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Bioorganic & Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/28927788/a-structural-investigation-of-fisle-412-a-peptidomimetic-compound-derived-from-saquinavir-that-targets-lupus-autoantibodies
#1
Mingzhu He, Kai Fan Cheng, Sonya VanPatten, Ona Bloom, Betty Diamond, Yousef Al-Abed
FISLE-412 is the first reported small molecule peptidomimetic that neutralizes anti-dsDNA autoantibodies associated with systemic lupus erythematosus (SLE) pathogenesis. FISLE-412 is a complex small molecule that involves a challenging synthesis scheme, but has attractive pharmacological activities as a potential small molecule therapeutic in lupus. Therefore, we initiated a Structure-Activity Relationship study to simplify the complexity of FISLE-412. We synthesized a small library of mimetopes around the FISLE-412 structure and identified several analogues which could neutralize anti-DNA lupus antibodies in vitro and ex vivo...
September 16, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28939121/discovery-of-novel-1-2-4-triazolo-4-3-a-quinoxaline-aminophenyl-derivatives-as-bet-inhibitors-for-cancer-treatment
#2
Imran Ali, Jooyun Lee, Areum Go, Gildon Choi, Kwangho Lee
Bromodomain and extra-terminal (BET) proteins, a class of epigenetic reader domains has emerged as a promising new target class for small molecule drug discovery for the treatment of cancer, inflammatory, and autoimmune diseases. Starting from in silico screening campaign, herein we report the discovery of novel BET inhibitors based on [1,2,4]triazolo[4,3-a]quinoxaline scaffold and their biological evaluation. The hit compound was optimized using the medicinal chemistry approach to the lead compound with excellent inhibitory activities against BRD4 in the binding assay...
September 14, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28939120/synthesis-characterization-and-cellular-localization-of-a-fluorescent-probe-of-the-antimalarial-8-aminoquinoline-primaquine
#3
Adonis McQueen, Lynn D Blake, Ala Azhari, M Trent Kemp, Tommy W McGaha, Niranjan Namelikonda, Randy W Larsen, Roman Manetsch, Dennis E Kyle
Primaquine (PQ) is the only commercially available drug that clears dormant liver stages of malaria and blocks transmission to mosquito vectors. Although an old drug, much remains to be known about the mechanism(s) of action. Herein we develop a fluorescent tagged PQ to discover cellular localization in the human malaria parasite, Plasmodium falciparum. Successful synthesis and characterization of a primaquine-coumarin fluorescent probe (PQCP) demonstrated potency equivalent to the parent drug and the probe was not cytotoxic to HepG2 carcinoma cells...
September 14, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28935266/diverse-amide-analogs-of-sulindac-for-cancer-treatment-and-prevention
#4
Bini Mathew, Judith V Hobrath, Michele C Connelly, R Kiplin Guy, Robert C Reynolds
Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivo antitumor activity that was comparable to sulindac in a human colon tumor xenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines...
September 13, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927786/discovery-of-highly-potent-selective-covalent-inhibitors-of-jak3
#5
James Kempson, Damaso Ovalle, Junqing Guo, Stephen T Wrobleski, Shuqun Lin, Steven H Spergel, James J-W Duan, Bin Jiang, Zhonghui Lu, Jagabandhu Das, Bingwei V Yang, John Hynes, Hong Wu, John Tokarski, John S Sack, Javed Khan, Gary Schieven, Yuval Blatt, Charu Chaudhry, Luisa M Salter-Cid, Aberra Fura, Joel C Barrish, Percy H Carter, William J Pitts
A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.
September 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28935264/a-potent-neuromedin-u-receptor-2-selective-alkylated-peptide
#6
Naoki Nishizawa, Yoko Kanematsu-Yamaki, Masaaki Funata, Hiroaki Nagai, Ayako Shimizu, Hisashi Fujita, Junichi Sakamoto, Shiro Takekawa, Taiji Asami
Neuromedin U (NMU) mediates various physiological functions via NMUR1 and NMUR2 receptors. NMUR2 has been considered a promising treatment option for diabetes and obesity. Although NMU-8, a shorter peptide, has potent agonist activity for both receptors, it is metabolically unstable. Therefore, NMU-8 analogs modified with long-chain alkyl moieties via a linker were synthesized. An octadecanoyl analog (17) with amino acid substitutions [αMePhe(19), Nle(21), and Arg(Me)(24)] and a linker [Tra-γGlu-PEG(2)] dramatically increased NMUR2 selectivity, with retention of high agonist activity...
