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

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 (<b>1c</b>), a pentacyclic triterpene, has anti-ABL kinase and a subsequent anti-CML activity. To optimize its activities, benzyl esters of carefully selected triterpenes (<b>PT1&#8722;PT6</b>), from different classes comprising oleanane, ursane and lupane, and new substituted benzyl esters of gypsogenin (<b>GP1&#8722;GP5</b>) 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 <b>PT5</b>, <b>GP2</b> and <b>GP5</b> (IC₅₀ 5.46, 4.78 and 3.19 &#956;M, respectively). These compounds were shown to inhibit extracellular signal-regulated kinase (ERK) downstream signaling, and induce apoptosis in K562 cells. Among them, <b>PT5</b> was identified to have in vitro activity (IC₅₀ = 1.44 &#956;M) against ABL1 kinase, about sixfold of <b>1c</b>, which was justified by molecular docking. The in vitro activities of <b>GP2</b> and <b>GP5</b> are less than <b>PT5</b>, 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.

Abstract licence: CC BY

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