SYNTHESIS OF 4-ARYLPIPERIDIN-4-OL DERIVATIVES OF LOPERAMIDE AS AGENTS WITH POTENT ANTIPROLIFERATIVE EFFECTS AGAINST HCT-116 AND HL-60 CELLS

The structure of 4-arylpiperidin-4-ol, a constituent of the antidiarrheal loperamide, is key to v. opioid receptor activation. Some opioid derivatives were recently reported to induce tumor cell death, but the chemical structures responsible for their antitumor activity remain unclear. We synthesized loperamide analogs and tested their antiproliferative activity against HCT-116 colon tumor cells and HL-60 leukemia cells. The N-substituents on 4-arylpiperidin-4-ol units were found to play an important role in their antiproliferative activity, and the N-diphenylpropanol analogs exhibited the most potent antiproliferative activity. Furthermore, the N-diphenylpropanol analog activated caspase-3, as was found previously for opioids that exhibited antitumor effects.