September 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927793/discovery-of-n-substituted-7-azaindoles-as-pan-pim-kinase-inhibitors-lead-series-identification-part-ii
#7
Claude Barberis, Neil Moorcroft, James Pribish, Elina Tserlin, Alexandre Gross, Mark Czekaj, Matthieu Barrague, Paul Erdman, Tahir Majid, Joseph Batchelor, Mikhail Levit, Andrew Hebert, Liduo Shen, Sandra Moreno-Mazza, Anlai Wang
N-Substituted azaindoles have been discovered as pan-PIM kinase inhibitors. Initial SAR, early ADME and PK/PD data of a series of compounds is described and led to the identification of promising pan-PIM inhibitors which validated our interest in the 7-azaindole scaffold and led us to pursue the identification of a clinical candidate.
September 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927792/heliotropiumides-a-and-b-new-phenolamides-with-n-carbamoyl-putrescine-moiety-from-heliotropium-foertherianum-collected-in-hawaii-and-their-biological-activities
#8
You-Sheng Cai, Ariel M Sarotti, Daniela Gündisch, Tamara P Kondratyuk, John M Pezzuto, James Turkson, Shugeng Cao
Two new compounds heliotropiumides A (1) and B (2), phenolamides each with an uncommon carbamoyl putrescine moiety, were isolated from the seeds of a naturalized Hawaiian higher plant, Heliotropium foertherianum Diane & Hilger in the borage family, which is widely used for the treatment of ciguatera fish poisoning. The structures of compounds 1 and 2 were characterized based on MS spectroscopic and NMR analysis, and DP4+ calculations. The absolute configuration (AC) of compound 1 was determined by comparison of its optical rotation with those reported in literature...
September 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927789/anticancer-efficacy-of-p-dodecylaminophenol-against-high-risk-and-refractory-neuroblastoma-cells-in-vitro-and-in-vivo
#9
Noriko Takahashi, Shunpei Koyama, Shinya Hasegawa, Masahiro Yamasaki, Masahiko Imai
Neuroblastoma is an aggressive and drug-resistant refractory cancer. The human high-risk neuroblastoma cell line, SK-N-AS (non-amplified N-myc) is derived from stromal cells and it is resistant to treatment with retinoic acid (1, RA), which is a chemotherapeutic agent used to induce neuronal cellular differentiation of neuroblastomas. We have developed p-dodecylaminophenol (3, p-DDAP), based on N-(4-hydroxyphenyl)retinamide (2, 4-HPR), a synthetic amide of 1, since 1 and 2 are associated with the side-effect of nyctalopia...
September 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927794/discovery-and-optimization-of-oxadiazole-based-flap-inhibitors
#10
Alessandra Bartolozzi, Asitha Abeywardane, Todd Bosanac, John A Broadwater, Zhidong Chen, J Matthew Hutzler, John D Huber, Peter Nemoto, Alan Olague, Doris Riether, Tom Simpson, Hidenori Takahashi, Lifen Wu, Yunlong Zhang, Renee M Zindell
Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling.
September 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927791/design-and-synthesis-of-novel-prmt1-inhibitors-and-investigation-of-their-binding-preferences-using-molecular-modelling
#11
Hao Yang, Yifan Ouyang, Hao Ma, Hui Cong, Chunlin Zhuang, Wun-Taai Lok, Zhe Wang, Xuanli Zhu, Yutong Sun, Wei Hong, Hao Wang
Protein arginine methyltransferase 1 (PRMT1) catalyses the methylation of substrate arginine by transferring the methyl group from SAM (S-adenosyl-l-methionine), which leads to the formation of S-adenosyl homocysteine (SAH) and methylated arginine. We have shown previously that the Asp84 on PRMT1 could be a potential inhibitor binding site. In the current study, 28 compounds were designed and synthesized that were predicted to bind the Asp84 and substrate arginine sites together. Among them, 6 compounds were identified as potential PRMT1 inhibitors, and showed strong inhibitory effects on cancer cell lines, especially HepG2...
