journal
MENU ▼
Read by QxMD icon Read
search

Bioorganic & Medicinal Chemistry

journal
https://www.readbyqxmd.com/read/28818462/discovery-of-non-zwitterionic-aryl-sulfonamides-as-nav1-7-inhibitors-with-efficacy-in-preclinical-behavioral-models-and-translational-measures-of-nociceptive-neuron-activation
#1
Yong-Jin Wu, Jason Guernon, Andrea McClure, Guanglin Luo, Ramkumar Rajamani, Alicia Ng, Amy Easton, Amy Newton, Clotilde Bourin, Dawn Parker, Kathleen Mosure, Omar Barnaby, Matthew G Soars, Ronald J Knox, Michele Matchett, Rick Pieschl, James Herrington, Ping Chen, D V Sivarao, Linda J Bristow, Nicholas A Meanwell, Joanne Bronson, Richard Olson, Lorin A Thompson, Carolyn Dzierba
Since zwitterionic benzenesulfonamide Nav1.7 inhibitors suffer from poor membrane permeability, we sought to eliminate this characteristic by replacing the basic moiety with non-basic bicyclic acetals and monocyclic ethers. These efforts led to the discovery of the non-zwitterionic aryl sulfonamide 49 as a selective Nav1.7 inhibitor with improved membrane permeability. Despite its moderate cellular activity, 49 exhibited robust efficacy in mouse models of neuropathic and inflammatory pain and modulated translational electromyogram measures associated with activation of nociceptive neurons...
August 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28818460/the-design-and-synthesis-of-a-novel-compound-of-berberine-and-baicalein-that-inhibits-the-efficacy-of-lipid-accumulation-in-3t3-l1-adipocytes
#2
Mengjiao Hao, Zhuoji Guan, Yan Li, Lixian Liu, Xiao Yuan, Ying Gao, Weimin Li
The combination of berberine and baicalein may have a better therapeutic effect against disease. To explore the combined effect of baicalein and berberine in the treatment of obesity, we designed and synthesized a hybrid compound, and its biological activities were evaluated in 3T3-L1 adipocytes. The structures of the berberine-baicalein (BBS) compounds were confirmed by (1)H NMR, (13)C NMR, ultraviolet spectroscopy and high resolution mass spectrometry (HRMS). The present study showed that the IC50 values of the inhibitory effects of baicalein, berberine and BBS against 3T3-L1 cells were 29...
August 9, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28818463/ribosomally-synthesised-cyclic-peptides-from-plants-as-drug-leads-and-pharmaceutical-scaffolds
#3
David J Craik, Meng-Han Lee, Fabian B H Rehm, Benjamin Tombling, Benjamin Doffek, Hayden Peacock
Owing to their exceptional stability and favourable pharmacokinetic properties, plant-derived cyclic peptides have recently attracted significant attention in the field of peptide-based drug design. This article describes the three major classes of ribosomally-synthesised plant peptides - the cyclotides, the PawS-derived peptides and the orbitides - and reviews their applications as leads or scaffolds in drug design. These ribosomally-produced peptides have a range of biological activities, including anti-HIV, cytotoxic and immunomodulatory activity...
August 8, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28818459/a-novel-delocalized-lipophilic-cation-chlorambucil-conjugate-inhibits-p-glycoprotein-in-hepg2-adm-cells
#4
Teng Liu, Yongbo Peng, Xiong Li, Lian Liu, Fang Liu, Leye He
Multidrug resistance (MDR) limits the application of a large number of cancer-fighting agents in clinical therapy. One reason is that P-glycoprotein (Pgp) efflux pumps are usually overexpressed and lead to drug efflux in the cancer cells, which limits the viability of many chemotherapeutics. Current available inhibitors which block the Pgp pump efflux are usually not widely used in clinical practice, because they change other drug pharmacokinetic profiles or increase side effects. Here, through covalent linkage of cancer-targeting delocalized lipophilic cation FF and DNA-damaging drug nitrogen mustard chlorambucil (CLB), we rationally designed and synthesized a tumor-targeting anticancer agent FFCLB...
