Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells
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...
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MDPI AG
2022-05-01
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| Online Access: | https://www.mdpi.com/1420-3049/27/10/3346 |
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| author | Su Bin Kim Yoon Sin Oh Kwang Joon Kim Sung Woo Cho Seung Ki Park Dong Jae Baek Eun-Young Park |
| author_facet | Su Bin Kim Yoon Sin Oh Kwang Joon Kim Sung Woo Cho Seung Ki Park Dong Jae Baek Eun-Young Park |
| author_sort | Su Bin Kim |
| collection | DOAJ |
| description | 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. |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T03:18:22Z |
| publishDate | 2022-05-01 |
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| spelling | doaj.art-65e0cbfc111e40968331cb014e976ce92023-11-23T12:24:57ZengMDPI AGMolecules1420-30492022-05-012710334610.3390/molecules27103346Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer CellsSu Bin Kim0Yoon Sin Oh1Kwang Joon Kim2Sung Woo Cho3Seung Ki Park4Dong Jae Baek5Eun-Young Park6College of Pharmacy, Mokpo National University, Jeonnam 58554, KoreaDepartment of Food and Nutrition, Eulji University, Seongnam 13135, KoreaCollege of Pharmacy, Mokpo National University, Jeonnam 58554, KoreaDepartment of Bio and Chemical Industry, College of Engineering, The University of Suwon, Hwaseong 18323, KoreaDepartment of Bio and Chemical Industry, College of Engineering, The University of Suwon, Hwaseong 18323, KoreaCollege of Pharmacy, Mokpo National University, Jeonnam 58554, KoreaCollege of Pharmacy, Mokpo National University, Jeonnam 58554, KoreaSphingosine 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.https://www.mdpi.com/1420-3049/27/10/3346sphingosine kinasePF-543anticancerinhibitorprotein phosphatase 2A |
| spellingShingle | Su Bin Kim Yoon Sin Oh Kwang Joon Kim Sung Woo Cho Seung Ki Park Dong Jae Baek Eun-Young Park Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells Molecules sphingosine kinase PF-543 anticancer inhibitor protein phosphatase 2A |
| title | Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells |
| title_full | Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells |
| title_fullStr | Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells |
| title_full_unstemmed | Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells |
| title_short | Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells |
| title_sort | synthesis of pp2a activating pf 543 derivatives and investigation of their inhibitory effects on pancreatic cancer cells |
| topic | sphingosine kinase PF-543 anticancer inhibitor protein phosphatase 2A |
| url | https://www.mdpi.com/1420-3049/27/10/3346 |
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