A series of novel, sterically hindered lipophilic analogs of AG 957 was designed and synthesized as potential protein tyrosine kinase (PTK) inhibitors. The in vitro activity, in vivo anti-leukemia activity, and pharmacology of these PTK inhibitors were studied. Some aspects of the structure-activity relationship associated with the carboxylic acid, phenol ring, and linker modifications are discussed. We have demonstrated that the 1,4-hydroquinone moiety is essential for activity and that sterically hindered esters contribute to enhanced in vivo efficacy. Adaphostin (NSC 680410) has emerged as the improved compound with the maximum in vivo anti-leukemia hollow fiber activity, concordant with the original lead compound AG 957. Currently, adaphostin is undergoing preclinical toxicology studies.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmc.2004.12.003 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Structure-Activity Relationship Studies of an Autophagy Inhibitor That Targets the ATG14L-Beclin1 Protein-Protein Interaction Reveal Modifications That Improve Potency and Solubility and Maintain Selectivity.
J Med Chem
January 2025
Chemical Biology Section, Molecular Targets Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, United States.
Autophagy, a recycling process in eukaryotes, contributes to tumor growth and metastasis by alleviating cellular stress and facilitating survival and chemoresistance. The development of small molecules that selectively inhibit this pathway has proven challenging and is required to determine if autophagy inhibition can be harnessed as an effective therapeutic strategy in cancer. Compound 19 was previously identified as a selective autophagy inhibitor that targets the ATG14L-Beclin1 protein-protein interaction, which regulates the formation, localization, and function of VPS34 Complex I to initiate autophagy.
View Article and Find Full Text PDFEvaluation of single nucleotide polymorphisms in the human norepinephrine transporter (hNET) gene for structural, functional, and pathogenic significance.
Nucleosides Nucleotides Nucleic Acids
January 2025
Department of Molecular Biology and Genetics, Hitit University, Corum, Türkiye.
The norepinephrine transporter (NET) is a key regulator of noradrenergic neurotransmission and homeostasis, regulating the norepinephrine levels in the brain and peripheral tissues. hNET is a major target in neuropsychiatric disorders such as major depressive disorder, autonomic dysfunction, and attention deficit hyperactivity disorder (ADHD). The human norepinephrine transporter gene (, ) contains 504 missense single nucleotide polymorphisms (SNPs).
View Article and Find Full Text PDF1,4,5-Trisubstituted-carboxylated 1,2,3-triazoles: an unconventional class of ribonuclease A inhibitors.
Org Biomol Chem
January 2025
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721 302, India.
The "catalytic triad" present at the active site of ribonuclease A (RNase A) is responsible for the cleavage of the 5'-phosphodiester bond; amino acid residues His12, Lys41 and His119 constituting this triad provide a positively charged environment at the physiological pH. Based on docking studies, 1,4,5-trisubstituted-carboxylated 1,2,3-triazoles (1,4,5-TTs) were identified as a new class of RNase A inhibitors. Therefore, two different groups of 1,4,5-TTs, functionalized with carboxylic acid groups, were synthesized by reacting pre functionalized butyne-1,4-diol derivatives with several aryl/alkyl azides under solvent and catalyst free conditions.
View Article and Find Full Text PDFA perspective on field-effect in energy and environmental catalysis.
Chem Sci
December 2024
Hunan Joint International Research Center for Carbon Dioxide Resource Utilization, State Key Laboratory of Powder Metallurgy, School of Physics, Central South University Changsha 410083 P. R. China
The development of catalytic technologies for sustainable energy conversion is a critical step toward addressing fossil fuel depletion and associated environmental challenges. High-efficiency catalysts are fundamental to advancing these technologies. Recently, field-effect facilitated catalytic processes have emerged as a promising approach in energy and environmental applications, including water splitting, CO reduction, nitrogen reduction, organic electrosynthesis, and biomass recycling.
View Article and Find Full Text PDFSplit application of phosphorus fertilizer in Chinese milk vetch-rice rotation enhanced rice yield by reshaping soil diazotrophic community.
Heliyon
December 2024
Microelement Research Center of Huazhong Agricultural University, Key Laboratory of Arable Land Conservation (Middle and Lower Reaches of Yangtze River), Ministry of Agriculture and Rural Affairs, Wuhan, Hubei Province, 430070, China.
Chinese milk vetch (CMV) is widely recognized as the leading leguminous green manure utilized in the rice-green manure rotation system throughout southern China. While bacteria that form symbiotic relationships with CMV are responsible for fixing a significant portion of nitrogen (N) within agroecosystems. diazotrophic organisms play an essential role in the N cycle and enhance the pool of N readily accessible to plants.
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!