September 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927790/design-semisynthesis-and-potent-cytotoxic-activity-of-novel-10-fluorocamptothecin-derivatives
#12
Cheng-Jie Yang, Zi-Long Song, Masuo Goto, Pei-Ling Hsu, Xiao-Shuai Zhang, Qian-Ru Yang, Ying-Qian Liu, Mei-Juan Wang, Susan L Morris-Natschke, Xiao-Fei Shang, Kuo-Hsiung Lee
Fluorination is a well-known strategy for improving the bioavailability of bioactive molecules in the lead optimization phase of drug discovery projects. In an attempt to improve the antitumor activity of camptothecins (CPTs), novel 10-fluoro-CPT derivatives were designed, synthesized and evaluated for cytotoxicity against five human cancer cell lines (A-549, MDA-MB-231, KB, KB-VIN and MCF-7). All of the derivatives showed more potent in vitro cytotoxic activity than the clinical CPT-derived drug irinotecan against the tumor cell lines tested, and most of them showed comparable or superior potency to topotecan...
September 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927767/gem-dithioacetylated-indole-derivatives-as-novel-antileishmanial-agents
#13
Sharad Porwal, Suman Gupta, Prem M S Chauhan
In this communication we report a serendipitously discovered hybrid molecule 1, combining fragment of 3 (an in vivo active antileishmanial molecule) with H2S donor moiety (known for bimodal behavior of cytoprotection and apoptosis), as antileishmanial agent. Compound 1 suppresses 99.82% parasitemia of L. donovani infected macrophages at 12.5μg/ml without even deforming them (CC50>100μg/ml). This compound appears cytotoxic for intracellular amastigotes while cytoprotective to host macrophages. The concept can be utilized to develop high therapeutic index NCE (New Chemical Entities) for other macrophage mediated diseases like tuberculosis and cancer...
September 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28919340/design-and-synthesis-of-pregnenolone-2-cyanoacryloyl-conjugates-with-dual-nf-%C3%AE%C2%BAb-inhibitory-and-anti-proliferative-activities
#14
Jia-Li Song, Juan Zhang, Chang-Liang Liu, Chao Liu, Kong-Kai Zhu, Fei-Fei Yang, Xi-Gong Liu, João Paulo Figueiró Longo, Luis Alexandre Muehlmann, Ricardo Bentes Azevedo, Yu-Ying Zhang, Yue-Wei Guo, Cheng-Shi Jiang, Hua Zhang
Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6-30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27-30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC50=2.5μM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC50=6.5-36...
September 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28919339/novel-xanthone-polyamine-conjugates-as-catalytic-inhibitors-of-human-topoisomerase-ii%C3%AE
#15
Elirosa Minniti, Jo Ann W Byl, Laura Riccardi, Claudia Sissi, Michela Rosini, Marco De Vivo, Anna Minarini, Neil Osheroff
It has been proposed that xanthone derivatives with anticancer potential act as topoisomerase II inhibitors because they interfere with the ability of the enzyme to bind its ATP cofactor. In order to further characterize xanthone mechanism and generate compounds with potential as anticancer drugs, we synthesized a series of derivatives in which position 3 was substituted with different polyamine chains. As determined by DNA relaxation and decatenation assays, the resulting compounds are potent topoisomerase IIα inhibitors...
