EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy

Glioma, particularly its most malignant form, glioblastoma multiforme (GBM), is the most common and aggressive malignant central nervous system tumor. The drawbacks of the current chemotherapy for GBM have aroused curiosity in the search for targeted therapies. Aberrantly overexpressed epidermal growth factor receptor (EGFR) in GBM results in poor prognosis, low survival rates, poor responses to therapy and recurrence, and therefore EGFR-targeted therapy stands out as a promising approach for the treatment of gliomas. In this context, a series of pentacyclic triterpene analogues were subjected to in vitro and in silico assays, which were conducted to assess their potency as EGFR-targeted anti-glioma agents. In particular, compound 10 was the most potent anti-glioma agent with an IC50 value of 5.82 mu M towards U251 human glioblastoma cells. Taking into account its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), compound 10 exerts selective antitumor action towards Jurkat human leukemic T-cells. This compound also induced apoptosis and inhibited EGFR with an IC50 value of 9.43 mu M compared to erlotinib (IC50 = 0.06 mu M). Based on in vitro and in silico data, compound 10 stands out as a potential orally bioavailable EGFR-targeted anti-glioma agent endowed with the ability to cross the blood-brain barrier (BBB).Anadolu University Scientific Research Projects Commission [1902S013]; Bilateral Joint Research Project from the Japanese Society for the Promotion of Science [18039111-000102]This research was funded by Anadolu University Scientific Research Projects Commission, grant number 1902S013. M.F. acknowledges support by Bilateral Joint Research Project from the Japanese Society for the Promotion of Science (the grant no: 18039111-000102)

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

Fujita, Mikako/0000-0001-6705-4052; , Mohamed/0000-0002-9220-2659; Ali, Taha/0000-0002-8881-0408; Abd-Alla, Howaida I./0000-0001-9638-8481WOS: 000496242300120PubMed: 31574910Imatinib, 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 mu M, 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 mu M) 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.Bilateral Joint Research Project from the Japanese Society for the Promotion of Science [18039111-000102]This study was supported by Bilateral Joint Research Project from the Japanese Society for the Promotion of Science (the grant no: 18039111-000102)

Design, synthesis and biological evaluation of pentacyclic triterpene derivatives: Optimization of anti-Abl kinase activity

PubMed ID: 31574910Imatinib, 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. © 2019 by the authorsJapan Society for the Promotion of Science, JSPS: 18039111-000102Funding: This study was supported by Bilateral Joint Research Project from the Japanese Society for the Promotion of Science (the grant no: 18039111-000102). -