Topochemical investigations of peptide systems

The basic principles of the topochemical approach to the investigation of the structure-function relation in peptide systems are formulated. This approach makes use of the new possibility of transforming natural peptides, consisting in the modification of the molecule as a whole and utilization of the resultant analogs to elucidate the boundaries of the stereoelectronic complementarity of the biologically active peptide to the corresponding receptor. In particular, on the example of depsipeptide antibiotics and their topochemical analogs the fruitfulness of using such compounds as tools in elucidating the physicochemical basis of functioning of biological membranes is shown. The topochemical principle has also been applied in preparing specific competitive inhibitors of proteolytic enzymes, whose study may shed light on the nature of the forces binding the substrate to the contact site of the corresponding enzyme.     

Facile synthesis of α-hydroxy carboxylic acids from the corresponding α-amino acids

An effective and improved procedure is developed for the synthesis of α-hydroxy carboxylic acids by treatment of the corresponding protonated α-amino acid with tert-butyl nitrite in 1,4-dioxane–water. The amino moiety must be protonated and located α to a carboxylic acid function in order to undergo initial diazotization and successive hydroxylation, since neither β-amino acids nor acid derivatives such as esters and amides undergo hydroxylations. The method is successfully applied for the synthesis of 18 proteinogenic amino acids.     

Dramatically enhanced N→O acyl migration during the trifluoroacetic acid-based deprotection step in solid phase peptide synthesis

N→O acyl migrations at serine or threonine residues in peptides or proteins have previously been observed upon treatment with strong acids. Here we show that the extent of such N→O shifts depends on the peptide sequence and even in the presence of moderately acidic trifluoroacetic acid, as during Fmoc or Bsmoc-based solid phase peptide synthesis, may give rise to large amounts of depsipeptide by-products.     

Total syntheses of 28,29-diepi-arenamide A, 29-epi-arenamide A, and 28-epi-arenamide A

This communication describes the synthesis of stereochemical analogs of arenamide A, a 19-membered cytotoxic depsipeptide isolated from the fermentation broth of a marine bacterial strain Salinispora arenicola. The key steps are diastereoselective aldol reaction, Mitsunobu reaction, and HATU mediated macrolactamization.     

Synthesis of cyclic peptides via O-N-acyl migration

We describe here a novel and convenient synthesis of head-to-tail cyclic peptide avoiding racemization. Linear depsipeptides including a serine residue as the key element for ester bond formation and acyl transfer were synthesized on 2-chlorotrityl chloride resin. After cleavage from the resin, intramolecular head-to-tail cyclization was performed in solution by C-terminal activation of urethane protected O-acyl serine residue. After removal of the N^α-serine protecting group, the final step consisted in O-N-acyl migration reaction on the ‘switch’ or ‘click’ element to restore native cyclic peptides.     

Determination of beauvericin and four other enniatins in grain by liquid chromatography-mass spectrometry

A method is described using LC-MS-MS for the detection of five different enniatins in grain. The method involves extraction of the fungal secondary metabolites using acetonitrile-water and quantification using LC-MS-MS with atmospheric pressure chemical ionisation, without further treatment of sample extracts. The selected ion reaction of [M + NH4]+ to [M + H]+ was utilised in the specific detection of the compounds. Mean recoveries (n = 5-12) of enniatins from spiked grain samples over a period of six months were 99-115%, 86-131%, 97-113%, 73-100% and 78-114% for beauvericin, enniatin A, A1, B and B1, respectively. The limits of detection were 3.0 microg/kg for beauvericin, enniatin A, B and B1 and 4.0 microg/kg for enniatin A1, which corresponds to on-column detection limits of 7.5 pg and 10 pg, respectively.     

NO as temporary guanidino-protecting group provides efficient access to Pbf-protected argininic acid

Pbf-protected argininic acid [H-OArg(Pbf)-OH], a building block for Fmoc-solid phase peptide synthesis, is obtained in high yield when a large excess of nitrosating agent is used in conjunction with intermediate N^δ-nitrosyl protection and N^δ-denitrosation in aqueous acidic medium.     

Total synthesis and structural validation of cyclodepsipeptides solonamide A and B

Microorganisms are an attractive source of new natural products with antimicrobial properties, and the marine environment constitutes a prolific resource of bioactive microorganisms. During a global research expedition (Galathea III), two depsipeptides, solonamide A and solonamide B, were isolated from the marine bacterium Photobacterium halotolerance and were found to inhibit virulence gene expression in the serious human pathogen, Staphylococcus aureus. They act by interfering with the agr quorum sensing system and show resemblance to the endogenous S. aureus quorum sensing peptide, autoinducing peptide I (AIP-I). To enable more comprehensive studies, we embarked on the chemical synthesis of solonamides A and B. The key synthetic steps were formation of the (R)-β-hydroxy-fatty-acids by stereo-selective aldol reactions and a cyclative macrolactamization, which proceeded under highly dilute conditions. Thus, the first total syntheses of the solonamides corroborated the originally assigned structures, and by changing the stereochemistry of the auxiliary in the aldol steps we gained access to the natural products as well as their β³-epimers.