journal
https://read.qxmd.com/read/32904210/high-affinity-rigidified-at-2-receptor-ligands-with-indane-scaffolds
#1
JOURNAL ARTICLE
Charlotta Wallinder, Christian Sköld, Sara Sundholm, Marie-Odile Guimond, Samir Yahiaoui, Gunnar Lindeberg, Nicole Gallo-Payet, Mathias Hallberg, Mathias Alterman
Rigidification of the isobutyl side chain of drug-like AT2 receptor agonists and antagonists that are structurally related to the first reported selective AT2 receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers 7a , 7b , 8a , 8b , 9a , 9b , 10a and 10b bind to the AT2 receptor with moderate ( K i = 54-223 nM) to high affinity ( K i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32904148/recent-insights-into-natural-product-inhibitors-of-matrix-metalloproteinases
#2
REVIEW
Geetha B Kumar, Bipin G Nair, J Jefferson P Perry, David B C Martin
Members of the matrix metalloproteinase (MMP) family have biological functions that are central to human health and disease, and MMP inhibitors have been investigated for the treatment of cardiovascular disease, cancer and neurodegenerative disorders. The outcomes of initial clinical trials with the first generation of MMP inhibitors proved disappointing. However, our growing understanding of the complexities of the MMP function in disease, and an increased understanding of MMP protein architecture and control of activity now provide new opportunities and avenues to develop MMP-focused therapies...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32904145/introducing-nitrogen-atoms-to-amidoalkylindoles-potent-and-selective-cannabinoid-type-2-receptor-agonists-with-improved-aqueous-solubility
#3
JOURNAL ARTICLE
Yue-Yang Ji, Zhi-Long Wang, Fang-Ning Pei, Jun-Jie Shi, Jiao-Jiao Li, Hendra Gunosewoyo, Fan Yang, Jie Tang, Xin Xie, Li-Fang Yu
Previously we identified a series of amidoalkylindoles as potent and selective CB2 partial agonists. In the present study, we report our continuous effort to improve the aqueous solubility by introducing N atoms to the amidoalkylindole framework. Synthesis, characterization, and pharmacology evaluations were described. Bioisosteric replacements of the indole nucleus with an indazole, azaindole and benzimidazole were explored. Benzimidazole 43 (EC50,CB1 = NA, EC50,CB2 = 0.067 μM) and azaindole 24 (EC50,CB1 = NA, EC50,CB2 = 0...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32904142/sirtuin-inhibition-and-anti-cancer-activities-of-ethyl-2-benzimidazole-5-carboxylate-derivatives
#4
JOURNAL ARTICLE
K Y Yeong, M I H Nor Azizi, N Berdigaliyev, W N Chen, W L Lee, A N Shirazi, K Parang
New benzimidazoles were synthesized based on the previously identified sirtuin inhibitor BZD9L1. The compounds were screened for their sirtuin (SIRT1, SIRT2 and SIRT3) inhibitory activities. Compound BZD9Q1 was determined to be a pan-SIRT1-3 inhibitor. Furthermore, the proliferation of various cancer cells was inhibited by BZD9Q1 . It was shown that BZD9Q1 elicits a cytostatic effect by inducing cell cycle arrest at the G2 /M phase while also showing a prominent induction of apoptosis against oral cancer cells...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32904124/radioiodinated-9-fluorenone-derivatives-for-imaging-%C3%AE-7-nicotinic-acetylcholine-receptors
#5
JOURNAL ARTICLE
Hang Gao, Shuxia Wang, Bingchao Qiang, Sixuan Wang, Huabei Zhang
A series of 9 H -fluoren-9-one substituents were synthesized and evaluated for imaging cerebral α7-nAChRs. Meta -iodine substituted 9-fluorenone 5 with high binding affinity ( K i = 9.3 nM) and selectivity was radiolabeled with 125 I. Fully in vitro and in vivo studies of [125 I] 5 have been performed. [125 I] 5 exhibited well brain uptake with a peak concentration of 7.5 ± 0.9% ID/g in mice brains. Moreover, ex vivo autoradiography studies and micro single-photon emission computed tomography (micro-SPECT/CT) dynamic imaging in mice confirmed its in vivo imaging properties...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32904113/synthesis-and-characterization-of-a-novel-18-f-labeled-2-5-diarylnicotinamide-derivative-targeting-orexin-2-receptor
#6
JOURNAL ARTICLE
Hiroyuki Watanabe, Naoki Matsushita, Yoichi Shimizu, Shimpei Iikuni, Yuji Nakamoto, Kaori Togashi, Masahiro Ono
