☆ 4.5 Article

Discovery and initial SAR of pyrimidin-4-yl-1H-imidazole derivatives with antiproliferative activity against melanoma cell lines

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2010)

期刊

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷 20, 期 5, 页码 1573-1577

出版社

PERGAMON-ELSEVIER SCIENCE LTD

DOI: 10.1016/j.bmcl.2010.01.064

关键词

Pyrimidin-4-yl-1H-imidazol-2-yl derivatives; Antiproliferative activity; Melanoma cell line; BRAF; CRAF; Selectivity

类别

Chemistry, Medicinal Chemistry, Organic

资金

Korea Institute of Science and Technology (KIST)
Ministry of Education, Science and Technology [2009-0087992]
National Research Foundation of Korea [2009-0087992] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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摘要

The synthesis of a novel series of pyrimidin-4-yl-1H-imidazol-2-yl derivatives 7, 8, 9 and their antiproliferative activities against A375P human melanoma cell line and WM3629 cell line were described. Most compounds showed superior antiproliferative activities compared to Sorafenib, the well-known RAF inhibitor. Among them, 7a exhibited potent activities on both cell lines (IC50 = 0.62 and 4.49 mu M, respectively) and turned out to be a selective and potent CRAF inhibitor. (C) 2010 Elsevier Ltd. All rights reserved.

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Sando, Chloe Sarnowski, Claudia L. Satizabal, Michela Scamosci, Nikolaos Scarmeas, Elio Scarpini, Philip Scheltens, Norbert Scherbaum, Martin Scherer, Matthias Schmid, Anja Schneider, Jonathan M. Schott, Geir Selbaek, Davide Seripa, Manuel Serrano, Jin Sha, Alexey A. Shadrin, Olivia Skrobot, Susan Slifer, Gijsje J. L. Snijders, Hilkka Soininen, Vincenzo Solfrizzi, Alina Solomon, Yeunjoo Song, Sandro Sorbi, Oscar Sotolongo-Grau, Gianfranco Spalletta, Annika Spottke, Alessio Squassina, Eystein Stordal, Juan Pablo Tartan, Lluis Tarraga, Niccolo Tesi, Anbupalam Thalamuthu, Tegos Thomas, Giuseppe Tosto, Latchezar Traykov, Lucio Tremolizzo, Anne Tybjaerg-Hansen, Andre Uitterlinden, Abbe Ullgren, Ingun Ulstein, Sergi Valero, Otto Valladares, Christine Van Broeckhoven, Jeffery Vance, Badri N. Vardarajan, Aad van der Lugt, Jasper Van Dongen, Jeroen van Rooij, John van Swieten, Rik Vandenberghe, Frans Verhey, Jean-Sebastien Vidal, Jonathan Vogelgsang, Martin Vyhnalek, Michael Wagner, David Wallon, Li-San Wang, Ruiqi Wang, Leonie Weinhold, Jens Wiltfang, Gill Windle, Bob Woods, Mary Yannakoulia, Habil Zare, Yi Zhao, Xiaoling Zhang, Congcong Zhu, Miren Zulaica, Lindsay A. Farrer, Bruce M. Psaty, Mohsen Ghanbari, Towfique Raj, Perminder Sachdev, Karen Mather, Frank Jessen, M. Arfan Ikram, Alexandre de Mendonca, Jakub Hort, Magda Tsolaki, Margaret A. Pericak-Vance, Philippe Amouyel, Julie Williams, Ruth Frikke-Schmidt, Jordi Clarimon, Jean-Francois Deleuze, Giacomina Rossi, Sudha Seshadri, Ole A. Andreassen, Martin Ingelsson, Mikko Hiltunen, Kristel Sleegers, Gerard D. Schellenberg, Cornelia M. van Duijn, Rebecca Sims, Wiesje M. van der Flier, Agustin Ruiz, Alfredo Ramirez, Jean-Charles Lambert

Summary: By characterizing the genetic landscape of Alzheimer's disease and related dementias, new loci have been identified and a new genetic risk score associated with the risk of future Alzheimer's disease and dementia has been generated.

