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Biomedical subjects

C Toniolo

Publications and source records attributed to C Toniolo.

At least 91 records · Page 5Linked to original sources
PubMed1991

Stereochemistry of peptides containing 1-aminocycloheptane-1-carboxylic acid (Ac7c).

The crystal structures of four peptides incorporating 1-aminocycloheptane-1-carboxylic acid (Ac7c) are described. Boc-Aib-Ac7c-NHMe and Boc-Pro-Ac7c-Ala-OMe adopt beta-turn conformations stabilized by an intramolecular 4----1 hydrogen bond, the former folding into a type-I/III beta-turn and the latter into a type-II beta-turn. In the dipeptide esters, Boc-Aib-Ac7c-OMe and Boc-Pro-Ac7c-OMe, the Ac7c and Aib residues adopt helical conformations, while the Pro residue remains semi-extended in both the molecules of Boc-Pro-Ac7c-OMe found in the asymmetric unit. The cycloheptane ring of Ac7c residues adopts a twist-chair conformation in all the peptides studied. 1H-NMR studies in CDCl3 and (CD3)2SO and IR studies in CDCl3 suggest that Boc-Aib-Ac7c-NHMe and Boc-Pro-Ac7c-Ala-OMe maintain the beta-turn conformations in solution.

Amino Acid Sequence↗
PubMed1991

Peptides from chiral C alpha,alpha-disubstituted glycines. Crystallographic characterization of conformation of C alpha-methyl, C alpha-isopropylglycine [(alpha Me)Val] in simple derivatives and model peptides.

The molecular and crystal structures of one derivative and three model peptides (to the pentapeptide level) of the chiral C alpha,alpha-disubstituted glycine C alpha-methyl, C alpha-isopropylglycine [(alpha Me)Val] have been determined by X-ray diffraction. The derivative is mClAc-L-(alpha Me)Val-OH, and the peptides are Z-L-(alpha Me)Val-(L-Ala)2-OMe monohydrate, Z-Aib-L-(alpha Me)Val-(Aib)2-OtBu, and Ac-(Aib)2-L-(alpha Me)Val-(Aib)2OtBu acetonitrile solvate. The tripeptide adopts a type-I beta-turn conformation stabilized by a 1----4N--H...O = C intramolecular H-bond. The tetra- and pentapeptides are folded in regular right-handed 3(10)-helices. All four L-(alpha Me)Val residues prefer phi, psi angles in the right-handed helical region of the conformational map. The results indicate that: (i) the (alpha Me)Val residue is a strong type-I/III beta-turn and helix former, and (ii) the relationship between (alpha Me)Val chirality and helix screw sense is the same as that of C alpha-monosubstituted protein amino-acids. The implications for the use of the (alpha Me)Val residue in designing conformationally constrained analogues of bioactive peptides are briefly discussed.

Amino Acid Sequence↗
PubMed1990

The longest, regular polypeptide 3(10) helix at atomic resolution.

A synthetic, terminally blocked homodecapeptide from the C alpha, alpha-dimethylated glycyl residue alpha-aminoisobutyric acid has been analyzed by single-crystal X-ray diffraction and the structure refined to R = 0.073. The compound crystallizes as a perfect 3(10) helix, stabilized by eight consecutive intramolecular N-H . . . O = C hydrogen bonds. This is the first observation at atomic resolution of a regular polypeptide 3(10) helix as long as three complete turns.

Aminoisobutyric Acids↗
PubMed1990

N alpha-formylated and tert-butyloxycarbonylated Phe-(Leu-Phe)n and (Leu-Phe)n peptides as agonists and antagonists of the chemotactic formylpeptide receptor of the rabbit peritoneal neutrophil.

The various diastereomers of the N alpha-formylated(CHO) and tert-butyloxycarbonylated (t-Boc) Phe-(Leu-Phe)n and (Leu-Phe)n methyl esters, where n = 1-2 and 1-3, respectively, have been newly synthesized and their physical properties described. The CHO-blocked peptides are all able to release beta-glucosaminidase from rabbit peritoneal neutrophils in a concentration-dependent manner. There is a strong effect of primary structure and of chirality on their biology activity; lengthening the peptide chain distinctly increases activity in each series and within a series the activity decreases in the order: all-L greater than D-L much greater than all-D. Of the t-Boc protected synthetic precursors, the all-L isomers have definite but weak agonist activity; the agonist activity of the other isomers is equivocal or not detectable. All the t-Boc peptides, however, are capable of acting as weak, specific antagonists. There is a dependence of antagonist activity on primary structure, but this is variable and contingent on the nature of the peptide. Similarly, an effect of chirality on antagonist activity, although present, also depends on the structure of the peptide. In the one instance directly tested, t-Boc-L-Phe-(D-Leu-L-Phe)2-OMe (OMe, methoxy) was found to be distinctly less active than the corresponding free acid.

