Conformational mimicry. 1. 1,5-Disubstituted tetrazole ring as a surrogate for the cis amide bond

Abstract

Assessment of the conformational implications of chemical modification is an important aspect of analogue design. A new procedure, the assessment of conformational mimicry, which determines the percentage of sterically accessible conformations for the parent compound also available to the analogue, is used to show that 88% of the conformers allowed for the cis amide bond are also available to peptides in which the amide bond is replaced by a 1,5-disubstituted tetrazole ring that locks the amide bond in the cis conformer. This analysis was made possible by the crystal structure of a cyclic dipeptide, cyclo[l-Phe-i/'(CN4)-L-Ala], determined in this paper. The crystals of the diketopiperazine analogue are monoclinic, space group P2\/c, with cell parameters a = 11.677 (1), b = 7.742 (1), c = 13.086 (1) A; /? = 93.39 (1)°; Z = 4; and = 1.368 g cm-3. The tetrazole ring system is planar with all five torsional angles equal to 0°. The diketopiperazine ring system is nearly planar, and the phenylalanine ring adopts the flagpole orientation over the cyclic dipeptide. A procedure for the preparation of this class of peptide analogues by synthetic routes avoiding racemization of the amino acids of the starting dipeptide is demonstrated. The tetrazole ring provides, therefore, a synthetic probe for the role of cis-trans isomerism of A'-alkylamide bonds, such as that of proline, in molecular recognition.Replacement of the amide bond by surrogates to enhance metabolic stability and/or probe receptor specificity has become an increasingly important topic of research1 as the central biological role of peptides as chemical effectors becomes more understood. Proline occupies a special role among those amino acids

Crystal structure of 1,6-bis(1-phenyl-1H-tetrazol-5-ylthio)hexane, C6H12(SCN4C6H5)2

“…5-Substituted 1H-tetrazoles and 1,5-disubstituted tetrazoles are often used as metabolismresistant isosteric replacements for carboxylic acids and as cis amide bond surrogates, respectively, in SAR-driven analogue synthesis in medicinal chemistry [1][2][3]. Besides, tetrazoles also receive application in agriculture, as plant growth regulators, herbicides and fungicides [4].…”

Tetrazole analogues of cyclolinopeptide A: Synthesis, conformation, and biology

“…This unusual low reactivity of proline residue toward acylation with activated carboxylic group of tetrazole tripeptide 10 might be due to inefficient release of its amino group from TFA salt with equimolar amount of tertiary amine. The known proclivity of the C-terminal ␣-carbon of tetrazole dipeptides to epimerize [23][24][25] on prolonged base exposure prompted us to omit the neutralisation step in solid phase synthesis protocol.…”

Synthesis of Novel bis-1,5-Disubstituted-1H-Tetrazoles by an Efficient Catalyst-Free Ugi-Azide Repetitive Process

“…1,5-Disubstituted-1H-tetrazoles (1,5-DS-1H-T) are a special kind of non-naturally occurring heterocycles having a wide range of applications, mainly in medicinal chemistry, since they have proven to be suitable bioisosteres of the cis-amide bonds of peptides, because of the capability to adopt their conformations [1]. For example, the 1,5-DS-1H-T 1 showed antifungal activity against Candida albicans, Cryptococcus neoformans and Aspergillus niger comparable to the most potent commercially available antimycotics, such as fluconazole and itraconazole [2].…”