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Songwen Lin, Chunyang Wang, Ming Ji, Deyu Wu, Yuanhao Lv, Kehui Zhang, Yi Dong, Jing Jin, Jiajing Chen, Jingbo Zhang, Li Sheng, Yan Li, Xiaoguang Chen, Heng Xu
Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g. 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent anti-proliferative activities, favorable PK profiles and robust in vivo antitumor efficacies...
June 21, 2018: Journal of Medicinal Chemistry
Yi Liu, Muhammad Junaid, Yan Wang, Yu-Mei Tang, Wan-Ping Bian, Wen-Xu Xiong, Hai-Yang Huang, Chun-Di Chen, De-Sheng Pei
Tetracycline hydrochloride (TH), indomethacin (IM), and bezafibrate (BF) belong to the three different important classes of pharmaceuticals, which are well known for their toxicity and environmental concerns. However, studies are still elusive to highlight the mechanistic toxicity of these pharmaceuticals and rank them using both, the toxicity prediction and confirmation approaches. Therefore, we employed the next generation toxicity testing in 21st century (TOX21) tools and estimated the in vitro/vivo toxic endpoints of mentioned pharmaceuticals, and then confirmed them using in vitro/vivo assays...
June 9, 2018: Aquatic Toxicology
Anita Matic, Ivana Jukic, Ana Stupin, Lidija Baric, Zrinka Mihaljevic, Sanela Unfirer, Ivana Tartaro Bujak, Branka Mihaljevic, Julian H Lombard, Ines Drenjancevic
The goal of this study was to examine the effect of 1-week of high salt (HS) intake and the role of oxidative stress in changing the mechanisms of flow-induced dilation (FID) in isolated pressurized middle cerebral arteries (MCA) of male Sprague-Dawley rats (N=15-16/per group). Reduced FID in the HS group was restored by intake of the superoxide scavenger TEMPOL (HS+TEMPOL in vivo group). Nitric oxide synthases (NOS) inhibitor Nω -nitro-L-arginine methyl ester (L-NAME), COX inhibitor indomethacin (INDO) and selective inhibitor of microsomal CYP450 epoxidase activity N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) significantly reduced FID in the LS group, while FID in the HS group was mediated by NO only...
June 15, 2018: American Journal of Physiology. Heart and Circulatory Physiology
Yuji Nishiura, Akira Matsumura, Naotake Kobayashi, Atsuyuki Shimazaki, Shingo Sakamoto, Naohisa Kitade, Yutaka Tonomura, Akira Ino, Takayuki Okuno
Novel acetyl-CoA carboxylase 2 (ACC2) selective inhibitors were identified by the conversion of the alkyne unit of A-908292 to the olefin linker. Modification of the center and left part of the lead compound 1b improved the ACC2 inhibitory activity and CYP450 inhibition profile, and afforded a highly selective ACC2 inhibitor 2e which showed in vivo efficacy in C57BL/6 mice.
June 4, 2018: Bioorganic & Medicinal Chemistry Letters
Hadir M Maher, Nourah Z Alzoman, Shereen M Shehata, Norah O Abanmy
Dasatinib (DAS) is a tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia and in the management of ulcerative colitis (UC). Since some nutraceuticals (e.g. curcumin, olive oil, and cocoa extract) could alter the function of ABC transporters and /or CYP450 enzymes, DAS bioavailability could potentially be affected following their co-administration. This work aims at studying the possibility of PK interaction between DAS and the selected nutraceuticals in UC rats using UPLC- MS/MS...
2018: PloS One
Wei Song, Longjiang Yu, Zhihong Peng
We provide detailed datasets from our analysis of proteins that are identified in human liver, lung, kidney and intestine microsomes by MS-based proteomics. Also included is a set of CYP450 enzymes and microsomal glutathione- S -transferase (MGSTs) activities in human liver microsomes. The data presented in this paper support the research article "Targeted label-free approach for quantification of epoxide hydrolase and glutathione transferases in microsomes" (Song et al., 2015) [1]. We expect that the data will contribute to the study of metabolism enzymes...
June 2018: Data in Brief
Myeong-Sang Yu, Hyang-Mi Lee, Aaron Park, Chungoo Park, Hyithaek Ceong, Ki-Hyeong Rhee, Dokyun Na
BACKGROUND: Administered drugs are often converted into an ineffective or activated form by enzymes in our body. Conventional in silico prediction approaches focused on therapeutically important enzymes such as CYP450. However, there are more than thousands of different cellular enzymes that potentially convert administered drug into other forms. RESULT: We developed an in silico model to predict which of human enzymes including metabolic enzymes as well as CYP450 family can catalyze a given chemical compound...