Amino Acid Sequence↗
PubMed1990

Conformationally restricted peptides through short-range cyclizations.

The various types of conformationally restricted peptides obtained by short-range cyclizations, from residue i to residue i + 1, are presented. Relevant examples of N in equilibrium C alpha, C' in equilibrium C alpha, N in equilibrium C', C alpha in equilibrium C alpha, C' in equilibrium C', and N in equilibrium N cyclizations are reported and the pertinent literature listed. In the discussion emphasis is place on the conformational consequences for peptides from the incorporation of such ring structures.

Cyclization↗
PubMed1990

Replacement of the N alpha-blocking group in the formyl-methionyl tripeptide chemoattractant: an insight into the mode of binding at the receptor on rabbit neutrophils.

The tripeptide N alpha-carbamoyl-L-methionyl-L-leucyl-L-phenylalanine methyl ester has been synthesized in solution by classical methods and fully characterized. This compound, prepared in order to obtain a deeper insight into the mode of binding at the formyl peptide chemotactic receptor, has been tested for its ability to induce granule enzyme secretion from rabbit peritoneal neutrophils and found to be a complete agonist. These results confirm the hypothesis that a proton on the N alpha-blocking group of the tripeptide forms a hydrogen bond with an acceptor in the binding site.

Amino Acid Sequence↗
PubMed1990

Critical main-chain length for conformational conversion from 3(10)-helix to alpha-helix in polypeptides.

To assess the minimal peptide length required for the stabilization of the alpha-helix relative to the 3(10)-helix in Aib-rich peptides, we have solved the X-ray diffraction structures of the terminally blocked sequential hexa- and octapeptides with the general formula-(Aib-L-Ala)n-(n = 3 and 4, respectively). The hexapeptide molecules are completely 3(10)-helical with four 1----4 intramolecular N-H . . . O = C H-bonds. On the other hand, the octapeptide molecules are essentially alpha-helical with four 1----5 H-bonds; however, the helix is elongated at the N-terminus, with two 1----4 H-bonds, giving these molecules a mixed alpha/3(10)-helical character. In both compounds the right-handed screw sense of the helix is dictated by the presence of the Ala residues of L-configuration. This study represents the first experimental proof for a 3(10)----alpha-helix conversion in the crystal state induced by peptide backbone lengthening only.

Chemical Phenomena↗
PubMed1989

Structure of (3S)-3-tert-butyloxycarbonylamino-2-piperidone.

C10H18N2O3, Mr = 214.27, monoclinic, P2(1), a = 15.515 (2), b = 6.730 (1), c = 12.541 (2) A, beta = 113.6 (2) degrees, V = 1200.0 A3, Z = 4, Dx = 1.186 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.54 cm-1, F(000) = 464, T = 295 K. The final R value for 1611 observed (3139 unique) reflections is 0.055. In both the independent molecules A and B of the asymmetric unit of the title compound, the conformation of the urethane moiety is trans. The lactam group of molecule A is non-planar, the C(9)-N(2)-C(10)-C(6) torsion angle being 12.4 (14) degrees. One main difference between molecules A and B is in the value of the phi[C(5)-N(1)-C(6)-C(10)] torsion angle [52.3 (11) degrees for molecule A while -86.5 (10) degrees for molecule B] as a consequence of a rotation of the ring relative to the tert-butyloxycarbonylamino substituent. A second major difference is the delta-lactam ring conformation which is approximate half-chair for molecule A while boat for molecule B.

Chemical Phenomena↗
PubMed1989

Structure of conformationally constrained peptides: from model compounds to bioactive peptides.

The use of backbone conformational constraints has acquired increasing importance in the design and synthesis of structurally restricted agonists and antagonists of bioactive peptides. Here I discuss the preferred conformations of four among the most popular types of such peptide surrogates: (a) Peptides from C alpha, alpha-dialkylated residues, (b) tetrazolyl peptides, (c) (gamma- and delta-) lactam-containing peptides, and (d) thiated peptides. Emphasis is given to conformational energy computations and x-ray diffraction analyses of selected model compounds and analogues of small bioactive peptides such as the formylmethionyl tripeptide chemoattractant and MIF.

Models, Molecular↗
PubMed1989

Structural versatility of peptides containing C alpha, alpha-dialkylated glycines: conformational energy computations, i.r. absorption and 1H n.m.r. analysis of 1-aminocyclopropane-1-carboxylic acid homopeptides.

Conformational energy computations on the 1-aminocyclopropane-1-carboxylic acid mono-, di-, and tripeptide amides, Ac-(Ac3c)n-NHMe (n = 1-3), indicate that this C alpha, alpha-dialkylated, cyclic alpha-amino acid residue is conformally restricted and that type-I(I') beta-bends and distorted 3(10)-helices are particularly stable conformations for the di- and tripeptide amides, respectively. The results of the theoretical analysis are in agreement with those obtained in an i.r. absorption and 1H n.m.r. investigation in chloroform solution of Ac3c-rich tri- and tetrapeptide esters. A comparison is also made with the conclusions extracted from our previous work on peptides rich in Aib (alpha-aminoisobutyric acid), Ac5c (1-aminocyclopentane-1-carboxylic acid), and Ac6c (1-aminocyclohexane-1-carboxylic acid).

