Design, synthesis, and evaluation of a water-soluble antofine analogue with high antiproliferative and antitumor activity
- Bioorg Med Chem. 2013 Feb 15;21(4):1006-17. doi: 10.1016/j.bmc.2012.11.039.
- 1. College of Pharmacy, Seoul National University, San 56-1, Shilim, Kwanak, Seoul 151-742, Republic of Korea.
New water soluble antofine C-13a analogues were designed, synthesized, and evaluated for antiproliferative activity against Cancer cells. Particularly, (-)-(R)-13a-hydroxymethylantofine ((-)-(R)-4b) demonstrated notable growth inhibition against a panel of human Cancer cell lines. This growth inhibition was associated with the arrest of the cell cycle in the G0/G1 phases and suppression of mTOR signaling in human lung A549 Cancer cells. Compound (-)-(R)-4b also overcame paclitaxel-resistance in human lung Cancer cells (A549-Pa) by suppressing P-glycoprotein expression. Furthermore, compound (-)-(R)-4b significantly inhibited the tumor growth of A549 and A549-Pa xenografts in a nude mouse model, which suggests it is a promising novel antitumor agent with sufficient aqueous solubility.