Synthesis of 4-Arylpiperidin-4-ol Derivatives of Loperamide as Agents with Potent Antiproliferative Effects against HCT-116 and HL-60 Cells

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

doi:10.3987/com-13-s(s)20

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2014

DOI: 10.3987/com-13-s(s)20

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Synthesis of 4-Arylpiperidin-4-ol Derivatives of Loperamide as Agents with Potent Antiproliferative Effects against HCT-116 and HL-60 Cells

Noriyuki Hatae¹,

Tatsunori Iwamura²,

Tomoyuki Nagayama³

et al.

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Cited by 3 publications

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Identification of novel small-molecule inhibitors targeting menin–MLL interaction, repurposing the antidiarrheal loperamide

et al. 2016

Org. Biomol. Chem.

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Leukemia with a mixed lineage leukemia (MLL) rearrangement, which harbors a variety of MLL fusion proteins, has a poor prognosis despite the latest improved treatment options. Menin has been reported to be a required cofactor for the leukemogenic activity of MLL fusion proteins. Thus, the disruption of the protein-protein interactions between menin and MLL represents a very promising strategy for curing MLL leukemia. Making use of menin-MLL inhibitors with a shape-based scaffold hopping approach, we have discovered that the antidiarrheal loperamide displays previously unreported mild inhibition for the menin-MLL interaction (IC50 = 69 ± 3 μM). In an effort to repurpose this drug, a series of chemical modification analyses was performed, and three of the loperamide-based analogues, DC_YM21, DC_YM25 and DC_YM26 displayed better activities with IC50 values of 0.83 ± 0.13 μM, 0.69 ± 0.07 μM and 0.66 ± 0.05 μM, respectively. Further treatment with DC_YM21 demonstrated potent and selective blockage of proliferation and induction of both cell cycle arrest and differentiation of leukemia cells harboring MLL translocations, which confirmed the specific mechanism of action. In conclusion, molecules of a novel scaffold targeting menin-MLL interactions were reported and they may serve as new potential therapeutic agents for MLL leukemia.

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Identification of novel small-molecule inhibitors targeting menin–MLL interaction, repurposing the antidiarrheal loperamide

et al. 2016

Org. Biomol. Chem.

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Antiproliferative Activity of Hybrid Compounds between 6-Methoxy-3-(4-methoxyphenyl)-1H-indole and 4-Phenylpiperidine against HCT-116 and HL-60 Cells

Hatae¹,

Nishiyama²,

Shoko³

et al. 2016

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Synthesis of N-ω-Phenylalkyl-4-(p-chlorophenyl)-piperidin-4-ol Analogues with Potent Antiproliferative Activity Against HCT-116 Cells

Hatae¹,

Yoshimura²,

Kujime³

et al. 2018

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Synthesis of 4-Arylpiperidin-4-ol Derivatives of Loperamide as Agents with Potent Antiproliferative Effects against HCT-116 and HL-60 Cells

Cited by 3 publications

References 18 publications

Identification of novel small-molecule inhibitors targeting menin–MLL interaction, repurposing the antidiarrheal loperamide

Identification of novel small-molecule inhibitors targeting menin–MLL interaction, repurposing the antidiarrheal loperamide

Antiproliferative Activity of Hybrid Compounds between 6-Methoxy-3-(4-methoxyphenyl)-1H-indole and 4-Phenylpiperidine against HCT-116 and HL-60 Cells

Synthesis of N-ω-Phenylalkyl-4-(p-chlorophenyl)-piperidin-4-ol Analogues with Potent Antiproliferative Activity Against HCT-116 Cells

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