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Journal of Enzyme Inhibition and Medicinal Chemistry

Ghina Alameh, Agnès Emptoz-Bonneton, Marc Rolland de Ravel, Eva L Matera, Elisabeth Mappus, Patrick Balaguer, Luc Rocheblave, Thierry Lomberget, Charles Dumontet, Marc Le Borgne, Michel Pugeat, Catherine Grenot, Claude Y Cuilleron
Synthetic progesterone and 5α/β-pregnane-3,20-dione derivatives were evaluated as in vitro and in vivo modulators of multidrug-resistance (MDR) using two P-gp-expressing human cell lines, the non-steroidogenic K562/R7 erythroleukaemia cells and the steroidogenic NCI-H295R adrenocortical carcinoma cells, both resistant to doxorubicin. The maximal effect in both cell lines was observed for 7α-O-benzoyloxy,11α(R)-O-tetrahydropyranyloxy-5β-pregnane-3,20-dione 4. This modulator co-injected with doxorubicin significantly decreased the tumour size and increased the survival time of immunodeficient mice xenografted with NCI-H295R or K562/R7 cells...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Yi-Lin Chiu, Yi-Ying Wu, Robert B Barndt, Yee Hui Yeo, Yu-Wen Lin, Hou-Ping Sytwo, Huan-Cheng Liu, Yuan Xu, Bailing Jia, Jehng-Kang Wang, Michael D Johnson, Chen-Yong Lin
Matriptase is ectopically expressed in neoplastic B-cells, in which matriptase activity is enhanced by negligible expression of its endogenous inhibitor, hepatocyte growth factor activator inhibitor (HAI)-1. HAI-1, however, is also involved in matriptase synthesis and intracellular trafficking. The lack of HAI-1 indicates that other related inhibitor, such as HAI-2, might be expressed. Here, we show that HAI-2 is commonly co-expressed in matriptase-expressing neoplastic B-cells. The level of active matriptase shed after induction of matriptase zymogen activation in 7 different neoplastic B-cells was next determined and characterised...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Jie Yang, Pingping Zhang, Yuheng Hu, Teng Liu, Jie Sun, Xiaojing Wang
Alzheimer's disease, a neurodegenerative illness, has the extremely complex pathogenesis. Accumulating evidence indicates there is a close relationship between several enzymes and Alzheimer's disease. Various substituted 3-arylcoumarin derivatives were synthesised, and their in vitro activity, including cholinesterase inhibitory activity, monoamine oxidase inhibitory activity, and antioxidant activity were investigated. Most of the compounds exhibited high activity; therefore 3-arylcoumarin compounds have the potential as drug candidates for the treatment of Alzheimer's disease...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Olga Bakulina, Anton Bannykh, Mirna Jovanović, Ilona Domračeva, Ana Podolski-Renić, Raivis Žalubovskis, Milica Pešić, Dmitry Dar'in, Mikhail Krasavin
Human thioredoxin reductase 1 (TrxR1) is a selenocysteine-containing enzyme which plays a crucial role in regulating numerous redox signalling pathways within the cell. While its functioning is important in all cells, levels of TrxR1 expression are higher in cancer cells, possibly as an adaptation to much higher levels of reactive oxygen species and the need for more extensive DNA synthesis. This makes TrxR1 an attractive target for cancer therapy development. Inspired by the structure of disulphide compounds which have advanced through various stages of clinical development, we designed a series of dithiodiglycolic acid derivatives...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Marouan Rami, Jean-Yves Winum, Claudiu T Supuran, Patricia Melnyk, Saïd Yous
Using histamine as lead molecule, a library of (hetero)aryl substituted thiazol-2,4-yl derivatives incorporating pyridine as proton shuttling moiety were obtained and investigated as activators of human carbonic anhydrase (CA, EC isoforms I, II, VII and XIV. Some derivatives displayed good activating and selectivity profiles. This study provides an interesting opportunity to study the thiazole scaffold for the design of CA activators (CAAs), possibly acting on the central nervous system and targeting pathologies involving memory and learning impairments...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Le Cong Huan, Cao Viet Phuong, Le Cong Truc, Vo Nguyen Thanh, Hai Pham-The, Le-Thi-Thu Huong, Nguyen Thi Thuan, Eun Jae Park, A Young Ji, Jong Soon Kang, Sang-Bae Han, Phuong-Thao Tran, Nguyen-Hai Nam
In our search for novel small molecules activating procaspase-3, we have designed and synthesised a series of novel acetohydrazides incorporating quinazolin-4(3H)-ones (5, 6, 7). Biological evaluation revealed eight compounds with significant cytotoxicity against three human cancer cell lines (SW620, colon cancer; PC-3, prostate cancer; NCI-H23, lung cancer). The most potent compound 5t displayed cytotoxicity up to 5-fold more potent than 5-FU. Analysis of structure-activity relationships showed that the introduction of different substituents at C-6 position on the quinazolin-4(3H)-4-one moiety, such as 6-chloro or 6-methoxy potentially increased the cytotoxicity of the compounds...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Lianshuang Zhang, Qin Chen, Guige Hou, Wei Zhao, Yun Hou
