Peptide nucleic acids (PNAs) are intensively studied DNA analogues. We elaborated an efficient procedure for the synthesis of N-, C-protected pseudodipeptides with a reduced peptide bond and then peptide nucleic acid (PNA) monomers, based on the Mitsunobu reaction of N-Boc-β-amino alcohols with N-o-nitrobenzenesulfonyl-protected (oNBS-protected) amino acid esters. Using the new procedure, we obtained protected PNA monomer backbones with various amino acid side chains. The pseudodipeptide secondary amine groups were then deprotected by thiolysis, and after appropriate work-up, acylated with thymin-1-ylacetic acid to give the protected monomers. The procedure seems to be of general applicability and allows various modifications of PNA structure by using diverse alcohols and amino acid esters.

PNAs are relatively novel DNA analogues, intensively studied due to their potential as gene-targeted drugs with antigene and antisense properties. In 1996 we elaborated a new method of synthesis of PNA monomer backbones based on the Mitsunobu reaction with N-tosyl-protected (Tos) amino acid esters as acidic components of the reaction. Since the method used for the Tos group removal requires conditions incompatible with various functional groups, here we modified the procedure by replacing the tosyl group with o-nitrobenzenesulfonyl (o-NBS) group. Using the new procedure we obtained protected PNA monomer backbones with various amino acid side chains. The pseudodipeptide secondary amine groups were then deprotected by thiolysis, and after standard work-up acylated with thymin-1-ylacetic acid, to give the protected monomers. Since the deprotection of the secondary amine group occurs under mild conditions, the procedure is of general applicability and allows various modifications of PNA structure by using diverse beta-amino alcohols and alpha-amino acid esters.

Analogs of oxytocin and arginine-vasopressin in which the glutamine residue in position 4 was substituted by the L-homoglutamine (alpha-aminoadipamic acid) residue have been synthesized by solid phase technique and their biological activities have been evaluated by pressor, uterotonic and galactogogic bioassays. The AVP analog showed a high pressor activity and a strikingly low uterotonic and milk-ejecting activities. The oxytocin analog showed a considerable galactogogic activity with a sharp decrease in uterotonic activity: its pressor response was, however, about 50% of that of oxytocin.

The CD spectra of simple derivatives, di- and tripeptides containing phenylalanine and β-homophenylalanine (β-Hph)∗∗ at their C-terminals were studied. The reverse sign contribution of the aromatic 1La transition of β-homophenylalanine in comparison of phenylalanine was found. The implication of this hitherto undescribed fact is discussed in relation to a diagnostic value of the CD measurements in spectral region 200–240 nm. Key Words: β-homoamino acidscircular dichroismpeptides

cyclo(D-Phenylalanyl-trans-4-fluoro-D-prolyl), c(D-Phe-D-FPro), was synthesized and its conformation determined both in solution and in the solid state by 1H NMR and X-ray analysis, respectively. In the crystals the 2.5-diketopiperazine (DKP) ring assumes the uncommon conformation, for cyclodipeptides containing Pro residue, of a flattened chair, which seemingly results from a compromise between, on the one hand, the DKP-aromatic intramolecular ring-ring attraction (folding), requiring the C alpha--C beta bond of the Phe to be axial, and, on the other hand, the intrinsic tendency of the Pro residue to have its C alpha--C beta bond equatorial. Unlike the solid state, the 1H NMR data in CDCl3 and C6D6 demonstrate that in both solutions the DKP ring assumes a boat-like shape, typical for the Pro-containing cyclodipeptides, with the equatorial C alpha--C beta bonds in both amino acid residues, which preclude ring-ring folding. A similar conformation was encountered in the closest analog of c(D-Phe-D-FPro), viz, in c(Phe-Pro), both in solution (21, 22, 26) and in the solid state (12). A subtle interplay of intramolecular interactions introduced into a cyclodipeptide by a Pro-type and a Phe-type residue is emphasized.

AFA analysis (AFA), also known as principal-component analysis, was used in conformational studies of the condensed 2,5-dioxopiperazine/pyrrolydine (DOP/PYR) 6/5-membered two-ring system, a compound typical of cyclodipeptides comprising prolyl-type amino acid residues. The study is based on the analysis of 30 various X-ray conformers of the molecular frame in question. The results were evaluated and discussed using ring-puckering theory (RPT) as a reference. Complete mutual correspondence between the AFA and the RPT results was found, when both rings are considered separately, which is the prerequisite to using RPT. This correspondence allows a clear-cut physical interpretation of the AFA results, which are otherwise abstract in nature. Thus, two or three independent puckering variables were found for the DOP and PYR rings, respectively, and they acquire the physical significance of the absolute amplitudes of the basic pucker modes, typical of the respective rings. The term absolute is used for puckering with respect to the planar conformer of reference. Subsequent AFA treatment of the condensed DOP/PYR system allowed identification of five conformational variables necessary and sufficient to describe the concerted two-ring puckering completely. Each of the respective basic pucker modes defines a unique pattern of conformational variation of the whole two-ring system. In contrast to the separated ring cases, the origin of the five-dimensional conformational space of DOP/PYR is placed at the mean conformer and it spans physically accessible conformational deviations around the mean. When a conformer other than the mean (e.g. planar) one is chosen initially as a reference, AFA automatically brings the system to the basis set of local deviations around the mean. The results obtained demonstrate that AFA may be a very powerful technique in conformational studies based on an evaluation of a large collection of mutually consistent data. Factor analysis is especially useful in analyses of condensed poly-ring systems, not amenable to the RPT treatment.

