Molecular Structure, In Vitro Anticancer Study and Molecular Docking of New Phosphate Derivatives of Betulin

Abstract

A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds <b>7a</b> and <b>7b</b> showed the highest activity against C-32 and SNB-19 cell lines. The IC₅₀ values for <b>7a</b> were 2.15 and 0.91 μM, and, for <b>7b,</b> they were 0.76 and 0.8 μM for the C-32 and SNB-19 lines, respectively. The most potent compounds, <b>7a</b> and <b>7b</b>, were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and K_DEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands <b>7a</b>,<b>b</b> form stable complexes and the plateau phase started after 7 ns.