Design, Synthesis and Biological Evaluation of Pentacyclic Triterpene Derivatives: Optimization of Anti-ABL Kinase Activity
Küçük Resim Yok
Tarih
2019
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Mdpi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
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 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.
Açıklama
Fujita, Mikako/0000-0001-6705-4052; , Mohamed/0000-0002-9220-2659; Ali, Taha/0000-0002-8881-0408; Abd-Alla, Howaida I./0000-0001-9638-8481
Anahtar Kelimeler
leukemia, chronic myelogenous leukemia, ABL kinase, pentacyclic triterpenes, gypsogenin, apoptosis
Kaynak
Molecules
WoS Q Değeri
Q2
Scopus Q Değeri
Cilt
24
Sayı
19
