Trifluoroacetic Acid Mediated Additive-free Late-Stage Native Pep-tide Cyclization to Form Disulfide Mimetics via Thioketalization with Ketones

Peptide cyclization is often used to introduce conformational rigidity and enhance the physiological stability of the peptide. This study presents a novel late-stage cyclization method for creating thioketal cyclic peptides from bis-cysteine peptides and drugs. Symmetrical cyclic ketones and acetone were found to react with bis-cysteine unprotected peptides efficiently to form thioketal linkages in trifluoroacetic acid (TFA) without any other additive. The attractive features of this method include high chemoselec-tivity, operational simplicity, robustness. In addition, TFA as the reaction solvent can dissolve any unprotected peptide. As a showcase, the dimethyl thioketal versions of lanreotide and octreotide were prepared and evaluated, both of which showed much improved reductive stability and comparable activity.