August 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28811071/biological-evaluation-of-2-pyrazolinyl-1-carbothioamide-derivatives-against-hct116-human-colorectal-cancer-cell-lines-and-elucidation-on-qsar-and-molecular-binding-modes
#5
Beom Soo Kim, Soon Young Shin, Seunghyun Ahn, Dongsoo Koh, Young Han Lee, Yoongho Lim
In the search of compounds exhibiting anticancer activity, 37 derivatives of 2-pyrazolinyl-1-carbothioamide were designed and synthesized. Clonogenic cell survival assays were adapted to measure the cytotoxicities of the synthetic derivatives against HCT116 human colon cancer cell lines. Half-maximal cell growth inhibitory concentrations (GI50) ranged from 0.49 to 41.22µM. The compound with the lowest GI50 value, 3-(2-hydroxy-4,5-dimethoxyphenyl)-5-(naphthalen-1-yl)-N-(3,4,5-trimethoxyphenyl)-pyrazolinyl-1-carbothioamide, was subjected to further biological studies, including cell viability and apoptosis assays to examine levels of annexin-V in the outer plasma membrane layer and poly ADP-ribose polymerase cleavage...
August 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28803798/radiosynthesis-and-preclinical-pet-evaluation-of-89-zr-nivolumab-bms-936558-in-healthy-non-human-primates
#6
Erin L Cole, Joonyoung Kim, David J Donnelly, R Adam Smith, Daniel Cohen, Virginie Lafont, Paul E Morin, Richard Y-C Huang, Patrick L Chow, Wendy Hayes, Samuel Bonacorsi
Cancer immunotherapy, unlike traditional cytotoxic chemotherapeutic treatments, engages the immune system to identify cancer cells and stimulate immune responses. The Programmed Death-1 (PD-1) protein is an immunoinhibitory receptor expressed by activated cytotoxic T-lymphocytes (CTL) that seek out and destroy cancer cells. Multiple cancer types express and upregulate the Programmed Death-Ligand 1 (PD-L1) and 2 (PD-L2) which bind to PD-1 as an immune escape mechanism. Nivolumab is a fully human IgG4 anti-PD-1 monoclonal antibody (mAb) approved for treatment of multiple cancer types...
August 4, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28807574/synthesis-and-evaluation-of-analogs-of-5-z-4-amino-2-butenyl-methylamino-5-deoxyadenosine-mdl-73811-or-abeado-an-inhibitor-of-s-adenosylmethionine-decarboxylase-with-antitrypanosomal-activity
#7
Anthony J Brockway, Oleg A Volkov, Casey C Cosner, Karen S MacMillan, Stephen A Wring, Thomas E Richardson, Michael Peel, Margaret A Phillips, Jef K De Brabander
We describe our efforts to improve the pharmacokinetic properties of a mechanism-based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African Trypanosomiasis (HAT). The lead compound, 5'-(((Z)-4-amino-2-butenyl)methylamino)-5'-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood-brain barrier permeation...
August 3, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28818461/discovery-and-process-development-of-a-novel-tace-inhibitor-for-the-topical-treatment-of-psoriasis
#8
Jean-Guy Boiteau, Gilles Ouvry, Jean-Marie Arlabosse, Stéphanie Astri, Audrey Beillard, Yushma Bhurruth-Alcor, Laetitia Bonnary, Claire Bouix-Peter, Karine Bouquet, Marilyne Bourotte, Isabelle Cardinaud, Catherine Comino, Benoît Deprez, Denis Duvert, Angélique Féret, Feriel Hacini-Rachinel, Craig S Harris, Anne-Pascale Luzy, Arnaud Mathieu, Corinne Millois, Nicolas Orsini, Jonathan Pascau, Artur Pinto, David Piwnica, Gaëlle Polge, Arnaud Reitz, Kevin Reversé, Nicolas Rodeville, Patricia Rossio, Delphine Spiesse, Samuel Tabet, Nathalie Taquet, Loïc Tomas, Emmanuel Vial, Laurent F Hennequin
Targeting the TNFα pathway is a validated approach to the treatment of psoriasis. In this pathway, TACE stands out as a druggable target and has been the focus of in-house research programs. In this article, we present the discovery of clinical candidate 26a. Starting from hits plagued with poor solubility or genotoxicity, 26a was identified through thorough multiparameter optimisation. Showing robust in vivo activity in an oxazolone-mediated inflammation model, the compound was selected for development. Following a polymorph screen, the hydrochloride salt was selected and the synthesis was efficiently developed to yield the API in 47% overall yield...
