[Amino acid and peptide derivatives of the tylosin family of macrolide antibiotics modified at the aldehyde group].

Fourteen new functionally active amino acid and peptide derivatives of the antibiotics tylosin, desmycosin, and 5-O-mycaminosyltylonolide were synthesized in order to study the interaction of the growing polypeptide chain with the ribosomal tunnel. The conjugation of various amino acids and peptides with a macrolide aldehyde group was carried out by two methods: direct reductive amination with the isolation of the intermediate Schiff bases or through binding via oxime using the preliminarily obtained derivatives of 2-aminooxyacetic acid.

[Synthesis of cyclic analogues of the nerve growth factor loop 4].

Cyclic peptides cyclo(-Gly-Asp-Glu-Lys-), cyclo(-Gly-Gly-Asp-Glu-Lys-) and cyclo(-Gly-Gly-Gly-Asp-Glu-Lys-) were synthesized as models of the beta-turn of nerve growth factor loop 4. The corresponding protected linear precursors were obtained in 52-83% yields by the solid-phase method with the use of the Fmoc/Bu(t) strategy and a chlorotrityl anchor group. The cyclization was carried out with benzotriazolyloxy-tris(dimethylamino)phosphonium (BOP) hexafluorophosphate, N-[(1H-benzotriazole-1-yl)-(dimethylamino)methylene]-N-methylmetanaminium-N-oxide (HBTU) hexafluorophosphate, and diphenylphosphorylazide (DPPA) at a dilution of 10(-3) M. The distribution of reaction products was studied for each cyclopeptide in dependence on the type of the coupling agent. The use of DPPA was shown to completely inhibit the formation of cyclodimers in the synthesis of five- and six-membered cyclopeptides; however, in the case of a four-membered peptide, an additional tenfold dilution of the reaction mixture was necessary to achieve the effect. The identification of several byproducts during the synthesis showed that the elongation of the polypeptide chain using the BOP reagent can be complicated by substantial racemization and the cleavage of the chlorotrityl anchor group by 0.5% TFA in dichloromethane proceeds with insufficient selectivity and is accompanied by the premature Boc deblocking of the lysine side function.

[Peptide derivatives of tylosin-related macrolides].

Approaches to the synthesis of model compounds based on the tylosin-related macrolides desmycosin and O-mycaminosyltylonolide were developed using specially designed peptide derivatives of macrolide antibiotics to study the conformation and topography of the nascent peptide chain in the ribosome tunnel. A method for selective bromoacetylation of desmycosin at the hydroxyl group of mycinose was developed, which involves preliminary acetylation of mycaminose. The reaction of the 4"-bromoacetyl derivative of the antibiotic with cesium salts of the dipeptide Boc-Ala-Ala-OH and the hexapeptide MeOTr-Gly-Pro-Gly-Pro-Gly-Pro-OH led to the corresponding peptide derivatives of desmycosin. The protected peptides Boc-Ala-Ala-OH, Boc-Ala-Ala-Phe-OH, and Boc-Gly-Pro-Gly-Pro-Gly-Pro-OH were condensed with the C23-hydroxyl group of O-mycaminosyltylonolide.

[New photoreactive cleavable reagents with (trifluoromethyl)diazirine group]. / Novye fotolabil'nye rasshchepliaemye reagenty, soderzhashchie (triftormetil)diazirinovyiu gruppu.

Photoreactive cross-linking reagents that simultaneously contain a trifluoromethyldiazirine and an o-nitrobenzyl groups were synthesized for the first time. Photochemical properties of the reagents were studied, and the possibility of separate activation of the diazirine group and o-nitrobenzyl linker was shown.

[Detection of nucleic amino acid enantiomers by HPLC with preliminary modification by o-phthalic aldehyde]. / Opredelenie énantiomerov nucleoaminokislot metodom vysoko'effektivnoi zhidkostnoi khromatografii s predkolonochnoi modifikatsiei o-ftalevym al'degidom.

The use of reversed-phase HPLC with UV detection at 254 nm for the separation of stereoisomers of nucleoamino acids, namely, pyrimidyl and purinyl derivatives of alanine, after premodification with o-phthalic aldehyde and N-acetyl-L-cysteine was studied. The use of 0.01 M phosphate buffer (pH 7.0) containing 5% acetonitrile as a mobile phase resulted in satisfactory separation. The range of the detectable amounts of nucleoamino acids was 0.08-1.0 nmol. This method was used for monitoring the formation of stereoisomers in the hydrolysis of N-phenylacetylcytosinylalanine.

[Lipophilic derivatives of caffeic acid as lipoxygenase inhibitors with antioxidant properties]. / Lipofil'nye proizvodnye kofeinoi kisloty--lipoksigenaznye ingibitory s antioksidantnymi svoistvami.

We have prepared two lipophilic derivatives of caffeic acid at the carboxylic function--caffeic acid phenethyl ester, an active component of propolis, and N,N'-dicyclohexyl-O-(3,4-dihydroxycinnamoyl)-isourea. Both substances inhibit barley 5-lipoxygenase and soybean 15-lipoxygenase at micromolar concentrations. The inhibition is uncompetitive, dose-dependent and reversible. The caffeic acid derivatives also exhibit antioxidant properties and at a concentration 5-10 microM completely block the production of the reactive oxygen species in human neutrophils and in the cell-free xanthine/xanthine oxidase system.

[Conformation-activity relations of dermorphin and its pentapeptide analogs]. / Konformatsionno-funktsional'nye otnosheniia dermorfina i ego pentapeptidnykh analogov.

Low-energy peptide backbone structures of dermorphin (DM), amide of its N-terminal pentapeptide (DM 1-5) and DM 1-5 analogues with substitutions of Gly4 for Leu, D-Gln, Aal or Tal were determined by energy calculations. The above analogues were shown to possess different affinities toward opiate receptors of mu-type. The comparison of low-energy backbone structures of DM, DM 1-5 and its analogues resulted in development of the dermorphin "biologically active" conformation being characteristic of its binding with mu-type receptors. The specific binding of dermorphin to this receptor apparently depends on the conformation of the whole N-terminal pentapeptide.

[Dermorphin: synthesis of analogs and structuro-functional relations]. / Dermorfin: sintez analogov i strukturno-funktsional'nye otnosheniia.

The review analyzes structure-activity relations among dermorphin analogues. Dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2) is one of natural opioid peptides having a unique structure and exerting a very potent and prolonged antinociceptive effect. Methods of dermorphin synthesis are summarized together with data on more than 300 dermorphin-like peptides: the physico-chemical characteristics and data on opioid tests in vitro and in vivo are discussed. Based on these studies, conclusions have been drawn on the functional role of each amino acid residue in the dermorphin molecule and on modifications leading to analogues with high and differential opioid activity.

[Comparison of the opioid activity of a number of enkephalin and dermorphin analogs]. / Sravnenie opioidnoi aktivnosti riada analogov énkefalinov i dermorfina.

In search of selective ligands of opioid receptors there was synthetized a number of shortened dermorphin analogues containing nucleic amino acid substituents in positions 4 and 5 and also nucleic amino acid analogues of enkephalins. All synthetized analogues of enkephalins and dermorphin possess opioid activity revealed on preparations of the guinea pig ileum and the mouse vas deferens. Among the obtained analogues there were detected analogues exhibiting a high delta-agonistic (Tyr-D-Ala-Phe-Gly-DL-Tal-OH) or mu-agonistic (Tyr-D-Phe-Gly-Tal-Leu-OH) activity comparable with that for standard preparations DADLE and DAGO.