Synthesis and conformational studies by peptidomimetics containing furanoid sugar amino acids an a sugar diacid

Furanoid sugar amino acids (1) were synthesized and used as dipeptide isost eres to induce interesting turn structures in small linear peptides. They b elong to a new variety of designed hybrid structures that carry both amino and carboxyl groups on rigid furanose sugar rings. Four such molecules, 6-a mino-2,5-anhydro-6-deoxy-D-gluconic acid (3, Gaa) and its mannonic (4, Maa) , idonic (5, Iaa),and a 3,4-dideoxyidonic (6, ddIaa) congeners were synthes ized. The synthesis followed a novel reaction path in which an intramolecul ar 5-exo S(N)2 opening of the hexose-derived terminal aziridine ring in 2 b y the gamma-benzyloxy oxygen with concomitant debenzylation occurred during pyridinium dichromate oxidation of the primary delta-hydroxyl group to car boxyl function; leading to the formation of furanoid sugar amino acid frame works in a single step. Incorporation of these furanoid sugar amino acids,i nto Leu-enkephalin replacing its Gly-Gly portion gave analogues 8-11. Detai led structural analysis of these molecules by circular dichroism (CD) and v arious NMR techniques in combination with constrained molecular dynamics (M D) simulations revealed that two of these analogues, 8a and 10a, have folde d conformations composed of-an unusual nine-membered pseudo beta-turn-like structure with a strong intramolecular H-bond between LeuNH --> sugarC3-OH. This, in turn, brings the two aromatic rings of Tyr and Phe in close proxi mity, a prerequisite for biological activities of opioid peptides. The anal gesic-activities of 8a,b determined by mouse hot-plate and tail-clip method s were similar to that of Leu-enkephalin methyl ester. The syn disposition of the beta-hydroxycarboxyl motif on the sugar rings appears to be the driv ing force; to nucleate the observed turn structures in some of these molecu les (8 and 10). Repetition of the motif on both sides of a furanose ring re sulted in a-novel molecular design of sugar diacid, 2,5-anhydro-D-idaric ac id (7, Idac). Bidirectional elongation of the diacid moieties of 7 with ide ntical peptide strands led to the formation of a C-2-symmetric reverse-turn mimetic 12 which displayed a very ordered structure consisting of identica l intramolecular H-bonds at two ends between LeuNH. --> sugar-OH, the same as in 8 and 10.