βγ-fused turn structures in sugar amino acid (SAA) containing cyclic tetrapeptides with α3δ architecture

Abstract

The current manuscript describes conformational analysis of 15-membered cyclic tetrapeptides (CTPs), with α3δ architecture, containing sugar amino acids (SAA) having variation in the stereocenter at C5 carbon. Conformational analyses of both the series, in protected and deprotected forms, were carried out in DMSO-d6 using various NMR techniques, supported by restrained MD calculations. It was intriguing to notice that the α3δ macrocycles got stabilized by both 10-membered β-turn as well as a seven-membered γ-turn, fused within the same macrocycle. The presence of fused sub-structures within a 15-membered macrocycle is rare to see. Also, the stereocenter variation at C5 did not affect the fused turn structures and exhibited similar conformations in both the series. The design becomes highly advantageous as fused reverse turn structures are occurring in the cyclic structure with minimalistic size macrocycle and this can be applied to develop suitable pharmacophores in the drug development process.