Designing of bioactive peptides containing ‘thioamide’ functionality to modulate their pharmacological properties has been thwarted so far because of various synthetic challenges. In spite of several intriguing utilities in the context of various structural and biological aspects, an uncomplicated synthetic methodology for the site-specific installation of such ‘thioamide’ moiety in a peptide backbone has hitherto remained relatively less explored. A fast, efficient, and inexpensive synthesis and incorporation of a wide range of thionated amino acids bearing various types of side chains, into a growing peptide on a solid support is reported using standard Fmoc-based chemistry. The commonly employed methodologies
are comprehensively investigated and optimized with significant improvements regarding the quantity of reagents and reaction conditions. The individual cases where this optimized protocol required special modifications have also been studied. The utility of the protocol is further demonstrated in the synthesis of dithionated linear and monothionated cyclic peptides, which thus far has remained a daunting task. The synthesis of endothioamide peptides by simply elongating an N-term thioamide peptide on a solid support is often accompanied with complications such as thioamide epimerization and undesired side reactions.
Hence, to utilize thiopeptides as novel chemical probes in the context of biophysics and pharmacology, a synthetic protocol to access long endothioamide peptides, while suppressing epimerization and concomitant side reactions is also reported herein.