Design, semi-synthesis and examination of new gypsogenin derivatives against leukemia via Abl tyrosine kinase inhibition and apoptosis induction
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, cilt.222, ss.1487-1499, 2022 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 222
- Basım Tarihi: 2022
- Doi Numarası: 10.1016/j.ijbiomac.2022.09.257
- Dergi Adı: INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, Food Science & Technology Abstracts, INSPEC, MEDLINE, Veterinary Science Database
- Sayfa Sayıları: ss.1487-1499
- Anahtar Kelimeler: Chronic myelogenous leukemia, Abl tyrosine kinase, Apoptosis, Gypsogenin derivatives, Imatinib, Molecular docking, CHRONIC MYELOGENOUS LEUKEMIA, BCR-ABL, TRITERPENOID SAPONINS, REDUCTIVE AMINATION, IN-VITRO, RESISTANCE, IMATINIB, KETONES, ROOTS, CELLS
- Anadolu Üniversitesi Adresli: Evet
Özet
Chronic myelogenous leukemia (CML) is characterized by Philadelphia translocation arising from Bcr-Abl fusion gene, which encodes abnormal oncoprotein showing tyrosine kinase (TK) function. Certain mutations in kinase domain, off-target effects and resistance problems of current TK inhibitors require the discovery of novel Abl TK inhibitors. For this purpose, herein, we synthesized new gypsogenin derivatives (6a-l) and evaluated their anticancer effects towards CML cells along with healthy cell line and different leukemic cells. Among these compounds, compound 6l was found as the most active anti-leukemic agent against K562 CML cells compared to imatinib exerting less cytotoxicity towards PBMCs (healthy). This compound also revealed significant anti -leukemic effects against Jurkat cell line. Besides, compound 6l enhanced apoptosis in CML cells with 52.4 % when compared with imatinib (61.8 %) and inhibited Abl TK significantly with an IC50 value of 13.04 +/- 2.48 mu M in a large panel of kinases accentuating Abl TK-mediated apoptosis of compound 6l in CML cells. Molecular docking outcomes showed that compound 6l formed mainly crucial interactions in the ATP-binding cleft of Abl TK similar to that of imatinib. Ultimately, in silico pharmacokinetic evaluation of compound 6l indicated that this compound was endowed with anti-leukemic drug candidate features.