureus and Bacillus subtilis, and Gram-negative bacteria, Klebsiella pneumoniae and Escherichia coli, revealed that the muchimangin analogs (±)-1,3,6,8-tetrahydroxy-4-(phenyl-(2',4',5'-trimethoxyphenyl)methyl)-xanthone (1), (±)-1,3,6-trihydroxy-4-(phenyl-(2',4',5'-trimethoxyphenyl)methyl)-xanthone (2), and (±)-1,3-dihydroxy-4-(phenyl-(2',4',5'-trimethoxyphenyl)methyl)-xanthone (3) showed significant activities against S...
April 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28427810/synthesis-of-novel-5-6-dehydrokawain-analogs-as-osteogenic-inducers-and-their-action-mechanisms
#15
Momochika Kumagai, Keisuke Nishikawa, Takashi Mishima, Izumi Yoshida, Masahiro Ide, Keiko Koizumi, Munetomo Nakamura, Yoshiki Morimoto
An imbalance between bone resorption by osteoclasts and bone formation by osteoblasts can cause bone loss and bone-related disease. In a previous search for natural products that increase osteogenic activity, we found that 5,6-dehydrokawain (1) from Alpinia zerumbet promotes osteoblastogenesis. In this study, we synthesized and evaluated series of 5,6-dehydrokawain analogs. Our structure-activity relationships revealed that alkylation of para or meta position of aromatic ring of 1 promote osteogenic activity...
April 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28416133/generation-of-a-cysteine-sulfinic-acid-analog-for-incorporation-in-peptides-using-solid-phase-peptide-synthesis
#16
Nixon Corpuz, Jason P Schwans
The sulfinic acid analog of aspartic acid, cysteine sulfinic acid, introduces a sulfur atom that perturbs the acidity and oxidation properties of aspartic acid. Cysteine sulfinic acids are often introduced in peptides and proteins by oxidation of cysteine, but this method is limited as all cysteine residues are oxidized and cysteine residues are often oxidized to sulfonic acids. To provide the foundation for the specific incorporation of cysteine sulfinic acids in peptides and proteins, we synthesized a 9-fluorenylmethyloxycarbonyl (Fmoc) benzothiazole sulfone analog...
April 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28416130/ph-dependant-fluorescence-switching-of-an-i-motif-structure-incorporating-an-isomeric-azobenzene-pyrene-fluorophore
#17
Han Na Joo, Thuy Van Thi Nguyen, Hyeon Kyeong Chae, Young Jun Seo
In this study, we synthesized an Azo-py phosphoramidite, featuring azobenzene and pyrene units, as a novel fluorescent and isomeric (trans- and cis-azobenzene units) material, which we incorporated in an i-motif DNA sequence. We then monitored the structural dynamics and changes in fluorescence as the modified DNA sequences transformed from single strands at pH 7 to i-motif quadruplex structures at pH 3. After incorporating Azo-py into the 4A loop position of an i-motif sequence, dramatic changes in fluorescence occurred as the DNA structures changed from single-strands to i-motif quadruplex structures...
April 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28433531/discovery-and-optimization-of-selective-fgfr4-inhibitors-via-scaffold-hopping
#18
Yikai Wang, Zhengxia Chen, Meibi Dai, Peipei Sun, Chunqiu Wang, Yang Gao, Haixia Zhao, Wenqin Zeng, Liang Shen, Weifeng Mao, Tian Wang, Guoping Hu, Jian Li, Shuhui Chen, Chaofeng Long, Xiaoxin Chen, Junhua Liu, Yang Zhang
Introduction of a Michael acceptor on a flexible scaffold derived from pan-FGFR inhibitors has successfully yielded a novel series of highly potent FGFR4 inhibitors with selectivity over FGFR1. Due to reduced lipophilicity and aromatic ring count, this series demonstrated improved solubility and permeability. However, plasma instability and fast metabolism limited its potential for in vivo studies. Efforts have been made to address these problems, which led to the discovery of compound (-)-11 with improved stability, CYP inhibition, and good activity/selectivity for further optimization...
April 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28408227/efficient-and-practical-synthesis-of-fondaparinux
#19
Yili Ding, Chamakura V N S Vara Prasad, Hua Bai, Bingyun Wang
Combining advantageous sequences of Alchemia and Sanofi methods of synthesis of Fondaparinux, a more efficient and practical synthetic strategy for the synthesis of corresponding protected pentasaccharide was developed. The protected pentasaccharide was smoothly converted into Fondaparinux in overall high yield (1%).
April 5, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28408220/first-insight-into-structure-activity-relationships-of-selective-meprin-%C3%AE-inhibitors
#20
Daniel Ramsbeck, Antje Hamann, Dagmar Schlenzig, Stephan Schilling, Mirko Buchholz
The astacin proteases meprin α and β are emerging drug targets for treatment of disorders such as kidney failure, fibrosis or inflammatory bowel disease. However, there are only few inhibitors of both proteases reported to date. Starting from NNGH as lead structure, a detailed elaboration of the structure-activity relationship of meprin β inhibitors was performed, leading to compounds with activities in the lower nanomolar range. Considering the preference of meprin β for acidic residues in the P1' position, the compounds were optimized...
April 5, 2017: Bioorganic & Medicinal Chemistry Letters
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