Synthesis and Conformational Studies of Peptidomimetics Containing Furanoid Sugar Amino Acids and a Sugar Diacid

• Published in: Journal of organic chemistry 2000-10, Vol.65 (20), p.6441-6457
• Main Authors: Chakraborty, T. K, Ghosh, S, Jayaprakash, S, Sharma, J. A. R. P, Ravikanth, V, Diwan, P. V, Nagaraj, R, Kunwar, A. C
• Format: Article
• Language: English
• Subjects: Amino Acids - chemical synthesis; Amino Acids - chemistry; Amino Acids - pharmacology; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - pharmacology; Animals; Circular Dichroism; Dipeptides - chemistry; Enkephalin, Leucine - chemical synthesis; Enkephalin, Leucine - chemistry; Enkephalin, Leucine - pharmacology; Furans - chemical synthesis; Furans - chemistry; Furans - pharmacology; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Molecular Conformation; Molecular Mimicry; Monosaccharides - chemical synthesis; Monosaccharides - chemistry; Monosaccharides - pharmacology; Pain Measurement
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo000408e

Furanoid sugar amino acids (1) were synthesized and used as dipeptide isosteres to induce interesting turn structures in small linear peptides. They belong to a new variety of designed hybrid structures that carry both amino and carboxyl groups on rigid furanose sugar rings. Four such molecules, 6-amino-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 synthesized. The synthesis followed a novel reaction path in which an intramolecular 5-exo SN2 opening of the hexose-derived terminal aziridine ring in 2 by the γ-benzyloxy oxygen with concomitant debenzylation occurred during pyridinium dichromate oxidation of the primary δ-hydroxyl group to carboxyl function, leading to the formation of furanoid sugar amino acid frameworks in a single step. Incorporation of these furanoid sugar amino acids into Leu-enkephalin replacing its Gly-Gly portion gave analogues 8−11. Detailed structural analysis of these molecules by circular dichroism (CD) and various NMR techniques in combination with constrained molecular dynamics (MD) simulations revealed that two of these analogues, 8a and 10a, have folded conformations composed of an unusual nine-membered pseudo β-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 proximity, a prerequisite for biological activities of opioid peptides. The analgesic activities of 8a,b determined by mouse hot-plate and tail-clip methods were similar to that of Leu-enkephalin methyl ester. The syn disposition of the β-hydroxycarboxyl motif on the sugar rings appears to be the driving force to nucleate the observed turn structures in some of these molecules (8 and 10). Repetition of the motif on both sides of a furanose ring resulted in a novel molecular design of sugar diacid, 2,5-anhydro-d-idaric acid (7, Idac). Bidirectional elongation of the diacid moieties of 7 with identical peptide strands led to the formation of a C 2-symmetric reverse-turn mimetic 12 which displayed a very ordered structure consisting of identical intramolecular H-bonds at two ends between LeuNH → sugar-OH, the same as in 8 and 10.