Novel hydroxyl-substituted double Schiff-base 4-piperidone/cyclohexanone derivatives, 3a-e, 4a-e, 5a-d, and 6a-c, were synthesized and fully characterized by 1 H NMR, IR and elemental analysis. The cytotoxicity against human carcinoma cell lines A549, SGC7901, HePG2, HeLa, K562, THP-1 and non-malignant LO2 cell lines were evaluated. The results showed 4-piperidinone derivatives displayed better cytotoxicity than cyclohexanone derivatives, especially for 3,4,5-trihydroxyphenyl-substituted BAP 5c. The western blot and flow cytometry results proved 5c can effectively promote cell apoptosis through up-regulating Bax protein and down-regulating Bcl-2 protein expression...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Xi Xu, Jie Ren, Yinghe Ma, Hongting Liu, Quanjin Rong, Yifan Feng, Yameng Wang, Yu Cheng, Ruijia Ge, Zhiyu Li, Jinlei Bian
With the aim of discovering novel IDO1 inhibitors, a combined similarity search and molecular docking approach was employed to the discovery of 32 hit compounds. Testing the screened hit compounds has led to several novel submicromolar inhibitors. Especially for compounds LVS-019 with cyanopyridine scaffold, showed good IDO1 inhibitory activity. To discover more compounds with similar structures to LVS-019, a shape-based model was then generated on the basis of it and the second-round virtual screening was carried out leading to 23 derivatives...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Lacramioara Popovici, Roxana-Maria Amarandi, Ionel I Mangalagiu, Violeta Mangalagiu, Ramona Danac
Two new series of heterocyclic derivatives with potential anticancer activity, in which a pyrrolo[1,2-b]pyridazine or a pyrrolo[2,1-a]phthalazine moiety was introduced in place of the 3'-hydroxy-4'-methoxyphenyl ring of phenstatin have been synthesised and their structure-activity relationship (SAR) was studied. Fourteen of the new compounds were evaluated for their in vitro cytotoxic activity by National Cancer Institute (NCI) against 60 human tumour cell lines panel. The best five compounds in terms of in vitro growth inhibition were screened in the second stage five dose-response studies, three of them showing a very good antiproliferative activity with GI50 <100 nM on several cell lines including colon, ovarian, renal, prostate, brain and breast cancer, melanoma and leukemia...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Tessianna A Misko, Yi-Ting Liu, Michael E Harris, Nancy L Oleinick, John Pink, Hsueh-Yun Lee, Chris G Dealwis
Ribonucleotide reductase (RR) catalyses the rate-limiting step of dNTP synthesis, establishing it as an important cancer target. While RR is traditionally inhibited by nucleoside-based antimetabolites, we recently discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH) that binds reversibly to the catalytic site (C-site). Here we report the synthesis and in vitro evaluation of 13 distinct compounds (TP1-13) with improved binding to hRR over NSAH (TP8), with lower KD 's and more predicted residue interactions...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Samaneh Zolghadri, Asieh Bahrami, Mahmud Tareq Hassan Khan, J Munoz-Munoz, F Garcia-Molina, F Garcia-Canovas, Ali Akbar Saboury
Tyrosinase is a multi-copper enzyme which is widely distributed in different organisms and plays an important role in the melanogenesis and enzymatic browning. Therefore, its inhibitors can be attractive in cosmetics and medicinal industries as depigmentation agents and also in food and agriculture industries as antibrowning compounds. For this purpose, many natural, semi-synthetic and synthetic inhibitors have been developed by different screening methods to date. This review has focused on the tyrosinase inhibitors discovered from all sources and biochemically characterised in the last four decades...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Maurizio Ronci, Sonia Del Prete, Valentina Puca, Simone Carradori, Vincenzo Carginale, Raffaella Muraro, Gabriella Mincione, Antonio Aceto, Francesca Sisto, Claudiu T Supuran, Rossella Grande, Clemente Capasso
The genome of Helicobacter pylori encodes for carbonic anhydrases (CAs, EC belonging to the α- and β-CA classes, which together with urease, have a pivotal role in the acid acclimation of the microorganism within the human stomach. Recently, in the exoproteome of H. pylori, a CA with no indication of the corresponding class was identified. Here, using the protonography and the mass spectrometry, a CA belonging to the α-class was detected in the outer membrane vesicles (OMVs) generated by planktonic and biofilm phenotypes of four H...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Liang Guo, Qin Ma, Wei Chen, Wenxi Fan, Jie Zhang, Bin Dai
A series of novel N9 -heterobivalent β-carbolines has been synthesized. All the novel compounds were tested for their anticancer activity against six tumour cell lines in vitro. Among these molecules, compounds 5b, and 5w exhibited strong cytotoxic activities with IC50 value of lower than 20 μM. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, compounds 5b and 5w exhibited that tumour inhibition rate of over 40% in the Sarcoma 180 and Lewis lung cancer animal models...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Yosselin Huentupil, Luis Peña, Néstor Novoa, Emanuela Berrino, Rodrigo Arancibia, Claudiu T Supuran
