1. Enantioselective synthesis of (R)-2-cubylglycine including unprecedented rhodium mediated C-H insertion of cubane
G Paul Savage, Sevan D Houston, Benjamin A Chalmers, Craig M Williams Org Biomol Chem . 2019 Jan 31;17(5):1067-1070. doi: 10.1039/c8ob02959h.
The first enantioselective synthesis of (R)-2-cubylglycine, an analogue of (R)-2-phenylglycine in which the phenyl ring has been replaced by cubane, is disclosed. The key step was a telescoped Strecker reaction using (S)-2-amino-2-phenylethanol as a chiral auxiliary. Exploration of an alternative synthetic approach resulted in unprecedented cubane C-H insertion.
2. Characterization of the phenylglycine aminotransferase PglE from Streptomyces pristinaespiralis
Andreas Kulik, Yvonne Mast, Natalie Osipenkov J Biotechnol . 2018 Jul 20;278:34-38. doi: 10.1016/j.jbiotec.2018.05.007.
l-phenylglycine is a rare non-proteinogenic amino acid, which only occurs in a few natural compounds, such as the streptogramin antibiotics pristinamycin I and virginiamycin S or the bicyclic peptide antibiotic dityromycin. Here we report on the biochemical characterization of the aminotransferase PglE that catalyzes the transamination from phenylglyoxylate to l-phenylglycine, which represents the final reaction step during phenylglycine biosynthesis. Enzyme assays with the purified PglE enzyme revealed that l-phenylalanine is used as an amino group donor for the transamination reaction, leading to the formation of phenylpyruvate, which may re-enter phenylglycine biosynthesis as a precursor. Based on these results, we postulate a novel l-phenylglycine biosynthetic pathway.
3. Evidence of D-phenylglycine as delivering tool for improving L-dopa absorption
Tung-Hu Tsai, Ming-Cheng Tsai, Yang-Bin Fan, Chun-Li Wang, Hui-Po Wang, Hsiao-Hwa Lu J Biomed Sci . 2010 Sep 6;17(1):71. doi: 10.1186/1423-0127-17-71.
Background:L-dopa has been used for Parkinson's disease management for a long time. However, its wide variety in the rate and the extent of absorption remained challenge in designing suitable therapeutic regime. We report here a design of using D-phenylglycine to guard L-dopa for better absorption in the intestine via intestinal peptide transporter I (PepT1).Methods:D-phenylglycine was chemically attached on L-dopa to form D-phenylglycine-L-dopa as a dipeptide prodrug of L-dopa. The cross-membrane transport of this dipeptide and L-dopa via PepT1 was compared in brush-boarder membrane vesicle (BBMV) prepared from rat intestine. The intestinal absorption was compared by in situ jejunal perfusion in rats. The pharmacokinetics after i.v. and p.o. administration of both compounds were also compared in Wistar rats. The striatal dopamine released after i.v. administration of D-phenylglycine-L-dopa was collected by brain microdialysis and monitored by HPLC. Anti-Parkinsonism effect was determined by counting the rotation of 6-OHDA-treated unilateral striatal lesioned rats elicited rotation with (+)-methamphetamine (MA).Results:The BBMV uptake of D-phenylglycine-L-dopa was inhibited by Gly-Pro, Gly-Phe and cephradine, the typical PepT1 substrates, but not by amino acids Phe or L-dopa. The cross-membrane permeability (Pm*) determined in rat jejunal perfusion of D-phenylglycine-L-dopa was higher than that of L-dopa (2.58 ± 0.14 vs. 0.94 ± 0.10). The oral bioavailability of D-phenylglycine-L-dopa was 31.7 times higher than that of L-dopa in rats. A sustained releasing profile of striatal dopamine was demonstrated after i. v. injection of D-phenylglycine-L-dopa (50 mg/kg), indicated that D-phenylglycine-L-dopa might be a prodrug of dopamine. D-phenylglycine-L-dopa was more efficient than L-dopa in lowering the rotation of unilateral striatal lesioned rats (19.1 ± 1.7% vs. 9.9 ± 1.4%).Conclusion:The BBMV uptake studies indicated that D-phenylglycine facilitated the transport of L-dopa through the intestinal PepT1 transporter. The higher jejunal permeability and the improved systemic bioavailability of D-phenylglycine-L-dopa in comparison to that of l-dopa suggested that D-phenylglycine is an effective delivery tool for improving the oral absorption of drugs like L-dopa with unsatisfactory pharmacokinetics. The gradual release of dopamine in brain striatum rendered this dipeptide as a potential dopamine sustained-releasing prodrug.
