Structure–activity relationship study to improve cytotoxicity and selectivity of lonafarnib against breast cancer cells

Abstract

AbstractLonafarnib is designed as a farnesyltransferase (FTase) inhibitor and displays inhibitory activities against a wide range of tumor cells. However, a major disadvantage is its unselective activity and high cytotoxicity against nonmalignant cells. Therefore, we structurally modified the terminal 4‐methylpiperidine‐1‐carboxamide residue of lonafarnib and evaluated the antiproliferative effects of the resulting derivatives in Michigan Cancer Foundation ‐ 7 (MCF‐7) breast cancer cells as well as simian virus 80 (SV‐80) fibroblasts. The highest cytotoxicity against both cell lines (IC50 about 2 µM) was shown by the piperidin‐4‐yl carbamate 15i and the S‐(piperidin‐4‐yl) carbamothioate 15j. Selectivity for tumor cells was realized in the case of the 1‐cyclohexyl‐1‐methylurea derivative 15b. It reduced the growth of MCF‐7 cells with an IC50 of 11.4 µM (lonafarnib: IC50 = 10.8 µM) without influence on the growth of SV‐80 cells (IC50 > 50 µM; lonafarnib: IC50 = 14.0 µM). Molecular modeling studies were performed to correlate the cytotoxicity with possible FTase interactions. The theoretical investigations, however, documented a comparable attachment of active, less active, and inactive compounds and did not allow an interpretation of the biological results based on these theoretical considerations.