Orexin 2 receptor (OX2 R) is thought to play an important role in the arousal-promoting function, but its distribution and function in the pathophysiology of orexin-mediated disorders remains to be fully elucidated. In the present study, we synthesized and characterized a novel 18 F-labeled 2,5-diarylnicotinamide (DAN) derivative as a potential positron emission tomography (PET) probe for in vivo imaging of OX2 R. In in vitro binding experiments, [18 F]DAN-1 selectively bound to OX2 R. In a biodistribution study using normal mice, [18 F]DAN-1 displayed moderate brain uptake (2...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32904099/synthesis-of-new-lophine-carbohydrate-hybrids-as-cholinesterase-inhibitors-cytotoxicity-evaluation-and-molecular-modeling
#7
JOURNAL ARTICLE
João Paulo Bizarro Lopes, Luana Silva, Marco Antonio Ceschi, Diogo Seibert Lüdtke, Aline Rigon Zimmer, Thais Carine Ruaro, Rafael Ferreira Dantas, Cristiane Martins Cardoso de Salles, Floriano Paes Silva-Jr, Mario Roberto Senger, Gisele Barbosa, Lídia Moreira Lima, Isabella Alvim Guedes, Laurent Emmanuel Dardenne
In this study, we synthesized nine novel hybrids derived from d-xylose, d-ribose, and d-galactose sugars connected by a methylene chain with lophine. The compounds were synthesized by a four-component reaction to afford the substituted imidazole moiety, followed by the displacement reaction between sugar derivatives with an appropriate N -alkylamino-lophine. All the compounds were found to be the potent and selective inhibitors of BuChE activity in mouse serum, with compound 9a (a d-galactose derivative) being the most potent inhibitor (IC50 = 0...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32879717/a-small-molecule-drug-conjugate-smdc-of-dupa-and-a-duocarmycin-built-on-the-solid-phase
#8
JOURNAL ARTICLE
Andrew Michael Beekman, Marco M D Cominetti, Oliver Charles Cartwright, Dale L Boger, Mark Searcey
In a proof-of-concept study, solid phase synthesis allowed the rapid generation of a small molecule drug conjugate in which the glutamate carboxypeptidase II (GCPII) targeting small molecule DUPA was conjugated to the alkylating subunit of the potent cytotoxin duocarmycin SA. The targeted SMDC contained a cathepsin B cleavable linker, which was shown to be active and selective against cathepsin B over-expressing and GCPII-expressing tumour cell lines.
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32206244/dual-target-inhibitors-of-mycobacterial-aminoacyl-trna-synthetases-among-n-benzylidene-n-thiazol-2-yl-hydrazines
#9
JOURNAL ARTICLE
Oksana P Kovalenko, Galyna P Volynets, Mariia Yu Rybak, Sergiy A Starosyla, Olga I Gudzera, Sergiy S Lukashov, Volodymyr G Bdzhola, Sergiy M Yarmoluk, Helena I Boshoff, Michael A Tukalo
Effective treatment of tuberculosis is challenged by the rapid development of Mycobacterium tuberculosis ( Mtb ) multidrug resistance that presumably could be overcome with novel multi-target drugs. Aminoacyl-tRNA synthetases (AARSs) are an essential part of protein biosynthesis machinery and attractive targets for drug discovery. Here, we experimentally verify a hypothesis of simultaneous targeting of structurally related AARSs by a single inhibitor. We previously identified a new class of mycobacterial leucyl-tRNA synthetase inhibitors, N -benzylidene- N '-thiazol-2-yl-hydrazines...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32206243/overcoming-synthetic-challenges-in-targeting-coenzyme-a-biosynthesis-with-the-antimicrobial-natural-product-cj-15-801
#10
JOURNAL ARTICLE
Riyad Domingo, Renier van der Westhuyzen, Anton R Hamann, Konrad J Mostert, Leanne Barnard, Tanya Paquet, Erick T Tjhin, Kevin J Saliba, Willem A L van Otterlo, Erick Strauss
The biosynthesis of the essential metabolic cofactor coenzyme A (CoA) has been receiving increasing attention as a new target that shows potential to counter the rising resistance to established antimicrobials. In particular, phosphopantothenoylcysteine synthetase (PPCS)-the second CoA biosynthesis enzyme that is found as part of the bifunctional CoaBC protein in bacteria, but is monofunctional in eukaryotes-has been validated as a target through extensive genetic knockdown studies in Mycobacterium tuberculosis ...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32206242/aurantiamide-related-dipeptide-derivatives-are-formyl-peptide-receptor-1-antagonists
#11
JOURNAL ARTICLE
Margherita Mastromarino, Liliya N Kirpotina, Igor A Schepetkin, Mark T Quinn, Enza Lacivita, Marcello Leopoldo