August 2, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28818464/one-pot-synthesis-of-bioactive-cyclopentenones-from-%C3%AE-linolenic-acid-and-docosahexaenoic-acid
#9
Daniel Maynard, Sara Mareike Müller, Monika Hahmeier, Jana Löwe, Ivo Feussner, Harald Gröger, Andrea Viehhauser, Karl-Josef Dietz
Oxidation products of the poly-unsaturated fatty acids (PUFAs) arachidonic acid, α-linolenic acid and docosahexaenoic acid are bioactive in plants and animals as shown for the cyclopentenones prostaglandin 15d-PGJ2 and PGA2, cis-(+)-12-oxophytodienoic acid (12-OPDA), and 14-A-4 neuroprostane. In this study an inexpensive and simple enzymatic multi-step one-pot synthesis is presented for 12-OPDA, which is derived from α-linolenic acid, and the analogous docosahexaenoic acid (DHA)-derived cyclopentenone [(4Z,7Z,10Z)-12-[[-(1S,5S)-4-oxo-5-(2Z)-pent-2-en-1yl]-cyclopent-2-en-1yl] dodeca-4,7,10-trienoic acid, OCPD]...
August 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28811070/evaluation-of-sequence-variability-in-hiv-1-gp41-c-peptide-helix-grafted-proteins
#10
Rachel L Tennyson, Susanne N Walker, Terumasa Ikeda, Reuben S Harris, Brian R McNaughton
Many therapeutically-relevant protein-protein interactions (PPIs) have been reported that feature a helix and helix-binding cleft at the interface. Given this, different approaches to disrupting such PPIs have been developed. While short peptides (<15 amino acids) typically do not fold into a stable helix, researchers have reported chemical approaches to constraining helix structure. However, these approaches rely on laborious, and often expensive, chemical synthesis and purification. Our premise is that protein-based solutions that stabilize a therapeutically-relevant helix offer a number of advantages...
August 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28807573/axially-substituted-silicon-iv-phthalocyanine-and-its-quaternized-derivative-as-photosensitizers-towards-tumor-cells-and-bacterial-pathogens
#11
İpek Ömeroğlu, Esra Nur Kaya, Meltem Göksel, Vesselin Kussovski, Vanya Mantareva, Mahmut Durmuş
Axially di-(alpha,alpha-diphenyl-4-pyridylmethoxy) silicon(IV) phthalocyanine (3) and its quaternized derivative (3Q) were synthesized and tested as photosensitizers against tumor and bacterial cells. These new phthalocyanines were characterized by elemental analysis, and different spectroscopic methods such as FT-IR, UV-Vis, MALDI-TOF and (1)H NMR. The photophysical properties such as absorption and fluorescence, and the photochemical properties such as singlet oxygen generation of both phthalocyanines were investigated in solutions...