NATURE GENETICS (2022)

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Article Clinical Neurology

Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women

Jaeyoon Chung, Anjali Das, Xinyu Sun, Debora R. Sobreira, Yuk Yee Leung, Catherine Igartua, Sahar Mozaffari, Yi-Fan Chou, Sam Thiagalingam, Jesse Mez, Xiaoling Zhang, Gyungah R. Jun, Thor D. Stein, Brian W. Kunkle, Eden R. Martin, Margaret A. Pericak-Vance, Richard Mayeux, Jonathan L. Haines, Gerard D. Schellenberg, Marcelo A. Nobrega, Kathryn L. Lunetta, Jayant M. Pinto, Li-San Wang, Carole Ober, Lindsay A. Farrer

Summary: Variants in the MGMT gene are associated with the development of Alzheimer's disease (AD), particularly in women. Multi-omics analyses suggest that this association may be mediated by the regulation of MGMT expression.

ALZHEIMERS & DEMENTIA (2023)

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Article Clinical Neurology

Association of APOE Genotypes and Chronic Traumatic Encephalopathy

Kathryn Atherton, Xudong Han, Jaeyoon Chung, Jonathan D. Cherry, Zachary Baucom, Nicole Saltiel, Evan Nair, Bobak Abdolmohammadi, Madeline Uretsky, Mohammed Muzamil Khan, Conor Shea, Shruti Durape, Brett M. Martin, Joseph N. Palmisano, Kurt Farrell, Christopher J. Nowinski, Victor E. Alvarez, Brigid Dwyer, Daniel H. Daneshvar, Douglas Katz, Lee E. Goldstein, Robert C. Cantu, Neil W. Kowall, Michael L. Alosco, Bertrand R. Huber, Yorghos Tripodis, John F. Crary, Lindsay Farrer, Robert A. Stern, Thor D. Stein, Ann C. McKee, Jesse Mez

Summary: This study analyzed brain donors from February 2008 to August 2019 and found that APOEε4 may increase the risk of CTE-related neuropathological and clinical outcomes among older individuals with a history of repetitive head impacts. Further validation in an independent sample is needed.

JAMA NEUROLOGY (2022)

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Article Clinical Neurology

Repetitive head impacts and chronic traumatic encephalopathy are associated with TDP-43 inclusions and hippocampal sclerosis

Raymond Nicks, Nathan F. Clement, Victor E. Alvarez, Yorghos Tripodis, Zachery H. Baucom, Bertrand R. Huber, Jesse Mez, Michael L. Alosco, Nurgul Aytan, Jonathan D. Cherry, Kerry A. Cormier, Carol Kubilius, Rebecca Mathias, Sarah E. Svirsky, Morgan J. Pothast, Audrey M. Hildebrandt, Jaeyoon Chung, Xudong Han, John F. Crary, Ann C. McKee, Matthew P. Frosch, Thor D. Stein

Summary: Hippocampal sclerosis (HS) and transactive response DNA-binding protein with 43 kDa (TDP-43) deposits are associated with advanced age. Chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to repetitive head impacts, also shows HS and TDP-43 pathology. However, the prevalence of HS in CTE, the pattern of TDP-43 pathology, and associations of HS and TDP-43 with repetitive head impacts are unknown.

ACTA NEUROPATHOLOGICA (2023)

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Article Medicine, General & Internal

Genome-Wide Pleiotropy Study Identifies Association of PDGFB with Age-Related Macular Degeneration and COVID-19 Infection Outcomes

Jaeyoon Chung, Viha Vig, Xinyu Sun, Xudong Han, George T. O'Connor, Xuejing Chen, Margaret M. DeAngelis, Lindsay A. Farrer, Manju L. Subramanian

Summary: Age-related macular degeneration (AMD) is a risk factor for severe consequences from COVID-19. Genetic analysis shows a significant correlation between AMD and COVID-19, and identified novel genetic associations between the two diseases.

