A. Calcagni

ψ(SO2-NH) transition state isosteres of peptides. Synthesis of the glutathione disulfide analogue

Abstract 6 has been synthesized starting from ethyl ( S )-2-benzyloxycarbonylamino-4-(chlorosulfonyl)butanoate and S -acetamidomethyl-L-cysteinyl-glycine ethyl ester. Compound 6 is a backbone modified analogue of glutathione disulfide containing the SO 2 NH transition state mimic in place of the native γ-glutamyl-cystine CONH bond.

Peptides containing the sulfonamide junction: Synthesis, structure, and conformation of Z-Tau-Pro-Phe-NHiPr

The taurine (Tau) containing tripeptide derivative Z-Tau-Pro-Phe-NHiPr (1) has been synthesized as suitable sulfonamido-pseudopeptide model to investigate formation and conformational properties of folded secondary structures stabilized by intramolecular H bonds directly involving the sulfonamide junction. In the crystal the pseudopeptide 1 adopts a type I β-turn with the Pro and Phe residues located at the (i + 1) and (i + 2) corner positions, respectively. The turn is stabilized by a 4 1 H bond engaging one of the SO2 oxygen atoms and the isopropylamide NH. In CDCl3 solution the β-turn folding is accompanied by a γ-turn centered at the Pro and involving a 3 1 H bond between the SO2 and the Phe NH. A comparison of the structural and conformational properties found in 1 with those of the already known sulfonamido-pseudopeptides, with particular reference to the models containing the Tau-Pro junction, is also reported.

Ψ(SO2NH) transition state isosteres of peptides. Synthesis and bioactivity of sulfonamido pseudopeptides related to carnosine

This paper reports the synthesis of tauryl dipeptides related to carnosine. In particular H-Tau-His-OH (5), H-Tau-His(pi-Me)-OH (6) and H-Tau-His(tau-Me)-OH (9) are described. The enzyme carnosinase has been isolated from pig kidney and after purification has been used to test the stability and the inhibitory activity of the three new analogues. H-Tau-His-OH (5) and H-Tau-His(tau-Me)-OH (9) were found to possess weak inhibitory properties towards carnosinase, while H-Tau-His(pi-Me)-OH (6) proved to be devoid of any significant activity. All the three sulfonamido pseudopeptides 5, 6 and 9 show stability to carnosinase activity.

Peptides containing the sulfonamide junction. 2. Structure and conformation of Z–Tau–Pro–D-Phe–NHiPr†

The taurine (Tau) containing N-protected pseudotripeptide isopropylamide Z-Tau-Pro-D-Phe-NHiPr (1) has been specifically designed and synthesized as suitable model to test the ability of the sulfonamido group to participate as H-bond acceptor to a type II beta-turn and to get information on the preferred rotameric conformation around the S-N bond and the hybridization state of the nitrogen atom. The present structural investigation reveals that, although the sulfonamide junction is invariably folded in a gauche mode, the beta-turn structure, stabilized by the 4 --> 1 hydrogen bond, is not found in the crystal and the sulfonamido oxygen atoms are not involved in any intra- or intermolecular hydrogen-bond interaction. More than one conformer populates the CDCl(3) solution with only a minor contribution by the expected beta-turn. The Pro nitrogen is significantly pyramidalized and the nitrogen lone pair points in opposite direction to that of the Pro C(alpha)H bond thus adopting R chirality, in an arrangement practically identical to that found in the previously studied homochiral analogue Z-Tau-Pro-Phe-NHiPr.

Approaches to pseudopeptidic ergopeptines. Part 2. Consequences of the incorporation of an α-azaproline residue into the oxacyclolic system

As part of a programme to synthesize pseudopeptidic ergopeptines, the introduction of an α-azaproline residue in place of native proline into an ergotamine-like oxacyclolic system has been investigated. Starting material N-[(R)-2- benzyloxypropionyl]cyclo(-Phe-azaPro-)10 was prepared following two alternative synthetic routes and was subjected to reductive O-debenzylation. N,O-Acyl transfer on the resulting N-[(R)-2-hydroxypropionyl]cyclo(Phe-azaPro-)14 leads, through a new type of four- heteroatom tetrahedral adduct, to (5R)-5-methyl-3-{(1S)-2-phenyl-1-[(pyrazolidin-1-yl)carbonyl]ethyl}oxazolidine-2,4-dione 16, as a unique isolable tautomer. Structural and conformational details of compound 14, as revealed by X-ray analysis, are reported and compared with those of previously studied related models.

Novel glutathione analogues containing the dithiol and disulfide form of the Cys-Cys dyad.

SummaryThe glutathione analogue γ-(H-Glu-OH)--OH (5), containing the 8-membered disulfide ring- replacing the native -Cys-Gly fragment, has been synthesized and characterized together with its reduced dithiol form γ-(H-Glu-OH)-Cys-Cys-OH (6).

Approaches to pseudopeptidic ergopeptines. Part 3.1 Consequences of the incorporation of an α-azaphenylalanine residue into the ergotamine oxa-cyclolic system

In the context of a research program aimed at synthesizing pseudopeptidic ergopeptines, the incorporation of an α-azaPhe residue into the peptidic moiety of ergotamine has been studied. Acylation of cyclo(-azaPhe-Pro-) 6 with (+)-(S)-2-benzyloxy-2-methylmalonyl monoethyl ester monochloride 5 gives the (E)-isoimide 7 as the predominant reaction product; contrary to expectation the conversion of 7 into the desired imide isomer 8 proceeds with difficulty and is accompanied by decomposition. Hydrogenolysis of 8 leads stereospecifically to the pseudopeptidic oxa-cyclol ethyl ester 9. Subsequent rearrangement of the corresponding oxa-cyclol acyl-azide 11 in the presence of benzyl alcohol fails to give the pseudopeptidic ergotamine oxa-cyclol. The new stable pseudopeptidic aza-cyclol 12 containing the residue of the didehydroalanine has been isolated together with a comparable amount of the imino aza-cyclol derivative 13. The mechanism of the formation of the new products 12 and 13 and the unexpected stability of the (E)-isoimide 7 are discussed.

Acid-catalysed reactions of 1α,2α-epoxy-1β-methyl- and 1α-hydroxy-1β-methyl-5α-steroids

The reaction of 1α,2α-epoxy-1β-methyl-5α-androstane-3β,17β-diol diacetate (4) with boron trifluoride–ether leads to both the A-nor derivative (5) and the 2α-hydroxy-1-methylene compound (6). The epoxide (4) on treatment with acetic anhydride–acetic acid and toluene-p-sulphonic acid gives, depending upon temperature, the 1α,2β-diacetoxy-compound (11) or the 2β-acetoxy-1-methylene compound (12), while with formic acid gives the 2-formate (13) of the 1α,2β-diol. The reaction of 1α,2α-epoxy-1β-methyl-5α-androstane-3α,17β-diol diacetate (14) with boron trifluoride affords the A-noraldehyde (15) and the 1-methylene derivative (16). 1β-Methyl-5α-androstane-1α,3β,17β-triol 3,17-diacetate (19) with toluene-p-sulphonic acid is simply acetylated to give (20) and dehydrated to give (21).