August 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28807572/identification-of-highly-selective-and-potent-orexin-receptor-1-antagonists-derived-from-a-dual-orexin-receptor-1-2-antagonist-based-on-the-structural-framework-of-pyrazoylethylbenzamide
#12
Aya Futamura, Dai Nozawa, Yuko Araki, Yunoshin Tamura, Seiken Tokura, Hiroshi Kawamoto, Yuichi Tokumaru, Sora Kakihara, Takeshi Aoki, Norikazu Ohtake
The design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead (1) by installing a (S)-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N-ethyl-5-fluoro-N-{(2S)-1-[5-(4-fluorophenyl)-2H-tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide (24), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC50 of 2...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28803799/constructing-novel-dihydrofuran-and-dihydroisoxazole-analogues-of-isocombretastatin-4-as-tubulin-polymerization-inhibitors-through-3-2-reactions
#13
Ming-Yu Song, Chen-Yu Cao, Qiu-Rui He, Qing-Miao Dong, Ding Li, Jiang-Jiang Tang, Jin-Ming Gao
[3+2] reactions play a key role in constructing various pharmaceutical moleculars. In this study, using Mn(OAc)3 mediated and 1,3-dipolar [3+2] cyclization reactions, 38 novel dihydrofuran and dihydroisoxazole analogues of isoCA-4 were synthesized as inhibitors of tubulin polymerization. Among them, compound 6g was found to be the most potent cytotoxic agents against PC-3 cells with IC50 value of 0.47μM, and compound 5p exhibted highest activity on HeLa cells with IC50 vaule of 2.32µM. Tubulin polymerization assay revealed that 6g was a dose-dependent and effective inhibitor of tubulin assembly...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28801066/identification-of-pyrazolopyrimidine-arylsulfonamides-as-cc-chemokine-receptor-4-ccr4-antagonists
#14
Afjal H Miah, Aurelie C Champigny, Rebecca H Graves, Simon T Hodgson, Jonathan M Percy, Panayiotis A Procopiou
A novel 4-aminoindazole sulfonamide hit (13) was identified as a human CCR4 antagonists from testing a focussed library of compounds in the primary GTPγS assay. Replacing the indazole core with a pyrazolopyrimidine, and introduction of a methoxy group adjacent to the sulfonamide substituent, resulted in the identification of pyrazolopyrimidine 37a, which exhibited good binding affinity in the GTPγS assay (pIC50=7.2), low lipophilicity (clogP=2.2, chromlogD7.4=2.4), high LE (0.41), high solubility (CLND solubility ≥581µM), and an excellent PK profile in both the rat (F=62%) and the dog (F=100%)...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28797773/methyl-propiolate-and-3-butynone-starting-points-for-synthesis-of-amphiphilic-1-2-3-triazole-peptidomimetics-for-antimicrobial-evaluation
#15
Thomas A Bakka, Morten B Strøm, Jeanette H Andersen, Odd R Gautun
A library of 29 small 1,4-substituted 1,2,3-triazoles was prepared for studies of antimicrobial activity. The pharmacophore model investigated with these substrates was based on small peptidomimetics of antimicrobial peptides and antimicrobials isolated from marine organisms from sub-arctic regions. Using methyl 1,2,3-triazole-carboxylates and 1,2,3-triazole methyl ketones prepared through "click" chemistry we were able to synthesize the different cationic amphiphiles through three steps or less. Several structural modifications to the lipopohilic side and hydrophilic sides of the amphiphiles were investigated and compared with regards to antimicrobial activity and cytotoxicity in particular...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28797772/synthesis-of-novel-flavonoid-alkaloids-as-%C3%AE-glucosidase-inhibitors
#16
Jing Zhen, Yujie Dai, Tom Villani, Daniel Giurleo, James E Simon, Qingli Wu
