Emilia Naydenova

Asymmetric synthesis of β2-tryptophan analogues via Friedel-Crafts alkylation of indoles with a chiral nitroacrylate.

The asymmetric Friedel-Crafts alkylation of various indoles with a chiral nitroacrylate provides optically active β-tryptophan analogues after reduction of the nitro group and removal of the chiral auxiliary. This reaction generally occurs in good yield and high diastereoselectivity (up to 90:10).

Synthesis and changes in affinity for NOP and opioid receptors of novel hexapeptides containing β2-tryptophan analogues

We report the synthesis and the biological activity of new analogues of Ac-RFMWMK-NH2 and Ac-RYYRWK-NH2, modified in position 4 and 5, respectively, with incorporation of newly synthesized β(2)-tryptophan analogues. Trp was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or by (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The biological activity (pEC50 and Emax) of these compounds was tested on electrically stimulated preparations of rat vas deferens. The 5-methoxy β-tryptophan group reverses the affinity of the compounds.

Synthesis and analgesic effects of novel β2-tryptophan hexapeptide analogs

Aiming to develop more potent analgesic substances a new series of hexapeptides containing β2-tryptophan analogues was synthesized. The Trp in position 4 and 5, respectively in Ac-Arg-Phe-Met-Trp-Met-Lys-NH2 (opioid receptor antagonist) and Ac-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 (highly potent and selective NOP-receptor agonist) was substituted by the (S)-2-(1-methyl-1H-indol-3-yl)propionic residue or the (S)-2-(5-methoxy-1H-indol-3-yl)propionic residue. The analgesic effect of the four newly synthesized compounds has been evaluated in male Wistar rats by PP- and HP tests and compared to the native templates. Further estimation of the mechanisms of action of each compound was achieved using specific antagonists—naloxone for opioid and JTC801 for the NOP receptor. Replacement of Trp with β2-tryptophan analogues in 4th position (Ac-Arg-Phe-Met-Trp-Met-Lys-NH2) led to increased and longer lasting analgesic effect. The results obtained permit us to assume that both opioid and NOP receptors take part in the newly synthesized compounds analgesic effects.

Selective homodimerization of unprotected peptides using hybrid hydroxydimethylsilane derivatives

We developed a simple and straightforward way to dimerize unprotected peptide sequences that relies on a chemoselective condensation of hybrid peptides bearing a hydroxydimethylsilyl group at a chosen position (either C-ter, N-ter or side-chain linked) to generate siloxane bonds upon freeze-drying. Interestingly, the siloxane bond sensitivity to hydrolysis is strongly pH-dependent. Thus, we investigated the stability of siloxane dimers in different experimental conditions. For that purpose, 29Si, 13C and 1H NMR spectra were recorded to accurately quantify the ratio of dimer/monomer. More interestingly, we showed that 1H resonances of the methylene and methyl groups connected to the Si can be used as sensitive probes to monitor siloxane hydrolysis and to determine the half-lives of the dimers. Importantly, we showed that the dimers were rather stable at pH 7.4 (t1/2 ≈ 400 h) and we applied the dimerization strategy to bioactive sequences. Once optimized, three dimers of the growth hormone releasing hexapeptide (GHRP-6) were prepared. Interestingly, their pharmacological evaluation revealed that the activity of the dimeric ligands could be switched from agonist to inverse agonist depending on the position of dimerization.

Synthesis and biological activity of new series of N-modified analogues of the N/OFQ(1–13)NH2 with aminophosphonate moiety

New series of N-modified analogues of the N/OFQ(1–13)NH2 with aminophosphonate moiety have been synthesized and investigated for biological activity. These peptides were prepared by solid-phase peptide synthesis—Fmoc-strategy. The N/OFQ(1–13)NH2 analogues were tested for agonistic activity in vitro on electrically stimulated rat vas deferens smooth-muscle preparations isolated from Wistar albino rats. Our study has shown that the selectivity of the peptides containing 1-[(methoxyphosphono)methylamino]cycloalkanecarboxylic acids to the N-side of Phe is not changed—they remain selective agonists of NOP receptors. The derivative with the largest ring (NOC-6) demonstrated efficacy similar to that of N/OFQ(1–13)NH2, but in a 10-fold higher concentration. The agonistic activity of newly synthesized N-modified analogues of N/OFQ(1–13)NH2 with aminophosphonate moiety was investigated for the first time.

