Abstract
PF-543, the most potent sphingosine kinase (SK) inhibitor, does not demonstrate effective anticancer activity in some cancer cells, unlike other known SK1 inhibitors. PF-543 has a non-lipid structure with a unique toluene backbone; however, the importance of this structure remains unclear. Therefore, the purpose of this study was to investigate changes in SK inhibitory and anticancer activities and to explore the role of the tolyl group structure of PF-543 through various modifications. We transformed the methyl group of PF-543 into hydrogen, fluorine, and hydroxy. PF-543 derivatives in which the methyl group was substituted by hydrogen and fluorine (compound 5) demonstrated SK1 inhibitory and anticancer activities similar to PF-543. Moreover, we performed molecular modeling studies of PF-543 and compound 5. To assess the metabolic stability of PF-543 and compound 5, we determined their degree of degradation using the liver microsomes of four different animal species (human, dog, rat, and mouse). However, both PF-543 and compound 5 showed poor microsomal stability. Therefore, for the medical applications of PF-543, the structural modifications of its other parts may be necessary. Our results provide important information for the design of additional PF-543 analogs.
Highlights
Sphingolipids are structurally modified by various enzymes and regulate various biological activities through the regulation of cancer cell signaling
To synthesize PF-543 derivatives that had been modified from toluene to benzene, a reaction was carried out using commercially available m-toly acetate
Previous results reported by Pfizer revealed slightly elevated SK1 inhibitory effects and selectivity of PF-543 derivative with a hydroxypyrrolidine head group (22c; Figure 1) [15]
Summary
Sphingolipids are structurally modified by various enzymes and regulate various biological activities through the regulation of cancer cell signaling. The majority of enzymes involved in sphingolipid metabolism have been identified through comprehensive research, and the regulation of these enzymes has the potential to be developed. Sphingosine kinase (SK) has two isoforms, i.e., SK1 and SK2, and these play various roles at different positions; the development of selective inhibitors is required. SK transforms sphingosine into S1P, which induces cell growth [1]. S1P and SK activities increase in various forms of cancers, which can be suppressed through SK inhibition. ABC294640 (an SK2 inhibitor developed by Apogee Biotechnology) has been shown to inhibit cell growth in various forms of cancer (Figure 1) [3]
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