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Bioorganic & Medicinal Chemistry

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https://www.readbyqxmd.com/read/27908753/synthesis-and-evaluation-of-a-68-ga-labeled-bradykinin-b1-receptor-agonist-for-imaging-with-positron-emission-tomography
#1
Guillaume Amouroux, Zhengxing Zhang, Jinhe Pan, Silvia Jenni, Chengcheng Zhang, Navjit Hundal-Jabal, Nadine Colpo, Jutta Zeisler, Kuo-Shyan Lin, François Bénard
A novel (68)Ga-labeled bradykinin B1 receptor (B1R) agonist, (68)Ga-Z01115, was synthesized and evaluated for imaging with positron emission tomography (PET). Z01115 exhibited good binding affinity (Ki=25.4±5.1nM) to hB1R. (68)Ga-Z01115 was prepared in 74±5 decay-corrected radiochemical yield with >99% radiochemical purity and 155±89GBq/µmol (4.2±2.4Ci/μmol) specific activity. (68)Ga-Z01115 was stable in vitro in mouse plasma (93% remaining intact after 60min incubation), and relatively stable in vivo (51±5% remaining intact at 5min post-injection)...
November 23, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27908757/synthesis-antioxidant-and-antichagasic-properties-of-a-selected-series-of-hydroxy-3-arylcoumarins
#2
Natalia Robledo-O'Ryan, Maria João Matos, Saleta Vazquez-Rodriguez, Lourdes Santana, Eugenio Uriarte, Mauricio Moncada-Basualto, Francisco Mura, Michel Lapier, Juan Diego Maya, Claudio Olea-Azar
Oxidative stress is involved in several parasitic diseases such as Chagas. Agents able to selectively modulate biochemical processes involved in the disease represent promising multifunctional agents for the delay or abolishment of the progression of this pathology. In the current work, differently substituted hydroxy-3-arylcoumarins are described, exerting both antioxidant and trypanocidal activity. Among the compounds synthesized, compound 8 showed the most interesting profile, presenting a moderate scavenging ability for peroxyl radicals (ORAC-FL=2...
November 19, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27908756/a-novel-curcumin-derivative-which-inhibits-p-glycoprotein-arrests-cell-cycle-and-induces-apoptosis-in-multidrug-resistance-cells
#3
Vanessa Lopes-Rodrigues, Ana Oliveira, Marta Correia-da-Silva, Madalena Pinto, Raquel T Lima, Emília Sousa, M Helena Vasconcelos
Cancer multidrug resistance (MDR) is a major limitation to the success of cancer treatment and is highly associated with the overexpression of drug efflux pumps such as P-glycoprotein (P-gp). In order to achieve more effective chemotherapeutic treatments, it is important to develop P-gp inhibitors to block/decrease its activity. Curcumin (1) is a secondary metabolite isolated from the turmeric of Curcuma longa L.. Diverse biological activities have been identified for this compound, particularly, MDR modulation in various cancer cell models...
November 19, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27908754/cyclic-citrullinated-mbp87-99-peptide-stimulates-t-cell-responses-implications-in-triggering-disease
#4
Vasso Apostolopoulos, George Deraos, Minos-Timotheos Matsoukas, Stephanie Day, Lily Stojanovska, Theodore Tselios, Maria-Eleni Androutsou, John Matsoukas
Amino acid mutations to agonist peptide epitopes of myelin proteins have been used to modulate immune responses and experimental autoimmune encephalomyelitis (EAE, animal model of multiple sclerosis). Such amino acid alteration are termed, altered peptide ligands (APL). We have shown that the agonist myelin basic protein (MBP) 87-99 epitope (MBP87-99) with crucial T cell receptor (TCR) substitutions at positions 91 and 96 (K(91),P(96) (TCR contact residues) to R(91),A(96); [R(91),A(96)]MBP87-99) results in altered T cell responses and inhibits EAE symptoms...
November 19, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27908752/n-propargylpiperidines-with-naphthalene-2-carboxamide-or-naphthalene-2-sulfonamide-moieties-potential-multifunctional-anti-alzheimer-s-agents
#5
Urban Košak, Damijan Knez, Nicolas Coquelle, Boris Brus, Anja Pišlar, Florian Nachon, Xavier Brazzolotto, Janko Kos, Jacques-Philippe Colletier, Stanislav Gobec
In the brains of patients with Alzheimer's disease, the enzymatic activities of butyrylcholinesterase (BChE) and monoamine oxidase B (MAO-B) are increased. While BChE is a viable therapeutic target for alleviation of symptoms caused by cholinergic hypofunction, MAO-B is a potential therapeutic target for prevention of neurodegeneration in Alzheimer's disease. Starting with piperidine-based selective human (h)BChE inhibitors and propargylamine-based MAO inhibitors, we have designed, synthesized and biochemically evaluated a series of N-propargylpiperidines...
