A new derivative of 1-phenyl-3-methyl-5-pyrazolone, 4,4-dichloro-1-(2,4-dichlorophenyl)-3-methyl-5-pyrazolone, named TELIN, was chemically synthesized and identified as a potent inhibitor of human telomerase in the cell-free telomeric repeat amplification protocol. TELIN inhibited telomerase activity at submicromolar level with IC50 of approximately 0.3 microM. Kinetic studies revealed that TELIN does not bind to DNA but to telomerase protein, and the mode of inhibition by this substance was competitive-noncompetitive mixed-type with respect to the TS primer, whereas it was uncompetitive or noncompetitive-uncompetitive mixed-type with respect to the three deoxyribonucleosides. These results demonstrate that TELIN is a specific potent catalytic blocker of telomerase,and is considered to be a valuable substance for medical treatment of cancer and related diseases.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bbrc.2004.06.094 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Applications of innovative synthetic strategies in anticancer drug Discovery: The Driving Force of new chemical reactions.
Bioorg Med Chem Lett
January 2025
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address:
The discovery of novel anticancer agents remains a critical goal in medicinal chemistry, with innovative synthetic methodologies playing a pivotal role in advancing this field. Recent breakthroughs in CH activation reactions, cyclization reactions, multicomponent reactions, cross-coupling reactions, and photo- and electro-catalytic reactions have enabled the efficient synthesis of new molecular scaffolds exhibiting potent biological activities, including anticancer properties. These methodologies have facilitated the functionalization of natural products, the modification of bioactive molecules, and the generation of entirely new compounds, many of which demonstrate strong antitumor activity.
View Article and Find Full Text PDFSynthesis of Pyrazole-Based Inhibitors of the Bacterial Enzyme -Succinyl-l,l-2,6-Diaminopimelic Acid Desuccinylase (DapE) as Potential Antibiotics.
Int J Mol Sci
December 2024
Department of Chemistry and Biochemistry, Loyola University Chicago, 1032 West Sheridan Road, Chicago, IL 60660, USA.
Based on the inhibitory potencies from earlier reported tetrazole thioether analogs, we now describe the synthesis and inhibition of pyrazole-based inhibitors of -succinyl-l,l-2,6-diaminopimelic acid desuccinylase (DapE) from (DapE). The most potent pyrazole analog bears an aminopyridine amide with an IC of 17.9 ± 8.
View Article and Find Full Text PDFThe Diverse Binding Modes Explain the Nanomolar Levels of Inhibitory Activities Against 1-Deoxy-d-Xylulose 5-Phosphate Reductoisomerase from Exhibited by Reverse Hydroxamate Analogs of Fosmidomycin with Varying -Substituents.
Molecules
December 2024
School of Pharmacy, Kitasato University, Minato-ku, Tokyo 108-8641, Japan.
It is established that reverse hydroxamate analogs of fosmidomycin inhibit the growth of by inhibiting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), the second enzyme of the non-mevalonate pathway, which is absent in humans. Recent biochemical studies have demonstrated that novel reverse fosmidomycin analogs with phenylalkyl substituents at the hydroxamate nitrogen exhibit inhibitory activities against DXR at the nanomolar level. Moreover, crystallographic analyses have revealed that the phenyl moiety of the -phenylpropyl substituent is accommodated in a previously unidentified subpocket within the active site of DXR.
View Article and Find Full Text PDFStudy on SHP2 Conformational Transition and Structural Characterization of Its High-Potency Allosteric Inhibitors by Molecular Dynamics Simulations Combined with Machine Learning.
Molecules
December 2024
School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, Yuquan Road, Beijing 100049, China.
The src-homology 2 domain-containing phosphatase 2 (SHP2) is a human cytoplasmic protein tyrosine phosphatase that plays a crucial role in cellular signal transduction. Aberrant activation and mutations of SHP2 are associated with tumor growth and immune suppression, thus making it a potential target for cancer therapy. Initially, researchers sought to develop inhibitors targeting SHP2's catalytic site (protein tyrosine phosphatase domain, PTP).
View Article and Find Full Text PDFIntracellular Co-Delivery of Carbon Monoxide and Nitric Oxide Induces Mitochondrial Apoptosis for Cancer Therapy.
Angew Chem Int Ed Engl
January 2025
University of Science and Technology of China, Department of Polymer Science and Engineering, 96 Jinzhai Road, 230026, , 230026, Hefei, CHINA.
Understanding the interplay between gasotransmitters is essential for unlocking their therapeutic potential. However, achieving spatiotemporally controlled co-delivery to target cells remains a significant challenge. Herein, we propose an innovative strategy for the intracellular co-delivery of carbon monoxide (CO) and nitric oxide (NO) gasotransmitters under clinically relevant wavelengths.
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!