Cystinophanes, a Novel Family of Aromatic-Bridged Cystine Cyclic Peptides: Synthesis, Crystal Structure, Molecular Recognition, and Conformational Studies

Abstract

A novel family of aromatic-bridged cystine cyclic peptides (cystinophanes) has been synthesized by a single-step procedure involving condensation of 1,3 aromatic (Ph or Pyr unit) dicarbonyl dichloride with either the simple l-cystine dimethyl ester to provide cystinophanes of 26-, 39-, and 52-membered rings through 2+2, 3+3, and 4+4 cyclization, respectively, or with cystine bis-peptides (H2N-Xaa-Cyst-Xaa-NH2) leading to a variety of 1+1 cystine-based peptidocyclophanes. 1H NMR and CD studies have shown these cystinophanes to adopt a β-turn-like structure in solution. X-ray crystal structure of a representative member (3a) containing two aromatic rings has shown a collapsed ring conformation with a near parallel face-to-face orientation of aromatic ringsa feature also suggested by NMR studies. The propensity of cystinocyclophanes to adopt β-turn-type conformation is attributed to the presence of S−S linkage and the need to maintain a near orthogonal value of its torsion angle. The potential of cystinophan...