September 8, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927787/a-mimetic-of-the-msin3-binding-helix-of-nrsf-rest-ameliorates-abnormal-pain-behavior-in-chronic-pain-models
#16
Hiroshi Ueda, Jun-Ichi Kurita, Hiroyuki Neyama, Yuuka Hirao, Hiroyuki Kouji, Tadashi Mishina, Masaji Kasai, Hirofumi Nakano, Atsushi Yoshimori, Yoshifumi Nishimura
The neuron-restrictive silencing factor NRSF/REST binds to neuron-restrictive silencing elements in neuronal genes and recruits corepressors such as mSin3 to inhibit epigenetically neuronal gene expression. Because dysregulation of NRSF/REST is related to neuropathic pain, here, we have designed compounds to target neuropathic pain based on the mSin3-binding helix structure of NRSF/REST and examined their ability to bind to mSin3 by NMR. One compound, mS-11, binds strongly to mSin3 with a binding mode similar to that of NRSF/REST...
September 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28927768/synthesis-and-biological-evaluation-of-peptide-derived-tslp-inhibitors
#17
Seonghu Park, Yeeun Park, Sang-Hyun Son, Kiho Lee, Yong Woo Jung, Ki Yong Lee, Young Ho Jeon, Youngjoo Byun
Thymic stromal lymphopoietin (TSLP) is a type II cytokine which is associated with most inflammatory allergic disorders in humans. It is produced mainly by epithelial cells with important role in the development of chronic inflammatory diseases by activating T-helper cell type-2 (TH2) pathways. In this study, a total of 16 peptides were prepared by solid phase peptide synthesis based on amino acid sequences of the interface between TSLP and TSLP receptor. Their TSLP inhibition activities were determined by ELISA assay...
September 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28917650/dodecyl-sorbitan-ethers-as-antimicrobials-against-gram-positive-bacteria
#18
Dorine Belmessieri, Charlotte Gozlan, Marie-Christine Duclos, Oana Dumitrescu, Gérard Lina, Andreas Redl, Nicolas Duguet, Marc Lemaire
A range of amphiphilic sorbitan ethers has been synthesized in two steps from sorbitan following an acetalization/hydrogenolysis sequence. These sorbitan ethers and the acetal intermediates have been evaluated as antimicrobials against Gram-negative and Gram-positive bacteria. No antimicrobial activity was observed for Gram-negative bacteria. However, the compounds bearing a linear dodecyl chain exhibit antimicrobial activity (MIC as low as 8μg/mL) against Gram-positive bacteria such as Listeria monocytogenes, Enterococcus faecalis and Staphylococcus aureus...
September 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28917649/evaluation-of-novel-111-in-labeled-gonadotropin-releasing-hormone-peptides-for-human-prostate-cancer-imaging
#19
Jingli Xu, Changjian Feng, Yubin Miao
The purpose of this study was to evaluate the tumor targeting and imaging properties of novel (111)In-labeled gonadotropin-releasing hormone (GnRH) peptides for human prostate cancer. Three new 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-linker-d-Phe-(d-Lys(6)-GnRH) peptides with different hydrocarbon linkers were designed to evaluate their effects on GnRH receptor binding affinities. The Aoc (aminooctanoic acid) linker was better than βAla (3-aminopropanoic acid) and Aun (aminoundecanoic acid) linkers in retaining strong receptor binding affinity...
September 7, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28916341/design-synthesis-and-biological-evaluation-of-benzamide-and-phenyltetrazole-derivatives-with-amide-and-urea-linkers-as-bcrp-inhibitors
#20
Nehaben A Gujarati, Leli Zeng, Pranav Gupta, Zhe-Sheng Chen, Vijaya L Korlipara
Breast cancer resistant protein (BCRP/ABCG2), a 72kDa plasma membrane transporter protein is a member of ABC transporter superfamily. Increased expression of BCRP causes increased efflux and therefore, reduced intracellular accumulation of many unrelated chemotherapeutic agents leading to multidrug resistance (MDR). A series of 31 benzamide and phenyltetrazole derivatives with amide and urea linkers has been synthesized to serve as potential BCRP inhibitors in order to overcome BCRP-mediated MDR. The target derivatives were tested for their cytotoxicity and reversal effects in human non-small cell lung cancer cell line H460 and mitoxantrone resistant cell line H460/MX20 using the MTT assay...
September 7, 2017: Bioorganic & Medicinal Chemistry Letters
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