November 19, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27908751/enhanced-potency-of-bivalent-small-molecule-gp41-inhibitors
#6
Vladimir Sofiyev, Hardeep Kaur, Beth A Snyder, Priscilla A Hogan, Roger G Ptak, Peter Hwang, Miriam Gochin
Low molecular weight peptidomimetic inhibitors with hydrophobic pocket binding properties and moderate fusion inhibitory activity against HIV-1 gp41-mediated cell fusion were elaborated by increasing the available surface area for interacting with the heptad repeat-1 (HR1) coiled coil on gp41. Two types of modifications were tested: 1) increasing the overall hydrophobicity of the molecules with an extension that could interact in the HR1 groove, and 2) forming symmetrical dimers with two peptidomimetic motifs that could potentially interact simultaneously in two hydrophobic pockets on the HR1 trimer...
November 19, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27908755/synthesis-evaluation-and-molecular-modelling-studies-of-2-carbazol-3-yl-2-oxoacetamide-analogues-as-a-new-class-of-potential-pancreatic-lipase-inhibitors
#7
S N C Sridhar, George Ginson, P O Venkataramana Reddy, Mukund P Tantak, Dalip Kumar, Atish T Paul
A series of twenty four 2-(carbazol-3-yl)-2-oxoacetamide analogues were synthesized, characterized and evaluated for their pancreatic lipase (PL) inhibitory activity. Porcine PL was used against 4-nitrophenyl butyrate (method A) and tributyrin (methods B and C) as substrates during the PL inhibition assay. Compounds 7e, 7f and 7p exhibited potential PL inhibitory activity (IC50 values of 6.31, 8.72 and 9.58μM, respectively in method A; and Xi50 of 21.85, 21.94 and 26.2, respectively in method B). Further, inhibition kinetics of 7e, 7f and 7p against PL, using method A, revealed their competitive nature of inhibition...
November 18, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27894589/discovery-and-preclinical-evaluation-of-7-benzyl-n-substituted-pyrrolo-3-2-d-pyrimidin-4-amines-as-single-agents-with-microtubule-targeting-effects-along-with-triple-acting-angiokinase-inhibition-as-antitumor-agents
#8
Roheeth Kumar Pavana, Shruti Choudhary, Anja Bastian, Michael A Ihnat, Ruoli Bai, Ernest Hamel, Aleem Gangjee
The utility of cytostatic antiangiogenic agents (AA) in cancer chemotherapy lies in their combination with cytotoxic chemotherapeutic agents. Clinical combinations of AA with microtubule targeting agents (MTAs) have been particularly successful. The discovery, synthesis and biological evaluations of a series of 7-benzyl-N-substituted-pyrrolo[3,2-d]pyrimidin-4-amines are reported. Novel compounds which inhibit proangiogenic receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR), along with microtubule targeting in single molecules are described...
November 15, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27887962/synthesis-of-a-biological-active-%C3%AE-hairpin-peptide-by-addition-of-two-structural-motifs
#9
Sabrina Fischer, Matthias Lamping, Maike Gold, Yvonne Röttger, Dörte Brödje, Richard Dodel, Renate Frantz, Mobarak Abu Mraheil, Trinad Chakraborty, Armin Geyer
The idea of privileged scaffolds - that there seem to be more bioactive compounds found around some structures than others - is well established for small drug molecules, but has little significance for standalone peptide secondary structures whose adaptable shapes escape the definition of a 3D motif in the absence of a protein scaffold. Here, we joined two independent biological functions in a single highly restricted peptide to support the hypothesis that the β-hairpin shape is the common basis of two otherwise unrelated biological recognition processes...
November 15, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27890450/src2-3-binds-to-vitamin-d-receptor-with-high-sensitivity-and-strong-affinity
#10
Daichi Egawa, Toshimasa Itoh, Akira Kato, Saori Kataoka, Yasuaki Anami, Keiko Yamamoto
Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and regulates the expression of target genes through ligand binding. To express the target gene, coactivator binding to the VDR/ligand complex is essential. Although there are many coactivators in living cells, precise interactions between coactivators and VDR have not been clarified. Here, we synthesized two coactivator peptides, DRIP205-2 and SRC2-3, evaluated their affinity for the ligand-binding domain (LBD) of VDR using 1α,25-dihydroxyvitamin D3, partial agonist 1, and antagonist 2 by surface plasmon resonance (SPR), and assessed their interaction modes with VDR-LBD using X-ray crystallographic analysis...
