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.
Highlights
Leukemia, a group of blood cancer which initiates in the bone marrow resulting in an abnormal production of white blood cells, is the leading cause of cancer-related deaths in a wide population range, from children to aged people
The reaction progress was monitored by a thin layer chromatography (TLC) on precoated plates [Merck (Darmstadt, Germany) TLC sheets silica 60 F254]
All experiments were performed in triplicate and IC50 values defined as the drug concentrations that reduced absorbance to 50% of control values were calculated from MTT results
Summary
A group of blood cancer which initiates in the bone marrow resulting in an abnormal production of white blood cells, is the leading cause of cancer-related deaths in a wide population range, from children to aged people. A significant percentage of CML patients treated with imatinib developed drug resistance and adverse side effects [13,14,15]. In our previous studies [33,34] and [35], it was demonstrated that gypsogenin and its derivatives exhibit remarkable activities against diverse human cancer cell lines. 1c has anti-ABL kinase and anti-CML activities [36]. To the best of our knowledge, this was the first study to show the inhibitory activity of pentacyclic triterpenoids and their derivatives on ABL kinase. We conduct biological evaluation of some pentacyclic triterpenes and their derivatives including newly synthesized compounds to optimize anti-ABL kinase and anti-CML activities
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