A series of organometallic acylhydrazones was prepared, incorporating Re(CO)3 , Mn(CO)3 and ferrocenyl moieties, which were subsequently reacted with amino-sulfonamides in order to obtain carbonic anhydrase (CA, EC inhibitors possessing organometallic moieties in their molecules. The new derivatives were investigated as inhibitors of four human (h) CA isoforms with pharmaceutical applications, such as the cytosolic hCA I, II and VII and the mitochondrial hCA VA. An interesting inhibitory profile against these isoforms was obtained, with some of these metal complexes acting as subnanomolar or low nanomolar inhibitors...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Priscila Hess Lopes, Mário T Murakami, Fernanda C V Portaro, Kerly Fernanda Mesquita Pasqualoto, Carmen van den Berg, Denise V Tambourgi
Loxosceles spiders' venoms consist of a mixture of proteins, including the sphingomyelinases D (SMases D), which are the main toxic components responsible for local and systemic effects in human envenomation. Herein, based on the structural information of SMase D from Loxosceles laeta spider venom and virtual docking-based screening approach, three benzene sulphonate compounds (named 1, 5 and 6) were identified as potential Loxosceles SMase D inhibitors. All compounds inhibited the hydrolysis of the sphingomyelin substrate by both recombinant and native SMases D...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Xinyuan Xu, Yingyi Chen, Qiang Fu, Duan Ni, Jian Zhang, Xiaolong Li, Shaoyong Lu
Phosphoinositide-dependent protein kinase-1 (PDK1) is an important protein in mediating the PI3K-AKT pathway and is thus identified as a promising target. The catalytic activity of PDK1 is tightly regulated by allosteric modulators, which bind to the PDK1 Interacting Fragment (PIF) pocket of the kinase domain that is topographically distinct from the orthosteric, ATP binding site. Allosteric modulators by attaching to the less conserved PIF-pocket have remarkable advantages such as higher selectivity, less side effect, and lower toxicity...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Andrea Angeli, Mariana Pinteala, Stelian S Maier, Sonia Del Prete, Clemente Capasso, Bogdan C Simionescu, Claudiu T Supuran
A series of benzenesulfonamides incorporating selenazoles with diverse substitution patterns were investigated as inhibitors of six bacterial carbonic anhydrases (CAs, EC from bacterial pathogens, such as Helicobacter pylori (hpCAα was the investigated enzyme), Vibrio cholerae (all the three CAs from this pathogen were considered, VchCAα, VchCAβ and VchCAγ) and Burkholderia pseudomallei (with its two CAs, BpsCAβ and BpsCAγ). All these sulfonamides were effective CA inhibitors, with potencies in the low micromolar or submicromolar range, making them attractive as lead compounds for designing antibacterials with a novel mechanism of action, which could counteract the extensive resistance problem observed with many clinically used antibiotics...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Camila C Bitencourt Brito, Hélder Vinicius Carneiro da Silva, Daci José Brondani, Antonio Rodolfo de Faria, Rafael Matos Ximenes, Ivanildo Mangueira da Silva, Julianna F C de Albuquerque, Marcelo Santos Castilho
Leishmaniasis is considered as one of the major neglected tropical diseases due to its magnitude and wide geographic distribution. Leishmania braziliensis, responsible for cutaneous leishmaniasis, is the most prevalent species in Brazil. Superoxide dismutase (SOD) belongs to the antioxidant pathway of the parasites and human host. Despite the differences between SOD of Leishmania braziliensis and human make this enzyme a promising target for drug development efforts. No medicinal chemistry effort has been made to identify LbSOD inhibitors...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Xiaoqiao Wang, Dongdong Tang, Yaowei Zou, Xiaoyu Wu, Yihua Chen, Hongying Li, Siqi Chen, Yue Shi, Hongxin Niu
Mitochondria play important roles in the development of diabetic kidney disease (DKD). The SS peptide is a tetrapeptide that is located and accumulated in the inner mitochondrial membrane; it reduces reactive oxygen species (ROS) and prevents mitochondrial dysfunction. Podocytes are key cellular components in DKD progression. However, whether the SS peptide can exert renal protection through podocytes and the mechanism involved are unknown. In the present study, we explored the mechanisms of the SS peptide on podocyte injury in vivo and in vitro...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
Jie Wu, Jing Liu, XiaoQing Wei, Qi Yu, XiangHuan Niu, ShuHong Tang, Lei Song
This study aimed to identify genetic biomarkers in pancreatic cancer (PC) and explore its function in PC via a feature-base analysis of bioinformatics. OMIM and DisGeNET databases discovered 209 PC connected genes and then 516 connected genes were identified. We selected 29 genes according to optimal features and chose COL1A2, which had the highest expression, for the following experiment. The expression of COL1A2 was determined by qRT-PCR; cell proliferation was determined by MTT assay; migration and invasion after COL1A2 and miR-25-3p transfection was evaluated by Transwell assay...
December 2019: Journal of Enzyme Inhibition and Medicinal Chemistry
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