Abstract
Since loss of function mutations of PINK1 lead to early onset Parkinson’s disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability, and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world.[1]
As part of our efforts into discovering novel PD therapeutics, we focused on PINK1 (PTEN-induced kinase 1), a protein kinase mutated in some patients with early onset PD.[3]
Following inner mitochondrial membrane depolarization, it becomes stabilized on the outer mitochondrial membrane (OMM) where it phosphorylates the E3 ubiquitin ligase Parkin at serine 65 (Ser65) on its
Summary
(Me), isopropyl (iPr), tert-butyl (tBu), and benzyl (Bn)] to probe the influence of these moieties on the ProTides’ biological activity. We incubated KR ProTide 14 in human (Figure 4C) or mouse serum (Supporting Information Figure S2) at 37 °C and followed the sample by 31P NMR. Following ∼11 h incubation in human and mouse serum there were no changes in the 31P NMR signals that correspond to the KR ProTide indicating its stability in these environments. MeOH (2 mL) was added to quench the reaction before solvent was removed under reduced pressure to leave the crude product as a pale yellow oil. This was purified via flash column chromatography and preparative.
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