Formyl peptide receptor 1 (FPR1) is expressed on a variety of immune system cells and is a key regulator of the inflammatory environment. Therefore, the development of FPR1 antagonists may represent a novel approach for modulating innate immunity and treating inflammatory diseases. Starting from a dipeptide scaffold that is structurally related to the natural product aurantiamide, we investigated the structure-activity relationships of the dipeptide (2 R ,2' S )- 6 , which was reported as an FPR1 antagonist...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32206241/current-and-emerging-therapeutic-targets-of-alzheimer-s-disease-for-the-design-of-multi-target-directed-ligands
#12
REVIEW
Laura Blaikie, Graeme Kay, Paul Kong Thoo Lin
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and a major cause of death worldwide. The number of people suffering from this debilitating disorder is rising at an unprecedented rate, with a subsequent surge in healthcare costs. Only four drugs are clinically available for the treatment of AD symptoms, but they are not disease-modifying. Consequently, there is an urgent need for a cure. Although the cause of this debilitating condition remains poorly understood, it is believed that several factors may be involved in combination - including, health and lifestyle, environmental, and genetic factors...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32206240/recent-developments-on-zinc-ii-metal-organic-framework-nanocarriers-for-physiological-ph-responsive-drug-delivery
#13
REVIEW
Weicong Liu, Ying Pan, Weiwei Xiao, Hongjia Xu, Dong Liu, Fei Ren, Xinsheng Peng, Jianqiang Liu
The high storage capacities and excellent biocompatibilities of zinc(ii) metal-organic frameworks (Zn-MOFs) have made them outstanding candidates as drug delivery carriers. Recent studies on the pH-responsive processes based on carrier-drug interactions have proven them to be the most efficient and effective way to control the release profiles of drugs. To satisfy the ever-growing demand in cancer therapy, great efforts are being devoted to the development of methods to precisely control drug release and achieve targeted use of an active substance at the right time and place...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32206239/interrupting-cyclic-dinucleotide-cgas-sting-axis-with-small-molecules
#14
REVIEW
Herman O Sintim, Clinton G Mikek, Modi Wang, Moloud A Sooreshjani
The cyclic dinucleotide-cGAS-STING axis plays important roles in host immunity. Activation of this signaling pathway, via cytosolic sensing of bacterial-derived c-di-GMP/c-di-AMP or host-derived cGAMP, leads to the production of inflammatory interferons and cytokines that help resolve infection. Small molecule activators of the cGAS-STING axis have the potential to augment immune response against various pathogens or cancer. The aberrant activation of this pathway, due to gain-of-function mutations in any of the proteins that are part of the signaling axis, could lead to various autoimmune diseases...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32190233/preparation-and-clinical-translation-of-99m-tc-psma-11-for-spect-imaging-of-prostate-cancer
#15
JOURNAL ARTICLE
Kusum Vats, Kanhaiyalal Agrawal, Rohit Sharma, Haladhar Dev Sarma, Drishty Satpati, Ashutosh Dash
This study explores the feasibility of radiolabeling the HBED-CC-PSMA (PSMA-11) ligand with Tc-99m for SPECT imaging of prostate cancer patients. 68 Ga-HBED-CC-PSMA (PSMA-11) is used clinically for PET/CT imaging of prostate cancer (PCa) patients. However, a PET/CT facility may not be affordable and/or accessible to remotely located health centers. Thus, economic considerations require development of a SPECT-based tracer to provide low cost effective health care to the entire global population. Hence, radiochemical parameters were varied and optimized to obtain the maximum radiochemical yield of 99m Tc-PSMA-11...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32133105/design-of-a-muc1-based-tricomponent-vaccine-adjuvanted-with-fsl-1-for-cancer-immunotherapy
#16
JOURNAL ARTICLE
Mingjing Li, Zhaoyu Wang, Bocheng Yan, Xiaona Yin, Yue Zhao, Fan Yu, Meng Meng, Yonghui Liu, Wei Zhao
MUC1 is an attractive target for cancer vaccines as a result of its over-expression and aberrant glycosylation pattern on many tumor cells. However, the low immunogenicity of MUC1 and immune tolerance have limited its application. Herein, we designed MUC1-based tricomponent antitumor vaccines adjuvanted with fibroblast stimulating lipopeptide 1 (FSL-1). Immunological results indicate that the glycosylated tricomponent vaccine candidate has elicited both humoral and cellular immune responses. The induced antibodies could effectively bind to MCF-7...