November 14, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27889287/structure-activity-relationship-study-of-a-small-cyclic-peptide-h-c-lys-pro-glu-arg-oh-a-potent-inhibitor-of-vascular-endothelial-growth-factor-interaction-with-neuropilin-1
#11
Karolina Grabowska, Anna K Puszko, Piotr F J Lipiński, Anna K Laskowska, Beata Wileńska, Ewa Witkowska, Gerard Y Perret, Aleksandra Misicka
Inhibition of angiogenesis is one of the most promising approaches in anticancer therapy. It was recently suggested that Neuropilin-1 (NRP-1) in tumour cells may serve as a separate receptor for Vascular Endothelial Growth Factor-165 (VEGF165) which is one of the main pro-angiogenic agents in the organism. Therefore molecules inhibiting VEGF165 binding to NRP-1 could be potential candidates for new antiangiogenic and anticancer drugs. Here we present a structure-activity relationship study of the peptide H-c[Lys-Pro-Glu]-Arg-OH which showed high inhibitory effect on VEGF165/NRP-1 binding (IC50=0...
November 14, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27887964/anti-inflammatory-tetraquinane-diterpenoids-from-a-crinipellis-species
#12
Markus Rohr, Katharina Oleinikov, Mathias Jung, Louis P Sandjo, Till Opatz, Gerhard Erkel
The small pro-inflammatory 10kDa chemokine CXCL10 (Interferon-inducible protein 10, IP-10) plays an important role in mediating immune responses through the activation and recruitment of leukocytes such as T cells, eosinophils, monocytes and NK cells to the sites of inflammation. Elevated levels of CXCL10 have been associated with chronic inflammatory and infectious diseases and therefore CXCL10 represents an attractive target for the development of new anti-inflammatory drugs. In a search for anti-inflammatory compounds from fungi inhibiting the inducible CXCL10 promoter activity, four new tetraquinane diterpenoids, crinipellin E (1), crinipellin F (2), crinipellin G (3) and crinipellin H (4) were isolated from fermentations of a Crinipellis species...
November 12, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27884513/biotransformation-of-rutabaga-phytoalexins-by-the-fungus-alternaria-brassicicola-unveiling-the-first-hybrid-metabolite-derived-from-a-phytoalexin-and-a-fungal-polyketide
#13
M Soledade C Pedras, Abbas Abdoli
The biotransformations of the rutabaga phytoalexins rutalexin, brassicanate A, isalexin and rapalexin A by the plant pathogenic fungus Alternaria brassicicola are reported. While the biotransformations of rutalexin, brassicanate A, and isalexin are fast, rapalexin A is resistant to fungal transformation. Unexpectedly, biotransformation of rutalexin yields a hybrid metabolite named rutapyrone, derived from rutalexin metabolism and phomapyrone G, a fungal metabolite produced by A. brassicicola. These fungal transformations are detoxification reactions likely carried out by different enzymes...
November 12, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27876250/structure-anticonvulsant-activity-studies-in-the-group-of-e-n-cinnamoyl-aminoalkanols-derivatives-monosubstituted-in-phenyl-ring-with-4-cl-4-ch3-or-2-ch3
#14
Agnieszka Gunia-Krzyżak, Dorota Żelaszczyk, Anna Rapacz, Ewa Żesławska, Anna M Waszkielewicz, Katarzyna Pańczyk, Karolina Słoczyńska, Elżbieta Pękala, Wojciech Nitek, Barbara Filipek, Henryk Marona
A series of twenty two (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl, 4-CH3 or 2-CH3 was designed, synthesized and evaluated for anticonvulsant activity in rodent models of seizures: maximal electroshock (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and 6-Hz test. There were identified three most active compounds: S-(2E)-N-(1-hydroxypropan-2-yl)-3-(2-methylphenyl)prop-2-enamide (5) (ED50 MES=42.56, ED50 scPTZ=58.38, ED50 6-Hz 44mA=42.27mg/kg tested in mice after intraperitoneal (i...
November 11, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27887963/animal-models-in-the-pharmacokinetic-pharmacodynamic-evaluation-of-antimicrobial-agents
#15
Miao Zhao, Alexander J Lepak, David R Andes
Animal infection models in the pharmacokinetic/pharmacodynamic (PK/PD) evaluation of antimicrobial therapy serve an important role in preclinical assessments of new antibiotics, dosing optimization for those that are clinically approved, and setting or confirming susceptibility breakpoints. The goal of animal model studies is to mimic the infectious diseases seen in humans to allow for robust PK/PD studies to find the optimal drug exposures that lead to therapeutic success. The PK/PD index and target drug exposures obtained in validated animal infection models are critical components in optimizing dosing regimen design in order to maximize efficacy while minimize the cost and duration of clinical trials...
