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Short Paper | Special issue | Vol 88, No. 1, 2014, pp.663-673
Published online, 21st June, 2013
DOI: 10.3987/COM-13-S(S)20
Synthesis of 4-Arylpiperidin-4-ol Derivatives of Loperamide as Agents with Potent Antiproliferative Effects against HCT-116 and HL-60 Cells

Noriyuki Hatae,* Tomoyuki Nagayama, Hiroyoshi Esaki, Eiko Kujime, Masabumi Minami, Minoru Ishikura, Tominari Choshi, Satoshi Hibino, Chiaki Okada, Eiko Toyota, Hideko Nagasawa, and Tatsunori Iwamura*

*Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan


The structure of 4-arylpiperidin-4-ol, a constituent of the antidiarrheal loperamide, is key to μ 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.