RRC ID 59803
Author I Ciftci H, O Radwan M, E Ozturk S, Ulusoy NG, Sozer E, E Ellakwa D, Ocak Z, Can M, F S Ali T, I Abd-Alla H, Yayli N, Tateishi H, Otsuka M, Fujita M.
Title Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity.
Journal Molecules
Abstract Imatinib, an Abelson (ABL) tyrosine kinase inhibitor, is a lead molecular-targeted drug against chronic myelogenous leukemia (CML). To overcome its resistance and adverse effects, new inhibitors of ABL kinase are needed. Our previous study showed that the benzyl ester of gypsogenin (1c), a pentacyclic triterpene, has anti-ABL kinase and a subsequent anti-CML activity. To optimize its activities, benzyl esters of carefully selected triterpenes (PT1-PT6), from different classes comprising oleanane, ursane and lupane, and new substituted benzyl esters of gypsogenin (GP1-GP5) were synthesized. All of the synthesized compounds were purified and charachterized by different spectroscopic methods. Cytotoxicity of the parent triterpenes and the synthesized compounds against CML cell line K562 was examined; revealing three promising compounds PT5, GP2 and GP5 (IC50 5.46, 4.78 and 3.19 μM, respectively). These compounds were shown to inhibit extracellular signal-regulated kinase (ERK) downstream signaling, and induce apoptosis in K562 cells. Among them, PT5 was identified to have in vitro activity (IC50 = 1.44 μM) against ABL1 kinase, about sixfold of 1c, which was justified by molecular docking. The in vitro activities of GP2 and GP5 are less than PT5, hence they were supposed to possess other more mechanisms of cytotoxicity. In general, our design and derivatizations resulted in enhancing the activity against ABL1 kinase and CML cells.
Volume 24(19)
Published 2019-1-1
DOI 10.3390/molecules24193535
PII molecules24193535
PMID 31574910
PMC PMC6804044
MeSH Antineoplastic Agents / chemical synthesis Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology Cell Survival / drug effects Chemistry Techniques, Synthetic Dose-Response Relationship, Drug Drug Design* Humans K562 Cells Models, Molecular Molecular Conformation Molecular Structure Pentacyclic Triterpenes / chemical synthesis* Pentacyclic Triterpenes / chemistry Pentacyclic Triterpenes / pharmacology* Protein Kinase Inhibitors / chemical synthesis* Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology* Proto-Oncogene Proteins c-abl / antagonists & inhibitors Proto-Oncogene Proteins c-abl / chemistry Structure-Activity Relationship
IF 3.06
Times Cited 4
Human and Animal Cells A549(RCB0098) MCF7(RCB19049