JOURNAL OF CLINICAL MEDICINE (2023)

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Article Clinical Neurology

Alzheimer's disease heterogeneity explained by polygenic risk scores derived from brain transcriptomic profiles

Jaeyoon Chung, Nathan Sahelijo, Toru Maruyama, Junming Hu, Rebecca Panitch, Weiming Xia, Jesse D. Mez, Thor J. Stein, Andrew J. Saykin, Haruko Takeyama, Lindsay A. Farrer, Paul K. Crane, Kwangsik Nho, Gyungah R. Jun

Summary: This study investigates the use of polygenic risk scores (PRSs) integrated with AD brain transcriptome profiles to explain clinical and neuropathological heterogeneity in AD. The findings indicate that two gene modules (M6 and M9) associated with NPs and NFTs are linked to language and visuospatial functioning, matching clinical subtypes and brain atrophy at specific regions.

ALZHEIMERS & DEMENTIA (2023)

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Article Clinical Neurology

A Genomic Risk Score Identifies Individuals at High Risk for Intracerebral Hemorrhage

Evangelos Pavlos Myserlis, Marios K. Georgakis, Stacie L. Demel, Padmini Sekar, Jaeyoon Chung, Rainer Malik, Hyacinth I. Hyacinth, Mary E. Comeau, Guido J. Falcone, Carl D. Langefeld, Jonathan Rosand, Daniel Woo, Christopher D. Anderson

Summary: Researchers developed a genomic risk score that predicts the risk of intracerebral hemorrhage (ICH) in individuals of European ancestry. The score showed better predictive power than standard clinical risk factors and may improve clinical decision making for high-risk populations.

STROKE (2023)

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Article Clinical Neurology

Deep Resequencing of the 1q22 Locus in Non-Lobar Intracerebral Hemorrhage

Livia Parodi, Mary E. Comeau, Marios K. Georgakis, Ernst Mayerhofer, Jaeyoon Chung, Guido J. Falcone, Rainer Malik, Stacie L. Demel, Bradford B. Worrall, Sebastian Koch, Fernando D. Testai, Steven J. Kittner, Jacob L. Mccauley, Christiana E. Hall, Douglas J. Mayson, Mitchell S. V. Elkind, Michael L. James, Daniel Woo, Jonathan Rosand, Carl D. Langefeld, Christopher D. Anderson

Summary: This study performed targeted high-depth sequencing and chromatin interaction analysis to characterize the 1q22 locus and identify potential causal mechanisms for cerebral small vessel diseases. The results showed that variants in SEMA4A and PMF1 genes were associated with non-lobar intracerebral hemorrhage risk. The analysis also revealed long-range chromatin interactions between the SEMA4A promoter and the PMF1 enhancer regions. Additionally, overexpression of the PMF1 gene was found to be causally related to non-lobar intracerebral hemorrhage risk.

ANNALS OF NEUROLOGY (2023)

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Article Chemistry, Medicinal

Design and synthesis of a library of C2-substituted sulfamidoadenosines to probe bacterial permeability

Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan

Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2024)

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Article Chemistry, Medicinal

Design of MERS-CoV entry inhibitory short peptides based on helix-stabilizing strategies

Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang

Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2024)

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Article Chemistry, Medicinal

Development of novel β2-adrenergic receptor agonists for the stimulation of glucose uptake - The importance of chirality and ring size of cyclic amines

Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman

Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2024)

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Article Chemistry, Medicinal

Conformationally constrained potent inhibitors for enhancer of zeste homolog 2 (EZH2)

Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li

Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2024)

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Article Chemistry, Medicinal

The potential of Rhein's aromatic amines for Parkinson's disease prevention and treatment: α-Synuclein aggregation inhibition and disaggregation of preformed fibers

Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang

Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2024)

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Article Chemistry, Medicinal

Design, synthesis and biological evaluation of novel cationic liposomes loaded with melphalan for the treatment of cancer

Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla

Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (2024)

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