5368-81-0Relevant articles and documents
Inhibitory effects of triarylpyrazole derivatives on LPS-induced nitric oxide and PGE2 productions in murine RAW 264.7 macrophages
Abdel-Maksoud, Mohammed S.,Baek, Daejin,Choi, Jungseung,El-Gamal, Mohammed I.,Gamal El-Din, Mahmoud M.,Kim, Hee-Kwon,Kim, Tae-Woo,Lee, Huijeong,Lee, Hwi-Ho,Lee, Kyung-Tae,Shin, Ji-Sun
, (2019)
In this article, a series of 22 triarylpyrazole derivatives were evaluated for in vitro antiinflammatory activity as inhibitors of nitric oxide (NO) and prostaglandin E2 (PGE2) release induced by lipopolysaccharide (LPS) in murine RAW 264.7 macrophages. The synthesized compounds 1a-h, 2a-f and 3a-h were first examined for their cytotoxicity for determination of the non-toxic concentration for antiinflammatory screening, so that the inhibitory effects against NO and PGE2 production were not caused by non-specific cytotoxicity. Compounds 1h and 2f were the most active PGE2 inhibitors with IC50 values of 2.94 μM and 4.21 μM, respectively. Western blotting and cell-free COX-2 screening revealed that their effects were due to inhibition of COX-2 protein expression. Moreover, compound 1h exerted strong inhibitory effect on the expression of COX-2 mRNA in LPS-induced murine RAW 264.7 macrophages.
Design, synthesis, broad-spectrum antiproliferative activity, and kinase inhibitory effect of triarylpyrazole derivatives possessing arylamides or arylureas moieties
Gamal El-Din, Mahmoud M.,El-Gamal, Mohammed I.,Abdel-Maksoud, Mohammed S.,Yoo, Kyung Ho,Oh, Chang-Hyun
, p. 122 - 131 (2016)
A novel series of 1,3,4-triarylpyrazole derivatives possessing terminal arylamide or arylurea terminal moieties has been designed and synthesized. Their in vitro antiproliferative activities were investigated against a panel of 58 cell lines of nine different cancer types at the NCI, USA. The urea analogues 2b, 2c, and 2f as well as the amide derivatives 3e and 3f exerted the highest mean % inhibition values over the 58 cell line panel at 10 μM, and thus were further tested in 5-dose testing mode to determine their GI50, TGI, and LC50 values. The above mentioned compounds have shown stronger antiproliferative activities in terms of potency and efficacy upon comparing their results with Sorafenib as a reference compound. Among them, compounds 2c and 2f possessing 3,4-dichlorophenylurea terminal moiety showed the highest mean %inhibition value of about 99.85 and 104.15% respectively over the 58-cell line panel at 10 μM concentration. Also compounds 2b, 3e, and 3f exhibited mean % inhibition over 80% at 10 μM concentration. The GI50 value of compound 3e over K-562 cancer cell line was 0.75 μM. Accordingly, compound 2f was screened over seven kinases at a single-dose concentration of 10 μM to profile its kinase inhibitory activity. Interestingly, the compound showed highly inhibitory activities (90.44% and 87.71%) against BRAF (V600E) and RAF1 kinases, respectively. Its IC50 value against BRAF (V600E) was 0.77 μM. Compounds 2b, 2c, 2f, 3e, and 3f exerted high selectivity towards cancer cell lines than L132 normal lung cells.
Design, synthesis and anti-inflammatory activity of imidazol-5-yl pyridine derivatives as p38α/MAPK14 inhibitor
Ali, Eslam M.H.,Abdel-Maksoud, Mohammed S.,Hassan, Rasha Mohamed,Mersal, Karim I.,Ammar, Usama M.,Se-In, Choi,He-Soo, Han,Kim, Hee-Kwon,Lee, Anna,Lee, Kyung-Tae,Oh, Chang-Hyun
, (2021)
P38α/MAPK14 is intracellular signalling regulator involved in biosynthesis of inflammatory mediator cytokines (TNF-α, IL-1, IL-6, and IL-1b), which induce the production of inflammatory proteins (iNOS, NF-kB, and COX-2). In this study, drug repurposing strategies were followed to repositioning of a series of B-RAF V600E imidazol-5-yl pyridine inhibitors to inhibit P38α kinase. A group 25 reported P38α kinase inhibitors were used to build a pharmacophore model for mapping the target compounds and proving their affinity for binding in P38α active site. Target compounds were evaluated for their potency against P38α kinase, compounds 11a and 11d were the most potent inhibitors (IC50 = 47 nM and 45 nM, respectively). In addition, compound 11d effectively inhibited the production of proinflammatory cytokines TNF-α, 1L-6, and 1L-1β in LPS-induced RAW 264.7 macrophages with IC50 values of 78.03 nM, 17.6 μM and 82.15 nM, respectively. The target compounds were tested for their anti-inflammatory activity by detecting the reduction of Nitric oxide (NO) and prostaglandin (PGE2) production in LPS-stimulated RAW 264.7 macrophages. Compound 11d exhibited satisfied inhibitory activity of the production of PGE2 and NO with IC50 values of 0.29 μM and 0.61 μM, respectively. Molecular dynamics simulations of the most potent inhibitor 11d were carried out to illustrate its conformational stability in the binding site of P38α kinase.
