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Article

Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells

1
College of Pharmacy, Mokpo National University, Jeonnam 58554, Korea
2
Department of Food and Nutrition, Eulji University, Seongnam 13135, Korea
3
Department of Bio and Chemical Industry, College of Engineering, The University of Suwon, Hwaseong 18323, Korea
*
Authors to whom correspondence should be addressed.
Academic Editors: Wei-dong Xie and Xiaowei Zeng
Molecules 2022, 27(10), 3346; https://doi.org/10.3390/molecules27103346
Received: 10 May 2022 / Revised: 20 May 2022 / Accepted: 21 May 2022 / Published: 23 May 2022
(This article belongs to the Special Issue Medicinal Chemistry in Asia)
Sphingosine kinase (SK) is involved in the growth of cells, including cancer cells. However, which of its two isotypes—SK1 and SK2—is more favorable for cancer growth remains unclear. Although PF-543 strongly and selectively inhibits SK1, its anticancer effect is not high, and the underlying reason remains difficult to explain. We previously determined that the tail group of PF-543 is responsible for its low metabolic stability (MS). In this study, compounds containing aromatic or aliphatic tails in the triazole group were synthesized, and changes in the SK-inhibitory effect and anticancer activity of PF-543 were assessed using pancreatic cancer cells. The compounds with aliphatic tails showed high inhibitory effects on pancreatic cancer cells but slightly lower selectivity for SK1. A compound with an introduced aliphatic tail activated protein phosphatase 2A (PP2A), showing an effect similar to that of FTY720. Molecular docking analysis revealed that the PP2A-binding form of this newly synthesized compound was different from that noted in the case of FTY720. This compound also improved the MS of PF-543. These results indicate that the tail structure of PF-543 influences MS. View Full-Text
Keywords: sphingosine kinase; PF-543; anticancer; inhibitor; protein phosphatase 2A sphingosine kinase; PF-543; anticancer; inhibitor; protein phosphatase 2A
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MDPI and ACS Style

Kim, S.B.; Oh, Y.S.; Kim, K.J.; Cho, S.W.; Park, S.K.; Baek, D.J.; Park, E.-Y. Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells. Molecules 2022, 27, 3346. https://doi.org/10.3390/molecules27103346

AMA Style

Kim SB, Oh YS, Kim KJ, Cho SW, Park SK, Baek DJ, Park E-Y. Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells. Molecules. 2022; 27(10):3346. https://doi.org/10.3390/molecules27103346

Chicago/Turabian Style

Kim, Su Bin, Yoon Sin Oh, Kwang Joon Kim, Sung Woo Cho, Seung Ki Park, Dong Jae Baek, and Eun-Young Park. 2022. "Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells" Molecules 27, no. 10: 3346. https://doi.org/10.3390/molecules27103346

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