A switchable stapled peptide

The O‐N acyl transfer reaction has gained significant popularity in peptide and medicinal chemistry. This reaction has been successfully applied to the synthesis of difficult sequence‐containing peptides, cyclic peptides, epimerization‐free fragment coupling and more recently, to switchable peptide polymers. Herein, we describe a related strategy to facilitate the synthesis and purification of a hydrophobic stapled peptide. The staple consists of a serine linked through an amide bond formed from its carboxylic acid function and the side chain amino group of diaminopropionic acid and through an ester bond formed from its amino group and the side chain carboxylic acid function of aspartic acid. The α‐amino group of serine was protonated during purification. Interestingly, when the peptide was placed at physiological pH, the free amino group initiated the O‐N shift reducing the staple length by one atom, leading to a more hydrophobic stapled peptide. Copyright

Synthesis and Analgesic Activity of New Analogues of Tyr-MIF Including Pyrrole Moiety

Pain is one of many medical problems of modern society. Together with a number of other diseases such as heart attacks, strokes, tumors, etc. it ranks among the first in manifestation. There are a huge number of medical drugs more or less effective against pain in a practice. Globally, the searching of new molecules with analgesic activity and better selectivity or greater effect at lower doses continues. In addition, some groups trying to improve the properties of known molecules in medical practice as various heterocyclic compounds by modifying one or another of their part. Other groups work on the creation of new mimetics of natural molecules with well established physiological activity. In this global context, here we report the synthesis of two new compounds which are hybrid molecules between the specifically substituted pyrrole (Pyr) and analogues of Tyr-MIF-1 peptide. All investigations on the analgesic activity show better activity at the same dose than natural Tyr-MIF-1 peptide for the analogue Pyr-Tyr-Phe-Leu-Ala-OH. Compound Pyr-Ala-Leu-Phe-Tyr-OH has no better effect comparable to that of the parent peptide. The obtained results clearly show that it is essential that Tyr residue occupies N-terminal position of MIF-1 analogue. The lack of better activity of the analogue Pyr-Ala-Leu-Phe-Tyr-OH reveals that Pyr residue does not influence on the analgesic activity. In addition we found that C-terminal amide function generally presented in natural MIF-1 is not absolutely necessary for activity.

Synthesis and biological activity of small peptides as NOP and opioid receptors' ligands: view on current developments.

The heptadecapeptide nociceptin, also called orphanin FQ (N/OFQ), is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor) and is involved in several central nervous system pathways, such as nociception, reward, tolerance, and feeding. The discovery of small molecule ligands for NOP is being actively pursued for several therapeutic applications. This review presents overview of the several recently reported NOP ligands (agonists and antagonists), with an emphasis of the structural features that may be important for modulating the intrinsic activity of these ligands. In addition, a brief account on the characterization of newly synthesized ligands of NOP receptor with aminophosphonate moiety and β-tryptophan analogues will be presented.

Synthesis and Biological Activity of Small Peptides as NOP and Opioid Receptors’ Ligands

The heptadecapeptide nociceptin, also called orphanin FQ (N/OFQ), is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor) and is involved in several central nervous system pathways, such as nociception, reward, tolerance, and feeding. The discovery of small molecule ligands for NOP is being actively pursued for several therapeutic applications. This review presents overview of the several recently reported NOP ligands (agonists and antagonists), with an emphasis of the structural features that may be important for modulating the intrinsic activity of these ligands. In addition, a brief account on the characterization of newly synthesized ligands of NOP receptor with aminophosphonate moiety and β-tryptophan analogues will be presented.