CYSTINOPHANES, A NOVEL FAMILY OF AROMATIC-BRIDGED CYSTINE CYCLIC-PEPTIDES - SYNTHESIS, CRYSTAL-STRUCTURE, MOLECULAR RECOGNITION, AND CONFORMATIONAL STUDIES

A novel family of aromatic-bridged cystine cyclic peptides (cystinopha nes) has been synthesized by a single-step procedure involving condens ation of 1,3 aromatic (Ph or Pyr unit) dicarbonyl dichloride with eith er 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, re spectively, or with cystine bis-peptides (H2N-Xaa-Cyst-Xaa-NH2) leadin g to a variety of 1+1 cystine-based peptidocyclophanes. H-1 NMR and CD studies have shown these cystinophanes to adopt a beta-turn-like stru cture in solution. X-ray crystal structure of a representative member (3a) containing two aromatic rings has shown a collapsed ring conforma tion with a near parallel face-to-face orientation of aromatic rings-- a feature also suggested by NMR studies. The propensity of cystinocycl ophanes to adopt beta-turn-type conformation is attributed to the pres ence of S-S linkage and the need to maintain st near orthogonal value of its torsion angle. The potential of cystinophanes to serve as artif icial receptors in molecular recognition and host-guest complexation s tudies has been demonstrated with 26-membered, pyridine-bridged macroc ycle 3b, which binds (H-1 NMR) to a number of 1,omega-alkane dicarboxy lic acids [(CH2)(n)(COOH)(2), n = 1, ..., 4] and shows maximum affinit y (K-assoc= 3.69 x 10(2) M-1) and selectivity for glutaric acid (n = 3 ) dicarboxylate. Crystal parameters for 3a are as follows: C32H36N4O12 S4 . H2O . 2C(4)H(8)O(2), space group P2(1)2(1)2(1) With a = 11.748(1) Angstrom, b = 17.317(1) Angstrom, and c = 24.306(2) Angstrom.