Fig. 2. Cross-link optimization and chemical stability of vinyl sulfide stapled peptides. (A) Screening for reaction conditions. ^aInitiator: (I) 0.5 eq. DMPA, 1 h; (II) no initiator, 1 h; (III) 0.5 eq. DMPA, 0.5 eq. MAP, 1 h; (IV) 0.5 eq. IHT-PI 659, 0.5 h. Abbreviations: MAP, 4-methoxyacetophenone; DMPA, 2,2-dimethoxy-2-phenylacetophenone; IHT-PI 659, 2-hydroxy-1-[4-(2-hydroxyethoxy)-phenyl]-2-methyl-1-propanone. ^bConversions [desired product/(desired product + starting material)] were determined by integration of reverse-phase HPLC. For peptides 2d–f, the Z-isomer is dominant. (B) CD spectra of vinyl sulfide stapled peptides in 10 mM phosphate buffer, pH 7.4, 20 °C; (A) is the E-isomer and (B) is the Z-isomer. (C) Chemical stability of peptide 2d in 3% TFA or 0.1 mM NaOH aqueous buffer. Percentage intact, mean ± s. d. and n = 3.