beta-Piperidinoethylsulfides are oxidized by m-chloroperbenzoic acid to intermediates containing both N-oxide and sulfone functions. These undergo a Cope-type elimination to a vinylsulfone that can be captured by amines to afford beta-aminoethylsulfones. When a beta-aminoethylsulfone group is linked to the 4-position of a phenyl group attached at N-2 of O6-cyclohexylmethylguanine, the resulting derivatives are inhibitors of the cyclin-dependent kinase CDK2. One of the most potent inhibitors (IC50 = 45 nM) contained a N-3-hydroxypropyl group on the aminoethylsulfonyl substituent. The crystal structure of this inhibitor bound to CDK2/cyclin A was determined and shows an unusual network of hydrogen bonds. The synthetic methodology developed can be utilized in multiple-parallel format and has numerous potential applications in medicinal chemistry.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/ja060595j | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Validation of a hypomorphic variant in CDK13 as the cause of CHDFIDD with autosomal recessive inheritance through determination of an episignature.
Clin Epigenetics
January 2025
Faculty of Medicine of TUD Dresden University of Technology, Institute for Clinical Genetics, University Hospital Carl Gustav Carus at TUD Dresden University of Technology, Dresden, Germany.
Autosomal dominant CDK13-related disease is characterized by congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD). Heterozygous pathogenic variants, particularly missense variants in the kinase domain, have previously been described as disease causing. Using the determination of a methylation pattern and comparison with an established episignature, we reveal the first hypomorphic variant in the kinase domain of CDK13, leading to a never before described autosomal recessive form of CHDFIDD in a boy with characteristic features.
View Article and Find Full Text PDFCyclin-dependent protein kinases and cell cycle regulation in biology and disease.
Signal Transduct Target Ther
January 2025
Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, National Cancer Institute, Aviano, Italy.
Cyclin Dependent Kinases (CDKs) are closely connected to the regulation of cell cycle progression, having been first identified as the kinases able to drive cell division. In reality, the human genome contains 20 different CDKs, which can be divided in at least three different sub-family with different functions, mechanisms of regulation, expression patterns and subcellular localization. Most of these kinases play fundamental roles the normal physiology of eucaryotic cells; therefore, their deregulation is associated with the onset and/or progression of multiple human disease including but not limited to neoplastic and neurodegenerative conditions.
View Article and Find Full Text PDFNVP-2, in combination with Orlistat, represents a promising therapeutic strategy for acute myeloid leukemia.
Cancer Biol Ther
December 2025
Department of Hematology, Children's Hospital of Soochow University, Suzhou, China.
Cell cycle dysregulation and the corresponding metabolic reprogramming play significant roles in tumor development and progression. CDK9, a kinase that regulates gene transcription and cell cycle, also induces oncogene transcription and abnormal cell cycle in AML cells. The function of CDK9 for gene regulation in AML cells requires further exploration.
View Article and Find Full Text PDFBackground: Lung cancer has high morbidity and mortality rates, which results in a poor prognosis. Cuproptosis is a novel cell death mechanism. The aim of this study was to examine the biological characteristics and clinical significance of genes associated with cuproptosis in lung adenocarcinoma (LUAD), and to understand the molecular mechanisms underlying the occurrence and progression of LUAD.
View Article and Find Full Text PDFThe Cost-Effectiveness of CDK4/6 Inhibitors in Treating HR+/HER2- Metastatic Breast Cancer Patients in the USA: When Non-medication Expenses are Considered.
Clin Drug Investig
January 2025
Department of Public Health Sciences, University of Virginia, 560 Ray C Hunt Dr., Room 2107, Charlottesville, VA, USA.
Background And Objective: Cyclin-dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy (ET) significantly enhance progression-free survival and overall survival in patients diagnosed with HR+/HER2- metastatic breast cancer (MBC). However, they are highly expensive, and their economic impact has not been fully evaluated. This is a retrospective secondary analysis evaluating the cost effectiveness of these drugs, differentiating between medication-related and non-medication costs from a healthcare perspective.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!