The variations of the bond lengths, the endo- and the exocyclic valence and torsion angles involved in the 2,5-dioxopiperazine, DOP, ring have been inv

The synthesis of δ-(L-α-aminoadipyl)-L-seryl-D-valine (LLD ASV), a naturally occuring congener of the well known tripeptide δ-(L-α-aminoadipyl)-L-cysteinyl-D-valine (LLD ACV) which is the linear precursor of isopenicillin N, penicillin N, cephalosporin C is described. An efficient method for producing the requisite α-monobenzyl ester of N-benzyloxycarbonyl-L-homoglutamic acid for subsequent condesation at the side chain δ-carboxy group is presented.

N‐benzyloxycarbonyl‐l‐homoglutamine was studied to answer the question whether or not there is any tendency for the dehydration of the δ‐carboxamide group during activation and coupling. Only a minor conversion to nitrile by‐products was found in the activation of the α‐carboxyl group and formation of peptide bond with the help of dicyclohexylcarbodiimide. Addition of N‐hydroxybenzotriazole to the reacting mixture eliminates the side chain dehydration reaction. The dehydration reaction is also overcome by protection of the side chain carboxamide with the benzyloxycarbonylcarbamoyl substituent.

AbstractThe monoprotected lysine derivative (I) is subjected to KMnO4 oxidation, yielding the amide (II) as the main product, together with the diamide (III) and the amido nitrile (IV).

Two efficient syntheses of the linear tripeptide precursor of penam and cephem antibiotics are presented. The routes are characterised by the use of L-lysine derivatives, Z-L-Lys(Z)-OH and H-L-Lys(Z)-OH as starting materials. By the permanganate oxidation the protected side chain amino grouping in L-lysine derivatives is transformed into the benzyloxycarbonylcarbamoyl substituent with formation of Z-L-Aad(NHZ)-OH and H-L-Aad(NHZ)-OH compounds. Both oxidation products are easily transformed into [N, Cα]-diprotected derivatives. Subsequent condensation at the δ-carboxy group afforded protected LLD ACV tripeptide.

The separations by reversed phase high‐performance liquid chromatography on a μBondapak‐C18 column of 53 epimeric N‐substituted di‐, tri‐ and tetrapeptide acids and esters have been attempted, with success in three quarters of the cases. Substituents include acetyl, benzoyl, benzyloxycarbonyl, tert.‐butoxycarbonyl and 9‐fluorenylmethoxycarbonyl. The series N‐benzyloxycarbonylglycyl‐Xxx‐valine ethyl ester with Xxx = alanyl, valyl, leucyl and phenylalanyl, is recommended for use in studies on racemization. Results on racemization attending the coupling of an amino acid ester as compared with a di‐ and tripeptide ester vary with the coupling method.

A new route to L‐homoglutamine (L‐α‐aminoadipamic acid) derivatives is presented via preferential KMnO4 oxidation in acidic media of the e‐methylene group in H‐L‐Lys(Z)‐OH and Z‐L‐Lys(Z)‐OH. The main oxidation products are 5‐benzyloxy‐carbonylcarbamoyl‐2‐aminopentanoic acid (H‐L‐Aad(NHZ)‐OH) 2 and 5‐benzyl‐oxycarbonylcarbamoyl‐2‐benzyloxycarbonylaminopentanoic acid (Z‐L‐Aad(NHZ)‐OH) 10, respectively, in which the intact benzyloxycarbonyl protection is now attached to the nitrogen atom of the δ‐amide group. The accompanying hydrolysis of the labile N‐protected amide group and the continuing oxidation, however, diminish the quantity of 2 and 10 in the reacting mixture. Therefore, to obtain fair yields of these products, useful in peptide synthesis, involving homoglutamic acid and homoglutamine (H‐L‐Aad(NHZ)‐OH and Z‐L‐Aad(NHZ)‐OH contain carboxylic groups in differential form) a compromise must be reached and the oxidation process stopped at the right moment. Besides the desired oxidation product involving the transformation of the e‐methylene group into the carbonyl group, a number of side products formed by oxidation of the α‐carbon atom (derivatives of δ‐aminovaleric acid) and e, α‐carbon atoms (derivatives of glutaric acid) have been isolated and identified.

1-Methyl-3,6-bis (phenylmethyl)2,5 -piperazinedione, C19H20N202, Mr= 308.3, orthorhombic, P212121, a = 10.254 (2), b = 13.370 (3), c = 24.294(4)A, V = 3 3 3 0 ( 1 ) A 3, z = 8 , Ox= 1.23 g cm -3, ~,(Cu Kt~) = 1.54178 A, # = 5.6 cm -~, F(000) = 1312, room temperature, R = 0.052 for 1697 observed reflections. Two crystallographically independent molecules joined through a pair of N H . . . O hydrogen bonds form dimers as distinct units in the crystal lattice. The general molecular conformation is similar to that of cyclo(L-Phe) 2 [Gdaniec & Liberek (1986). Acta Cryst. C42, 1343-1345]. In molecule B the aromatic side chain of the N-methylated phenylalanine residue folds over the diketopiperazine moiety [,~ =61.1 (7) °] while the other side chain is in extended conformation [2~=-62.5(6)°] . The opposite conformation of the side chains is observed in molecule A [ZI = -65 .9 (6), X2 ~ = 68.7 (6)°

Optimum conditions of synthesis of eight diazoketones derived from optically active N-(t-butyloxycarbonyl)- and N-benzyloxycarbonylamino acids have been described. The problem of formation of by-products during Arndt-Eistert synthesis of β-homoamino acids at the stage of reaction of mixed anhydride with a weak nucleophile-diazomethane - has been discussed.