June 13, 2018: BMC Bioinformatics
Nebojsa Nick Knezevic, Tatiana Tverdohleb, Ivana Knezevic, Kenneth D Candido
It is estimated that the total annual financial cost for pain management in the U.S. exceeds 100 billion dollars. However, when indirect costs are included, such as functional disability and reduction in working hours, the cost can reach more than 300 billion dollars. In chronic pain patients, the role of pharmacogenetics is determined by genetic effects on various pain types, as well as the genetic effect on drug safety and efficacy. In this review article, we discuss genetic polymorphisms present in different types of chronic pain, such as fibromyalgia, low back pain, migraine, painful peripheral diabetic neuropathy and trigeminal neuralgia...
June 8, 2018: International Journal of Molecular Sciences
Emine B Yalcin, Ming Tong, Gina Gallucci, Suzanne M de la Monte
BACKGROUND: The high levels of blood alcohol achieved with chronic plus binge alcohol exposures are somewhat reduced by co-administration of tobacco specific Nicotine-Derived Nitrosamine Ketone (NNK) suggesting that NNK may alter alcohol metabolism. OBJECTIVE: To test this hypothesis, we We examined ethanol and acetaldehyde-metabolizing enzyme activities and malondialdehyde adduct formation in rats exposed to ethanol (chronic + binge), NNK, or both. METHODS: 4-week old Long Evans rats were fed liquid diets containing 0% or 26% caloric ethanol for 8 weeks...
June 10, 2018: Drug Metabolism Letters
Joske Millecam, Laura De Clerck, Elisabeth Govaert, Mathias Devreese, Elke Gasthuys, Wim Schelstraete, Dieter Deforce, Lies De Bock, Jan Van Bocxlaer, Stanislas Sys, Siska Croubels
Since the implementation of several legislations to improve pediatric drug research, more pediatric clinical trials are being performed. In order to optimize these pediatric trials, adequate preclinical data are necessary, which are usually obtained by juvenile animal models. The growing piglet has been increasingly suggested as a potential animal model due to a high degree of anatomical and physiological similarities with humans. However, physiological data in pigs on the ontogeny of major organs involved in absorption, distribution, metabolism, and excretion of drugs are largely lacking...
2018: Frontiers in Pharmacology
Feng Li, Nenggang Zhang, Siddharth Gorantla, Scott R Gilbertson, Debananda Pati
Separase, a known oncogene, is widely overexpressed in numerous human tumors of breast, bone, brain, blood, and prostate. Separase is an emerging target for cancer therapy, and separase enzymatic inhibitors such as sepin-1 are currently being developed to treat separase-overexpressed tumors. Drug metabolism plays a critical role in the efficacy and safety of drug development, as well as possible drug-drug interactions. In this study, we investigated the in vitro metabolism of sepin-1 in human, mouse, and rat liver microsomes (RLM) using metabolomic approaches...
2018: Frontiers in Pharmacology
Jia Lin, Hua-Shan Zhao, Xue-Nan Li, Lei Qin, Cong Zhang, Jun Xia, Jinlong Li
The residues from the widely used broad-spectrum environmental herbicide, atrazine (ATR) results in the exposure of non-target organisms and persisted as a global major public health hazard. ATR is neurotoxic and may cause adverse health effects in mammals, birds and fishes. Nevertheless, the molecular mechanism of ATR induced neurotoxicity is remains unclear. To assess the molecular mechanisms of ATR-induced cerebral toxicity through potential oxidative damage, quail were treated with ATR by oral gavage administration at doses of 0, 50, 250 and 500 mg/kg body weight daily for 45 days...
June 5, 2018: Journal of Agricultural and Food Chemistry
Yiping Lin, Yanli Wei, Xiaoxia Hu, Meilling Wu, Xiaoqian Ying, Mingxing Ding
Oldenlandia diffusa has been used to treat various cancers. Cytochrome P450, a drug metabolic enzyme, might be influenced by herbal medicine. Currently, the problem that remains is the effective treatment in drug-drug interaction situation. Potential influences of Oldenlandia diffusa were elucidated on the CYP450 activities in rats using a cocktail method. Blood samples were precipitated by acetonitrile. Quantitative determination of target test object was done by ultra-performance liquid chromatography tandem mass spectrometry detection...
2018: Biochemistry Research International
Jiaojiao Yu, Qiuyan Liu, Xiaoyu Lu, Xiaonan Li, Ning Li, Baolin Liu, Fang Huang, Zhixia Qiu
Corydalis saxicola Bunting, a well-known traditional Chinese medicine in south China, has been widely used for the treatment of various hepatic diseases. Its active ingredients are Corydalis saxicola Bunting total alkaloids (CSBTA), which primarily include dehydrocavidine, palmatine, and berberine. These representative alkaloids could be metabolized by hepatic CYP450s. Hence, it is necessary to investigate the potential influences of CSBTA on CYP450s to explore the possibility of herb-drug interactions. In present study, in vitro inhibition and in vivo induction studies were performed to evaluate the potential effects of CSBTA extract on CYP450s in rats...