November 9, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27884512/design-synthesis-and-antithrombotic-evaluation-of-novel-non-peptide-thrombin-inhibitors
#16
Dongxing Chen, Jinyu Shi, Jing Liu, Xueying Zhang, Xiaoying Deng, Yanyan Yang, Shuang Cui, Qihua Zhu, Guoqing Gong, Yungen Xu
Ten derivatives of 4-((1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-1-yl)methyl)benzimida-mide (I-1∼I-2, II-1∼II-8) were designed, synthesized and evaluated for their inhibitory effect on human thrombin. Compound II-7 (IC50=82.8nM), which showed the strongest thrombin inhibitory activity among the tested compounds, was chosen as the lead compound, and ten carbamate derivatives (II-9a∼II-13a, II-9b∼II-12b, II-14) were prepared and evaluated for their anticoagulant activity. The results indicate that most of the tested compounds exhibit a certain degree of inhibitory effect on thrombin-induced platelet aggregation, among which compounds II-11a (IC50=8...
November 9, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27865644/bioactivity-of-topologically-confined-gramicidin-a-dimers
#17
Kirtikumar B Jadhav, Claudia Stein, Oliwia Makarewicz, Gabriele Pradel, Roman J Lichtenecker, Holger Sack, Stefan H Heinemann, Hans-Dieter Arndt
The d-/l-peptide gramicidin A (gA) is well known as a pivotal ion channel model and shows a broad spectrum of bioactivities such as antibiosis, antimalarial activity, as well as hemolysis. We applied inter-chain disulfide bonds to constrain the conformational freedom of gA into parallel and antiparallel dimeric topologies. Albeit the constructs were not found to be monoconformational, CD- and IR-spectroscopic studies suggested that this strategy indeed restricted the conformational space of the d-/l-peptide construct, and that β-helical secondary structures prevail...
November 9, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27856238/evaluation-of-known-and-novel-inhibitors-of-orai1-mediated-store-operated-ca-2-entry-in-mda-mb-231-breast-cancer-cells-using-a-fluorescence-imaging-plate-reader-assay
#18
Iman Azimi, Jack U Flanagan, Ralph J Stevenson, Marco Inserra, Irina Vetter, Gregory R Monteith, William A Denny
The Orai1 Ca(2+) permeable ion channel is an important component of store operated Ca(2+) entry (SOCE) in cells. It's over-expression in basal molecular subtype breast cancers has been linked with poor prognosis, making it a potential target for drug development. We pharmacologically characterised a number of reported inhibitors of SOCE in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader (FLIPR) assay, and show that the rank order of their potencies in this assay is the same as those reported in a wide range of published assays...
November 7, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27876249/synthesis-anti-proliferative-activity-sar-study-and-preliminary-in-vivo-toxicity-study-of-substituted-n-n-bis-arylmethyl-benzimidazolium-salts-against-a-panel-of-non-small-cell-lung-cancer-cell-lines
#19
Kerri L Shelton, Michael A DeBord, Patrick O Wagers, Marie R Southerland, Travis M Williams, Nikki K Robishaw, Leah P Shriver, Claire A Tessier, Matthew J Panzner, Wiley J Youngs
A series of N,N'-bis(arylmethyl)benzimidazolium salts have been synthesized and evaluated for their in vitro anti-cancer activity against select non-small cell lung cancer cell lines to create a structure activity relationship profile. The results indicate that hydrophobic substituents on the salts increase the overall anti-proliferative activity. Our data confirms that naphthylmethyl substituents at the nitrogen atoms (N(1)(N(3))) and highly lipophilic substituents at the carbon atoms (C(2) and C(5)(C(6))) can generate benzimidazolium salts with anti-proliferative activity that is comparable to that of cisplatin...
November 5, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27856236/design-synthesis-biological-evaluation-and-molecular-modeling-studies-of-chalcone-rivastigmine-hybrids-as-cholinesterase-inhibitors
#20
Ling Wang, Yu Wang, Yiguang Tian, Jinling Shang, Xiaoou Sun, Hongzhuan Chen, Hao Wang, Wen Tan
A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC50 to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out...
November 5, 2016: Bioorganic & Medicinal Chemistry
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