Published January 1, 2022
| Version v1
Journal article
Open
Design, semi-synthesis and examination of new gypsogenin derivatives against leukemia via Abl tyrosine kinase inhibition and apoptosis induction
Creators
- 1. Ege Univ, Fac Sci, Chem Dept, TR-35040 Izmir, Turkey
- 2. Adnan Menderes Univ, Fac Med, Dept Biophys, TR-09010 Aydin, Turkey
- 3. Adnan Menderes Univ, Fac Med, Dept Med Biol, TR-09010 Aydin, Turkey
- 4. Karadeniz Tech Univ, Fac Pharm, TR-61080 Trabzon, Turkey
- 5. Kumamoto Univ, Fac Life Sci, Med & Biol Chem Sci Farm Joint Res Lab, Chuo Ku, 5-1 Oe Honmachi, Kumamoto 8620973, Japan
- 6. Afyonkarahisar Hlth Sci Univ, Fac Pharm, Dept Biochem, Afyon, Turkey
Description
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.
Files
bib-2d5a1fe0-0fa4-4ee0-961c-01760fa96684.txt
Files
(415 Bytes)
| Name | Size | Download all |
|---|---|---|
|
md5:ccb1f3d956883015ea6febe2696dda94
|
415 Bytes | Preview Download |