A series of novel flavonoid alkaloids were synthesized with different flavonoids and attached nitrogen-containing moieties. These new compounds were screened for inhibitory activity of α-glucosidase, among which compound 23 was found to show the lowest IC50 of 4.13μM. Kinetic analysis indicates that the synthesized compounds 15 and 23 inhibit the enzyme in a non-competitive model with Ki value of 37.8±0.8μM and 13.2±0.6μM. Further docking studies suggest that the preferred binding pocket is close to the catalytic center, correlating to the experimental results...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28797771/biphenyloxy-alkyl-piperidine-and-azepane-derivatives-as-histamine-h3-receptor-ligands
#17
Dorota Łażewska, Maria Kaleta, J Stephan Schwed, Tadeusz Karcz, Szczepan Mogilski, Gniewomir Latacz, Agnieszka Olejarz, Agata Siwek, Monika Kubacka, Annamaria Lubelska, Ewelina Honkisz, Jadwiga Handzlik, Barbara Filipek, Holger Stark, Katarzyna Kieć-Kononowicz
Novel biphenyloxy-alkyl derivatives of piperidine and azepane were synthesized and evaluated for their binding properties at the human histamine H3 receptor. Two series of compounds were obtained with a meta- and a para-biphenyl moiety. The alkyl chain spacer contained five and six carbon atoms. The highest affinity among all compounds was shown by 1-(6-(3-phenylphenoxy)hexyl)azepane (13) with a Ki value of 18nM. Two para-biphenyl derivatives, 1-(5-(4-phenylphenoxy)pentyl)piperidine (14; Ki=25nM) and 1-(5-(4-phenylphenoxy)pentyl)azepane (16; Ki=34nM), classified as antagonists in a cAMP accumulation assay (IC50=4 and 9nM, respectively), were studied in detail...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28797770/replacement-of-benzylic-hydroxy-group-by-vinyl-or-hydroxymethyl-moiety-at-the-3-benzazepine-scaffold-retaining-glun2b-affinity
#18
Susann Rath, Dirk Schepmann, Bernhard Wünsch
Since overactivation of NMDA receptors is associated with neurodegenerative disorders, the design and development of subunit-selective NMDA receptor antagonists are of great interest. In order to avoid the formation of quinone-like intermediates as starting point for degradation the benzylic OH group of the lead compounds 2 was replaced by an electron rich vinyl or homologous hydroxymethyl moiety. The Bi(OTf)3 catalyzed intramolecular Friedel-Crafts alkylation of 9a represents the key step in the synthesis of 1-vinyl substituted tetrahydro-3-benzazepine 10...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28789910/one-pot-enzymatic-glycan-remodeling-of-a-therapeutic-monoclonal-antibody-by-endoglycosidase-s-endo-s-from-streptococcus-pyogenes
#19
Xin Tong, Tiezheng Li, Jared Orwenyo, Christian Toonstra, Lai-Xi Wang
A facile, one-pot enzymatic glycan remodeling of antibody rituximab to produce homogeneous high-mannose and hybrid type antibody glycoforms is described. This method was based on the unique substrate specificity of the endoglycosidase S (Endo-S) from Streptococcus pyogenes. While Endo-S efficiently hydrolyzes the bi-antennary complex type IgG Fc N-glycans, we found that Endo-S did not hydrolyze the "ground state" high-mannose or hybrid glycoforms, and only slowly hydrolyzed the highly activated high-mannose or hybrid N-glycan oxazolines...
July 29, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28789908/synthesis-and-carbonic-anhydrase-inhibition-of-polycyclic-imides-incorporating-n-benzenesulfonamide-moieties
#20
Andrea Angeli, Alaa A-M Abdel-Aziz, Alessio Nocentini, Adel S El-Azab, Paola Gratteri, Claudiu T Supuran
A series of polycyclic imides was prepared by reaction of the benzenesulfonamide with an appropriate polycyclic acid anhydride in refluxing glacial acetic acid. The synthesized mono- and bis-sulfonamides were evaluated as a carbonic anhydrase inhibitors (CA, EC 4.2.1.1), more precisely against the human (h) isoforms hCA I, II, IX and XII, some of which are involved in various pathologies, such as glaucoma, epilepsy and cancer. Several low nanomolar and isoform-selective hCA II, IX and XII inhibitors were detected, and the structure-activity relationship for CA inhibition with this class of compounds is discussed in details...
July 29, 2017: Bioorganic & Medicinal Chemistry
journal
journal
31538
1
2
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read
×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"