Lithium perhydroantamanide complex (2:1): exposure of the peptide backbone in the analog of antamanide with antitoxic impotency

The synthetic analog of antamanide in which all four phenylalanyl residues are hydrogenated to cyclohexylalanyl (Cha) residues, cyclic(Val-Pro-Pro-Ala-Cha-Cha-Pro-Pro-Cha-Cha), has a complete loss of antitoxic potency despite its ability to form ion complexes in the same manner as antamanide. The conformation of Li+.perhydroantamanide has been established in the present paper by x-ray diffraction analysis of a single crystal. The backbone encapsulates a Li+ ion in an almost identical manner as in Li+ antamanide. However, in Li+ antamanide the four phenyl groups are folded against the globular backbone, thus providing a hydrophobic surface for the complex, whereas in Li+ X perhydroantamanide the four cyclohexyl moieties are extended away from the folded backbone, resulting in the exposure of large portions of the polar backbone to the environment. As a consequence, four NH groups form hydrogen bonds with Br- ions, three C--O groups form hydrogen bonds with water molecules, and one C--O group makes a ligand to an additional external Li+ ion. The internal Li+ ion is pentacoordinated, whereas the external Li+ ion is tetracoordinated. The large change of the hydrophobicity around the midsection of the perhydroantamanide complex may be related to the biological inactivity. The content per asymmetric unit of the crystal is C64H102N10O10 X 2Li+ X 4H2O X 2CH3CN.2Br- in space group P2(1)2(1)2(1) with a = 21.740(7), b = 21.566(4), and c = 17.361(4) A. The agreement factor is 8.2% for 5135 data.