December 1, 2019: MedChemComm
https://read.qxmd.com/read/32952997/a-focused-structure-activity-relationship-study-of-psoralen-based-immunoproteasome-inhibitors
#17
JOURNAL ARTICLE
Eva Shannon Schiffrer, Izidor Sosič, Andrej Šterman, Janez Mravljak, Irena Mlinarič Raščan, Stanislav Gobec, Martina Gobec
The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. The development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. Here, we describe a focused series of psoralen-based inhibitors of the β5i subunit of the immunoproteasome with different substituents placed at position 4'. The most promising compound was further evaluated through changes at position 3 of the psoralen ring...
November 1, 2019: MedChemComm
https://read.qxmd.com/read/32952996/characterization-of-the-genomically-encoded-fosfomycin-resistance-enzyme-from-mycobacterium-abscessus
#18
JOURNAL ARTICLE
Skye Travis, Madeline R Shay, Shino Manabe, Nathaniel C Gilbert, Patrick A Frantom, Matthew K Thompson
Mycobacterium abscessus belongs to a group of rapidly growing mycobacteria (RGM) and accounts for approximately 65-80% of lung disease caused by RGM. It is highly pathogenic and is considered the prominent Mycobacterium involved in pulmonary infection in patients with cystic fibrosis and chronic pulmonary disease (CPD). FosM is a putative 134 amino acid fosfomycin resistance enzyme from M. abscessus subsp. bolletii that shares approximately 30-55% sequence identity with other vicinal oxygen chelate (VOC) fosfomycin resistance enzymes and represents the first of its type found in any Mycobacterium species...
November 1, 2019: MedChemComm
https://read.qxmd.com/read/32952995/indole-compounds-with-n-ethyl-morpholine-moieties-as-cb2-receptor-agonists-for-anti-inflammatory-management-of-pain-synthesis-and-biological-evaluation
#19
JOURNAL ARTICLE
Jiaojiao Li, Jing Ji, Ruibo Xu, Zhengfu Li
The CB2 receptor plays a crucial role in analgesia and anti-inflammation. To develop novel CB2 agonists with high efficacy and selectivity, a series of indole derivatives with N -ethyl morpholine moieties (compounds 1-56 ) were designed, synthesized and biologically evaluated. Compounds 1 , 2 , 3 , 46 and 53 exhibited high CB2 receptor affinity at low nanomolar concentrations and good receptor selectivity (EC50 (CB1)/EC50 (CB2) greater than 1000). The most active compound, compound 2 , was more potent than the standard drug GW405833 for in vitro agonistic action on the CB2 receptor...
November 1, 2019: MedChemComm
https://read.qxmd.com/read/32952994/the-cytotoxic-potential-of-cationic-triangulenes-against-tumour-cells
#20
JOURNAL ARTICLE
Euphemia Leung, Lisa I Pilkington, Mohinder M Naiya, David Barker, Ayesha Zafar, Chatchakorn Eurtivong, Jóhannes Reynisson
TOTA (trioxatriangulenium ion) is a close-shelled carbocation known to intercalate strongly with the DNA double helix (J. Reynisson, G. B. Schuster, S. B. Howerton, L. D. Williams, R. N. Barnett, C. L. Cleveland, U. Landman, N. Harrit, J. B. Chaires, J. Am. Chem. Soc. 2003, 125 , 2072). The cytotoxicity of TOTA and its four close structural analogues, ADOTA , Pr-ADOTA , Pr-DAOTA and n -Butyl-TATA were tested against the breast cancer cell line MDA-MB-231 and colon cancer cell line HCT116. The most potent derivatives Pr-ADOTA and Pr-DAOTA had IC50 values of ∼80 nM for MDA-MB-231 but slightly higher for HCT116 in the low hundreds nM range...
November 1, 2019: MedChemComm
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