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Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells
Synthesis of PP2A-Activating PF-543 Derivatives and Investigation of Their Inhibitory Effects on Pancreatic Cancer Cells
- Source :
- Molecules, Vol 27, Iss 10, p 3346 (2022)
- Publication Year :
- 2022
- Publisher :
- MDPI AG, 2022.
-
Abstract
- 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.
Details
- Language :
- English
- ISSN :
- 14203049
- Volume :
- 27
- Issue :
- 10
- Database :
- Directory of Open Access Journals
- Journal :
- Molecules
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.65e0cbfc111e40968331cb014e976ce9
- Document Type :
- article
- Full Text :
- https://doi.org/10.3390/molecules27103346