Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity

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.

A novel series of chlorinated plastoquinone analogs: Design, synthesis, and evaluation of anticancer activity

“…The MTT test was performed as previously described in the literature with small modifications (Ali et al, ; Ciftci, Radwan et al, ). Cells were cultured in the presence of various concentrations (0.3–100 µM) of the tested compounds for 24 hr and then stained with MTT solution and incubated for an additional 4 hr at 37°C.…”

In Vitro and In Silico Evaluation of Anticancer Activity of New Indole-Based 1,3,4-Oxadiazoles as EGFR and COX-2 Inhibitors

“…The effects of compounds 2a-i and erlotinib on cell viability were assessed by using MTT (Dojindo Molecular Technologies, Kumamoto, Japan), as previously described in the literature [62,63]. Cells were exposed to various concentrations (1-100 µM) of the compounds for 48 h at 37 • C and then stained with MTT solution and incubated for additional 4 h. At the end of this period, supernatants were removed, and 100 µL DMSO was added to each well to solubilize the formazan crystals.…”

Differential Anti-Proliferative and Anti-Migratory Activities of Ursolic Acid, 3-O-Acetylursolic Acid and Their Combination Treatments with Quercetin on Melanoma Cells

“…In the case of ursolic acid, the anti-proliferative effect was improved when a hydrogen acceptor group was introduced to exhibiting more potent cytotoxicity than their α-counterparts ( Figure 1) [11][12][13][14]. However, modification at position 28, namely amidation and esterification carboxylic acid, led to a decrease of its selectivity index [15]. The simplicity of the 3-acetyl derivative, commonly referred to as acetylursolic acid or 3-Oacetylursolic acid, makes it a good candidate for further mechanistic studies and has not yet been studied for its anti-migratory activities.…”

“…In the case of ursolic acid, the anti-proliferative effect was improved when a hydrogen acceptor group was introduced to positions 3, 11, 17 and 28 like acetyl or aminoalkyl groups, with β-oriented hydrogen-bond forming groups at C-3 exhibiting more potent cytotoxicity than their α-counterparts ( Figure 1 ) [ 11 , 12 , 13 , 14 ]. However, modification at position 28, namely amidation and esterification carboxylic acid, led to a decrease of its selectivity index [ 15 ].…”