May 28, 2018: Phytotherapy Research: PTR
Fernando Sanzi Cortez, Lorena da Silva Souza, Luciana Lopes Guimarães, João Emanoel Almeida, Fabio Hermes Pusceddu, Luciane Alves Maranho, Luciana Gonçalves Mota, Caio Rodrigues Nobre, Beatriz Barbosa Moreno, Denis Moledo de Souza Abessa, Augusto Cesar, Aldo Ramos Santos, Camilo Dias Seabra Pereira
The antihypertensive losartan (LOS) has been detected in wastewater and environmental matrices, however further studies focused on assessing the ecotoxicological effects on aquatic ecosystems are necessary. Considering the intensive use of this pharmaceutical and its discharges into coastal zones, our study aimed to determine the environmental concentrations of LOS in seawater, as well as to assess the biological effects of LOS on the marine bivalve Perna perna. For this purpose, fertilization rate and embryolarval development were evaluated through standardized assays...
May 15, 2018: Science of the Total Environment
Yesim A Tahirovic, Valarie M Truax, Robert J Wilson, Edgars Jecs, Huy H Nguyen, Eric J Miller, Michelle B Kim, Katie M Kuo, Tao Wang, Chi S Sum, Mary E Cvijic, Gretchen M Schroeder, Lawrence J Wilson, Dennis C Liotta
A novel series of CXCR4 antagonists with piperidinyl and piperazinyl alkylamine side chains designed as butyl amine replacements are described. Several of these compounds showed similar activity to the parent compound TIQ-15 ( 5 ) in a SDF-1 induced calcium flux assay. Preliminary structure-activity relationship investigations led us to identify a series containing N -propyl piperazine side chain analogs exemplified by 16 with improved off-target effects as measured in a muscarinic acetylcholine receptor (mAChR) calcium flux assay and in a limited drug safety panel screen...
May 10, 2018: ACS Medicinal Chemistry Letters
Ibrahim Torktaz, Ali Najafi, Reza Golmohamadi, Sorour Hassani
The ToxT transcription factor mediates the transcription of the two major virulence factors in Vibrio cholerae. It has a DNA binding domain made of α4, α5, α6, α7, α8, α9 and α10 helices that is responsible for the transcription of virulence genes. Therefore, it is of interest to screen ToxT against the ZINC ligand database containing data for a million compounds. The QSAR model identified 40 top hits for ToxT. Two target protein complexes with ligands Lig N1 and Lig N2 with high score were selected for molecular dynamics simulation...
2018: Bioinformation
Vinayak Agarwal
Cytochrome P450 (CYP450) enzymes are ubiquitous catalysts in natural product biosynthetic schemes where they catalyze numerous different transformations using radical intermediates. In this protocol, we describe procedures to assay the activity of a marine bacterial CYP450 enzyme Bmp7 which catalyzes the oxidative radical coupling of polyhalogenated aromatic substrates. The broad substrate tolerance of Bmp7, together with rearrangements of the aryl radical intermediates leads to a large number of products to be generated by the enzymatic action of Bmp7...
2018: Methods in Enzymology
J J M Rood, P J A Dormans, M J van Haren, J H M Schellens, J H Beijnen, R W Sparidans
Ibrutinib is a targeted covalent inhibitor frequently used for the treatment of various lymphomas. In addition to oxidative metabolism, it is metabolized through glutathione coupling. The quantitative insight into this kind of metabolism is scarce, and tools for quantitation are lacking. The non-oxidative metabolism could prove a more prominent role when oxidative metabolism is impaired. Also, in-vitro studies could over-estimate the effect of CYP450-inhibition. To gain quantitative insight into this relatively unknown biotransformation pathway of the drug we have developed a validated simple, fast and sensitive bio-analytical assay for ibrutinib, dihydrodiol-ibrutinib, and the glutathione, cysteinylglycine and cysteine conjugates of ibrutinib in human plasma...
May 11, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Xiang Li, Youjun Xu, Luhua Lai, Jianfeng Pei
Adverse side effects of drug-drug interactions induced by human cytochrome P450 (CYP450) inhibition is an important consideration in drug discovery. It is highly desirable to develop computational models that can predict the inhibitive effect of a compound against a specific CYP450 isoform. In this study, we developed a multi-task model for concurrent inhibition prediction of five major CYP450 isoforms, namely 1A2, 2C9, 2C19, 2D6, and 3A4. The model was built by training multi-task autoencoder deep neural network (DNN) on a large dataset containing more than 13000 compounds, extracted from PubChem BioAssay Database...
May 18, 2018: Molecular Pharmaceutics
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