Efficient synthesis of terminal-diazirine-based histone peptide probes

Abstract

Histone post-translational modifications (hPTMs) regulate series fundamental cellular processes through the specific recognition of “reader” or “effector” proteins. The chemical probes containing photo-cross-linking groups, especially diazirine group has been developed to capture proteins recognized by hPTMs. However, the construction of diazirine-based photo-reactive amino acids requires multiple synthetic steps. Herein, we report the efficient synthesis of a new diazirine-based histone peptide probes through the construction of terminal diazirine via phenyliodonium diacetate (PIDA) mediated transformation. The key building block tert-butyl 3-(3H-diazirin-3-yl)propanoate can be obtained in one step with 90% yield. The synthetic H3K4Me3 photo-cross-linking probe was demonstrated to label H3K4Me3 specific reader in vitro and in cell lysates.