Synthesis and biological investigation of protein phosphatase 2A-activating compounds with dimeric tail as non-small cell lung cancer cell death agents
BULLETIN OF THE KOREAN CHEMICAL SOCIETY(2023)
Abstract
FTY720 exerts an anticancer effect through the activation of protein phosphatase 2A (PP2A), which acts as a tumor suppressor, and inhibits SK1 activity. However, FTY720 taken into the body is phosphorylated by endogenous SK2. The structure of FTY720 is well-studied as a basis for developing SK inhibitors and PP2A activators. We synthesized analogs of PF-543 with a dimeric tail structure and reported the efficacy of SK1 inhibition. The compounds with this structure had improved anticancer activity and stability compared with PF-543. To confirm whether the dimeric tail structure could be applied as a PP2A-active material, we synthesized four types of compounds with a dimeric tail structure and confirmed the anticancer activity and PP2A activation in A549 non-small cell lung cancer cells. Compounds 2 and 4 were more cytotoxic to A549 cells than RB005, and induced similar levels of cytotoxic and PP2A activation as FTY720.
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Key words
FTY720,non-small cell lung cancer,protein phosphatase 2A,PF-543,sphingosine kinase
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