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SummaryThe discovery of the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3-hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC 50 value of 9.3 µM. In contrast, the IC 50 against normal peripheral blood mononuclear cells was 276.0 µM, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABL1) (IC 50 =8.7 μM), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and 1c was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppresses signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors. KeywordsGypsogenin, Abelson tyrosine-protein kinase 1, chronic myelogenous leukemia Biological and Pharmaceutical Bulletin Advance PublicationCancer is a worldwide health problem, and despite intensive research efforts over the last several decades, an effective cure has not been identified. 1)However, the recent discovery of molecular targeted drugs against cancer at the end of the 20 th century has led to promising results. 1,2) Imatinib (Fig. 1), which targets the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL), [3][4][5][6] was discovered based on the findings that chronic myelogenous leukemia (CML) is caused by a chromosomal translocation that results in the constitutively expressed and active BCR-ABL. 7,8) While imatinib can be initially effective in treating CML, some patients have shown drug resistance to imatinib. [9][10][11] Several new generation drugs with a different binding mode to Abelson kinase (ABL) have thus been developed. 6,[12][13][14][15][16] These drugs are artificial heterocyclic compounds, however, if widely distributed natural products and/or their derivatives show the inhibitory activity against BCR-ABL, it would be more convenient to get.Pentacyclic triterpenoids, a category of natural compounds, can be extracted from a variety of plants and show various activities. 17,18) Some of these triterpenoids were reported to exhibit anti-tyrosine kinase activity. 19,20) Here we focused on a pentacyclic triterpenoid gypsogenin, 21,22) extracted from Gypsophila species, 23,24) which is widely distributed in the Eu...

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.

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SUMMARY Objective:The aim of the present study was to investigate the effects on antioxidant defense system in human erythrocytes exposed to egonol that isolated from seeds of Styrax officinalis L.Method: A solution of Egonol was added so that final concentrations of Egonol were 0.2, 0.4, 0.6, 0.8, and 1 mg/ml and erythrocyte pellets were incubated for 15 minutes. Malondialdehyde (MDA) level, activities of glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), glutathione-S-transferase (GST) glutathione were determined in hemolysis of human erythrocytes.Results: Activities of SOD and GST were markedly increased in erythrocyte of human blood compared to the control group (p<0.05) in all concentrations of egonol. This increase also dosedependent manner. The activities of SOD and GST enzymes were increased 30% and 70%, respectively, in 1 mg/ml egonol concentration. There were no statistically significant alterations in GPx and CAT enzyme activities. In addition, MDA level that is an indicator of lipid peroxidation was not found to be increased significantly. Conclusion:Those results revealed that egonol has no effect of enhancing free radical formation in erythrocyte thus also causes no increase lipid peroxidation was observed. It was observed that, egonol was increased SOD and GST enzymes activities and free radicals were disappeared by the antioxidant defense system so erythrocytes were preserved from the lipid peroxidation.Keywords: Antioxidant defense system, egonol, human erythrocytes, Styrax officinalis L. Bulgular: Egonol uygulanan insan kan eritrosit grupları, kontrol grubuyla karşılaştırıldığında, SOD ve GST enzim aktivitelerinde doz bağımlı olarak belirgin artışlar gözlendi (p<0.05). 1 mg/ml egonol derişiminde, SOD ve GST enzim aktivitelerinde sırasıyla, % 30 ve % 70 artış saptandı. GPx ve CAT enzim aktiviteleri arasında istatistiksel olarak anlamlı değişiklikler gözlenmedi. Buna ek olarak, lipid peroksidasyonunun bir göstergesi olan MDA düzeyinde de anlamlı artış saptanmadı. 169 CMJ Cumhuriyet Medical JournalSonuç: Bu sonuçlar, egonolün eritrositlerde serbest oksijen radikali oluşumunu arttırıcı bir etkisinin olmamasının yanısıra lipid peroksidasyonunda da artışa neden olmadığını ortaya koymuştur. Egonolün, SOD ve GST enzim aktivitelerini arttırarak, serbest radikallerin antioksidan savunma sistemi tarafından temizlenmeleri ve eritrositlerin lipid peroksidasyonundan korunmalarına yardımcı olduğu düşünülmektedir.