Design, Synthesis, and Evaluation of Phe-Gly Mimetics:  Heterocyclic Building Blocks for Pseudopeptides

Abstract

Enantiopure heterocyclic Boc-protected Phe-Gly dipeptidomimetics containing 1,3,4-oxadiazole, 1,2,4-oxadiazole, and 1,2,4-triazole ring systems have been synthesized as building blocks in the synthesis of pseudopeptides. Three derivatives (1-3) have the carboxylic acid function directly bound to the heterocyclic ring, and three derivatives (4-6) have an extra methylene group between the heterocyclic ring and the acid function to allow for an increased conformational flexibility. The mimetics were used as Phe-Gly replacements in the biologically active peptides dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH(2)) and substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-MetNH(2), SP). The pseudopeptide synthesis was performed using solid-phase methodology on a MBHA-resin using Boc-chemistry. The biological evaluation was performed by testing the micro- and delta-opioid receptor affinities of the dermorphin pseudopeptides and the NK(1) receptor affinities of the SP pseudopeptides. The results showed that all mimetics except 3 were excellent replacements of Phe-Gly in dermorphin since they displayed affinities for the micro-receptor (IC(50) = 12-31 nM) in the same range as dermorphin itself (IC(50) = 6.2 nM). The agonist activity of three pseudopeptides at human micro-receptors was also evaluated. It was shown that the tested compounds retained their agonist activity. The SP pseudopeptides showed considerably lower affinities (IC(50) > 1 microM) for the NK(1) receptor than SP itself (IC(50) = 1.5 nM) indicating that the Phe-Gly replacements prevent the pseudopeptides from adopting bioactive conformations.

Synthetic Studies toward Aryl-(4-aryl-4H-[1,2,4]triazole-3-yl)-amine from 1,3-Diarylthiourea as Urea Mimetics

“…17 Replacement of the amide bond in Phe-Gly in substance P with [1,2,4]triazole peptide bond surrogate led to dramatic loss of affinity to the NK 1 receptor. 18 On the other hand, introduction of the same modification to dermorphin led to potent and selective pseudopeptides toward the μ receptor sub-type. 18 We anticipate that replacement of the amide/thioamide bond in the urea/thiourea with heterocyclic bioiosteric moieties such as the triazoles may increase the structural diversity and generate novel and interesting bioactive compounds of therapeutic potential.…”

(E)-Methyl N′-[1-(4-hydroxyphenyl)ethylidene]hydrazinecarboxylate

“…Meanwhile, it is an important intermediate of 1,3,4-oxadiazoles, which have been reported to be versatile compounds with interesting properties (Borg et al, 1999). As a further investigation of this type of derivatives, the crystal structure of the title compound, C 10 H 12 N 2 O 3 ( Fig.1), is described here.…”

“…For general background, see: Parashar et al (1988); Hadjoudis et al (1987); Borg et al (1999). For related structures, see: Shang et al (2007).…”

Crystal structure of methyl (E)-2-(4-(diethylamino)-2-hydroxybenzylidene)hydrazine-1-carboxylate, C13H19N3O3

“…Meanwhile, it is an important intermediate in the synthethic protocol of 1,3,4-oxadiazoles, which have interesting properties [6]. In our recent report, a benzaldehydehydrazone is involved in a key step of the synthesis of dimethyl-3,6-di(aryl)-1,4-dihydro-1,2,4,5-tetrazine-1,4-dicarboxylates which was proved to have antitumour activity [7].…”