Synthesis and Characterization of 4-Thiobutyl-triphenylphosphonium-pantetheine, a Pantetheine Derivative
Roald A. Lambrechts
Department of Cell Biology, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Balaji Srinivasan
Department of Cell Biology, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Edzard M. Geertsema
Department of Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Gerrit J. Poelarends
Department of Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Ody C. M. Sibon *
Department of Cell Biology, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
Marianne De Villiers
Department of Cell Biology, University Medical Centre Groningen, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands and Department of Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands
*Author to whom correspondence should be addressed.
Abstract
Pantetheine, a low molecular weight thiol, has been found to ameliorate symptoms in various disease models but specifically in Pantothenate Kinase-Associated Neurodegeneration (PKAN). Pantetheine is usually administered in its disulfide form (i.e. pantethine) since pantethine is commercially available and is reduced to pantetheine in biological systems. The applicability and efficacy of pantethine (therefore also pantetheine) as a clinical therapeutic however is hampered since both forms can be degraded by pantetheinases present in the body. Here, we report the synthesis of a masked form of pantetheine, namely 4-thiobutyltriphenylphosphonium-pantetheine (TBTP-pantetheine), following our hypothesis that this pantetheine-derivative might be more stable in the presence of pantetheinases than pantetheine itself. Higher stability would enhance transport into the cytoplasm where TBTP-pantetheine is metabolized into pantetheine which can subsequently execute its medicinal action. We find that TBTP-pantetheine is stable in aqueous solution, however it was found to be less stable in 10% fetal calf serum (which contains pantetheinases) compared to pantethine, the commercially availabile disulfide of pantetheine. We show that TBTP-pantetheine has improved lipophilicity, but equal passive membrane permeability/diffusion, as compared with pantethine.
Keywords: TBTP-pantetheine, pantetheine, pantetheinase, coenzyme A, PKAN, serum stability