Design, synthesis, in vitro anticancer evaluation, kinase inhibitory effects, and pharmacokinetic profile of new 1,3,4-triarylpyrazole derivatives possessing terminal sulfonamide moiety
Abdel-Maksoud, Mohammed S.,El-Gamal, Mohammed I.,Gamal El-Din, Mahmoud M.,Oh, Chang Hyun
, p. 97 - 109 (2019)
The present work describes the design and synthesis of a novel series of 1,3-diaryl-4-sulfonamidoarylpyrazole derivatives 1a–q and 2a–q and their in vitro biological activities. The target compounds were evaluated for antiproliferative activity against NCI-60 cell line panel. Compounds 1c, 1g, 1k–m, 1o, 2g, 2h, 2k–m, 2o, and 2q showed the highest mean inhibition percentages at 10?μM single-dose testing and were selected to be tested at 5-dose mode. The ICs50 of the most potent compounds were determined over the 60 cell lines. Compound 2l exhibited the strongest activity against different cell lines with IC50 0.33?μM against A498 renal cancer cell line. Compound 2l was tested over a panel of 20 kinases to determine its molecular target(s), and its IC50 values over the most sensitive kinases were defined. In vitro stability and in vivo pharmacokinetic profile of compound 2l was also investigated.
Design, synthesis, and biological evaluation of novel imidazole derivatives possessing terminal sulphonamides as potential BRAFV600E inhibitors
Ali, Eslam M.H.,Abdel-Maksoud, Mohammed S.,Ammar, Usama M.,Mersal, Karim I.,Ho Yoo, Kyung,Jooryeong, Park,Oh, Chang-Hyun
, (2021)
BRAFV600E mutation has been detected in various malignant tumours. Developing of potent BRAFV600E inhibitors is considered a leading step in the way to cure different cancer types. In the current work, a series of 38 4-(1H-imidazol-5-yl)pyridin-2-amine derivatives was designed and synthesized using Dabrafenib as a lead compound for structural-guided optimization. The target compounds were evaluated as potential anticancer agents against NCI 60 human cancer cell lines. In 5-dose testing mode, two compounds 14h and 16e were tested to determine their IC50 values over each of the 60 cell lines. The selected candidates exhibited promising activity with mean IC50 values of 2.4 μM and 3.6 μM, respectively. Melanoma cancer cell lines exhibited the highest sensitivity after the treatment with the tested compounds 14h and 16e. The mean IC50 values of compounds 14h and 16e against Melanoma cancer cell lines are 1.8 μM and 1.88 μM, respectively. In addition, BRAFV600E kinase inhibitory activity was determined for each derivative. Compounds 15i, 15j, 16a, and 16d were the most potent inhibitors against BRAFV600E with IC50 76 nM, 32 nM, 35 nM, and 68 nM. The newly developed compounds represent a therapeutically promising approach for the treating various cancer types.
