Selenocysteine (Sec) is a naturally occurring amino acid and is typically utilized in the active sites of proteins that have anti-oxidative functionality, such as glutathione peroxidase. If subjected to a highly oxidative environment, such as reoxidation after ischemia, these enzymes can become overwhelmed and irreversibly deactivated by the β-elimination of selenium from Sec. Enzymes and peptides containing an α-methyl variant of Sec (α-MeSec) are an attractive solution to this problem, as they should display similar kinetics while also having increased stability, since β-elimination is no longer possible. A synthetic strategy was developed for the synthesis of α-MeSec by first alkylating dimethyl methylmalonate with a seleno-alkylating agent forming a tert-butyl protected selenomalonate. By employing pig liver esterase on this substrate, a highly enantioenriched (88% ee, 98% yield) tert-butyl protected seleno-half ester was synthesized, and by comparing to previously synthesized cysteine analogues, polarimetry suggests the (R)-enantiomer was made. Through additional synthetic steps, the seleno-half ester was converted to a protected version of α-MeSec in moderate yields (54%) while preserving the stereocenter. The synthesized α-MeSec was incorporated into a peptide and compared to an analogous peptide containing natural Sec. By utilizing a coupled glutathione reductase assay, the kinetic behavior of the peptides were studied. The peptide containing α-MeSec showed drastically increased longevity and a slight kinetic advantage when compared to the native form.

Synthesis of (R)-α-methylselenocysteine and its application as a glutathione peroxidase mimic

2019 Fall National Meeting

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