Design and synthesis of novel pipernonaline derivatives as anti-austerity agents against human pancreatic cancer PANC-1 cells

Takuya Okada; Yuri Chino; Keita Yokoyama; Yuki Fujihashi; Nguyễn Duy Phan; Juthamart Maneenet; Lanke Prudhvi; Suresh Awale; Naoki Toyooka

doi:10.1016/j.bmc.2022.116963

Design and synthesis of novel pipernonaline derivatives as anti-austerity agents against human pancreatic cancer PANC-1 cells

Bioorg Med Chem. 2022 Oct 1:71:116963. doi: 10.1016/j.bmc.2022.116963. Epub 2022 Aug 10.

Authors

Takuya Okada¹, Yuri Chino², Keita Yokoyama³, Yuki Fujihashi⁴, Nguyễn Duy Phan⁴, Juthamart Maneenet⁴, Lanke Prudhvi³, Suresh Awale⁵, Naoki Toyooka⁶

Affiliations

¹ Graduate School of Pharma-Medical Sciences, University of Toyama, Toyama 930-8555, Japan; Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan. Electronic address: tokada@eng.u-toyama.ac.jp.
² Graduate School of Pharma-Medical Sciences, University of Toyama, Toyama 930-8555, Japan.
³ Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
⁴ Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
⁵ Natural Drug Discovery Laboratory, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: suresh@inm.u-toyama.ac.jp.
⁶ Graduate School of Pharma-Medical Sciences, University of Toyama, Toyama 930-8555, Japan; Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.

PMID: 35969895
DOI: 10.1016/j.bmc.2022.116963

Abstract

Pipernonaline (1), one of the components of the spice pepper, preferentially reduced the survival of human pancreatic cancer PANC-1 cells under nutrient-deprived conditions witha PC₅₀ value of 7.2 μM, suggesting that1couldpotentially lead to the development ofnew anticanceragents basedon theanti-austerity strategy. We have synthesized a total of 31 pipernonaline derivatives, revealing clear structure-activity relationships. Compound 9, which showed the strongest preferential cytotoxicity among synthesized derivatives, inhibited Akt activation and cancer cell migration, making it an extremely promising candidate compound for new pancreatic cancer agents based on the anti-austerity strategy.

Keywords: Anti-austerity strategy; Pancreatic cancer; Pipernonaline; Structure-activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkaloids* / therapeutic use
Antineoplastic Agents*
Antineoplastic Agents, Phytogenic* / pharmacology
Cell Line, Tumor
Drug Screening Assays, Antitumor
Humans
Pancreatic Neoplasms* / drug therapy
Piperidines

Substances

Alkaloids
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Piperidines
pipernonaline