New phosphate derivatives of betulin as anticancer agents: Synthesis, crystal structure, and molecular docking study

• Published in: Bioorganic chemistry 2019-06, Vol.87, p.613-628
• Main Authors: Chrobak, Elwira, Kadela-Tomanek, Monika, Bębenek, Ewa, Marciniec, Krzysztof, Wietrzyk, Joanna, Trynda, Justyna, Pawełczak, Bartosz, Kusz, Joachim, Kasperczyk, Janusz, Chodurek, Ewa, Paduszyński, Piotr, Boryczka, Stanisław
• Format: Article
• Language: English
• Subjects: Anticancer; Betulin; Crystal structure; Molecular docking; Phosphate
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.03.060

[Display omitted] •Synthesized a series of novel 3-phosphate derivatives of betulin.•Evaluated antiproliferative invitro activity against five human cell lines.•Performed molecular docking to six potential anticancer targets. Betulin derivatives exhibit an antiproliferative activity and have been tested for many cancer cell lines. This paper describes a new series of 3-phosphate derivatives of betulin bearing different substituents at C28 position. The synthesized compounds were tested in vitro for their antiproliferative effect against human leukemia (MV-4-11 and CCRF/CEM), lung carcinoma (A549), prostate cancer (DU 145), melanoma (Hs 294T) cell lines, and murine leukemia P388. To explore the possible mechanism of anticancer activity for the most in vitro active compounds (4, 5, 7 and 8) and betulin, molecular docking was performed to the binding sites of potential anticancer targets, described for the various triterpene derivatives, including topoisomerase I and II, epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGFR), transcription factor NF-κB, anti-apoptotic protein Bcl-2 and peroxisome proliferator-activated receptor (PPARγ). According to the results of the docking, the best fit to the binding pocket of PPARγ was shown by compound 4.