Synthesis of new triarylpyrazole derivatives possessing terminal sulfonamide moiety and their inhibitory effects on PGE2 and nitric oxide productions in lipopolysaccharide-induced RAW 264.7 macrophages
Abdel-Maksoud, Mohammed S.,El-Gamal, Mohammed I.,Gamal El-Din, Mahmoud M.,Choi, Yunji,Choi, Jungseung,Shin, Ji-Sun,Kang, Shin-Young,Yoo, Kyung Ho,Lee, Kyung-Tae,Baek, Daejin,Oh, Chang-Hyun
, (2018)
This article describes the design, synthesis, and in vitro anti-inflammatory screening of new triarylpyrazole derivatives. A total of 34 new compounds were synthesized containing a terminal arylsulfonamide moiety and a different linker between the sulfonamide and pyridine ring at position 4 of the pyrazole ring. All the target compounds were tested for both cytotoxicity and nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Compounds 1b, 1d, 1g, 2a, and 2c showed the highest NO inhibition percentages and the lowest cytotoxic effect. The most potent derivatives were tested for their ability to inhibit prostaglandin E2 (PGE2) in LPS-induced RAW 264.7 macrophages. The IC50 for nitric oxide inhibition, PGE2 inhibition, and cell viability were determined. In addition, 1b, 1d, 1g, 2a, and 2c were tested for their inhibitory effect on LPS-induced inducible nitric oxide synthase (iNOS) and Cyclooxygenase 2 (COX-2) protein expression as well as iNOS enzymatic activity.
GPR52 Antagonist Reduces Huntingtin Levels and Ameliorates Huntington's Disease-Related Phenotypes
Wang, Congcong,Zhang, Yu-Fang,Guo, Shimeng,Zhao, Quan,Zeng, Yanping,Xie, Zhicheng,Xie, Xin,Lu, Boxun,Hu, Youhong
, p. 941 - 957 (2020/11/30)
GPR52 is an orphan G protein-coupled receptor (GPCR) that has been recently implicated as a potential drug target of Huntington's disease (HD), an incurable monogenic neurodegenerative disorder. In this research, we found that striatal knockdown of GPR52 reduces mHTT levels in adult HdhQ140 mice, validating GPR52 as an HD target. In addition, we discovered a highly potent and specific GPR52 antagonist Comp-43 with an IC50 value of 0.63 μM by a structure-activity relationship (SAR) study. Further studies showed that Comp-43 reduces mHTT levels by targeting GPR52 and promotes survival of mouse primary striatal neurons. Moreover, in vivo study showed that Comp-43 not only reduces mHTT levels but also rescues HD-related phenotypes in HdhQ140 mice. Taken together, our study confirms that inhibition of GPR52 is a promising strategy for HD therapy, and the GPR52 antagonist Comp-43 might serve as a lead compound for further investigation.
Development of phenyltriazole thiol-based derivatives as highly potent inhibitors of DCN1-UBC12 interaction
Zhou, Wenjuan,Xu, Chenhao,Dong, Guanjun,Qiao, Hui,Yang, Jing,Liu, Hongmin,Ding, Lina,Sun, Kai,Zhao, Wen
, (2021/03/24)
Defective in cullin neddylation 1(DCN1) is a co-E3 ligase that is important for cullin neddylation. Dysregulation of DCN1 highly correlates with the development of various cancers. Herein, from the initial high-throughput screening, a novel hit compound 5a containing a phenyltriazole thiol core (IC50 value of 0.95 μM for DCN1-UBC12 interaction) was discovered. Further structure-based optimization leads to the development of SK-464 (IC50 value of 26 nM). We found that SK-464 not only directly bound to DCN1 in vitro, but also engaged cellular DCN1, suppressed the neddylation of cullin3, and hindered the migration and invasion of two DCN1-overexpressed squamous carcinoma cell lines (KYSE70 and H2170). These findings indicate that SK-464 may be a novel lead compound targeting DCN1-UBC12 interaction.
Copper-Catalyzed Methoxylation of Aryl Bromides with 9-BBN-OMe
Li, Chen,Song, Zhi-Qiang,Wang, Dong-Hui,Wang, Jing-Ru
supporting information, p. 8450 - 8454 (2021/11/17)
A Cu-catalyzed cross-coupling reaction between aryl bromides and 9-BBN-OMe to provide aryl methyl ethers under mild conditions is reported. The oxalamide ligand BHMPO plays a key role in the transformation. Various functional groups on bromobenzenes are well tolerated, providing the desired anisole products in moderate to high yields.
Demonstrating Ligandability of the LC3A and LC3B Adapter Interface
Hartmann, Markus,Huber, Jessica,Kramer, Jan S.,Heering, Jan,Pietsch, Larissa,Stark, Holger,Odadzic, Dalibor,Bischoff, Iris,Fürst, Robert,Schr?der, Martin,Akutsu, Masato,Chaikuad, Apirat,D?tsch, Volker,Knapp, Stefan,Biondi, Ricardo M.,Rogov, Vladimir V.,Proschak, Ewgenij
, p. 3720 - 3746 (2021/05/04)
Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).