Alkylation↗
PubMed1989

Crystal-state structural analysis of two gamma-lactam-restricted analogs of Pro-Leu-Gly-NH2.

The crystal structures of two analogs of Pro-Leu-Gly-NH2 (1), containing a gamma-lactam conformational constraint in place of the -Leu-Gly- sequences, are described. The highly biologically active (S,R)-diastereomer 2a is semi-extended at the C-terminus, with the N-terminal Pro residue in the unusual "C5" conformation [psi 1 = -0.8(15) degrees] stabilized by a (peptide)N-H...N(amino) intramolecular H-bond [the N(3)...N(4) separation is 2.687(11)A]. Conversely, the N,N'-isopropylidene aminal trihydrate of the (S,S)-diastereomer 2b, compound 3, adopts a beta-bend conformation at the C-terminus, as already reported for 1. However, the backbone torsion angles [phi 2 = 57.4(4), psi 2 = -129.9(3) degrees; psi 3 = -92.3(4), phi 3 = 6.4(5) degrees] lie close to the values expected for the corner residues of an ideal type-II' beta-bend. A weak intramolecular 4----1 H-bond is seen between the Gly carboxyamide anti-NH and Pro C = O groups. In the newly formed 2,2,3,4-tetraalkyl-5-oxo-imidazolidin-1-yl moiety the psi 1 torsion angle is 12.9(4) degrees and the intramolecular N(3)...N(4) separation is 2.321(4)A.

Lactams↗
PubMed1989

Crystallographic characterization of conformation of 1-aminocyclopropane-1-carboxylic acid residue (Ac3c) in simple derivatives and peptides.

The molecular and crystal structures of the C alpha,alpha-dialkylated alpha-amino acid residue 1-aminocyclopropane-1-carboxylic acid hemihydrate (H2+-Ac3c-O-.1/2 H2O) and nine derivatives and dipeptides have been determined by X-ray diffraction. The derivatives are pBrBz-Ac3c-OH, Piv-Ac3c-OH, Z-Ac3c-OH, the alpha-and beta-forms of t-Boc-Ac3c-OH, Z-Ac3c-OMe, and the 5(4H)-oxazolone from pBrBz-Ac3c-OH; the dipeptides are H-(Ac3c)-OMe and c(Ac3c)2. The values determined for the torsion angles about the N-C alpha (phi) and C alpha-C' (psi) bonds for the single Ac3c residue of Piv-Ac3c-OH, the alpha- and beta-forms of t-Boc-Ac3-OH and Z-Ac3c-OMe, and the C-terminal Ac3c residue of H-(Ac3c)2-OMe correspond to folded conformations in the "bridge" region of the Ramachandran map. The structures of pBrBz-Ac3c-OH and Z-Ac3c-OH, however, are unusual in having a semi-extended conformation for the phi, psi angles. The N-terminal Ac3c residue of H-(Ac3c)2-OMe adopts a novel type of C5 conformation, characterized inter alia by an (amino) N. . .H-N (peptide) intramolecular hydrogen bond. While the acyl N alpha-blocking groups form trans amides (pBrBz-Ac3c-OH and Piv-Ac3c-OH), the urethane groups may adopt either the trans [Z-Ac3c-OH and t-Boc-Ac3c-OH (alpha-form)] or the cis amide conformations [t-Boc-Ac3c-OH(beta-form) and Z-Ac3c-OMe]. The five- and six-membered rings of the 5(4H)-oxazolone and the 2,5-dioxopiperazine, respectively, are planar. The four independent molecules in the asymmetric unit of the free alpha-amino acid are zwitterionic.

Amino Acids↗
PubMed1988

A computergraphic determination of the chemotactic peptide preferred conformation.

Replacement of leucine in the chemotactic peptide For-Met-Leu-Phe by the sterically constrained amino acids alpha-aminoisobutyric acid and aminocyclohexanecarboxylic acid affords compounds of equal or greater activity than the parent. NMR studies indicate that the parent compound is present as a beta-sheet in solution, whereas the analogues prefer a beta-turn. Application of molecular modelling would indicate that the beta-turn conformer is energetically preferable and thus suggests that it is the orientation adopted by the peptides.

Computer Graphics↗
PubMed1988

Structure of a peptide surrogate, tert-butoxycarbonylalanyl-psi(CH2S)-phenylalanine [Boc-Ala-psi(CH2S)-Phe-OH].

C17H25NO4S, Mr = 339.5, monoclonic, C2 a = 24.927 (8), b = 5.252 (4), c = 16.867 (7) A, beta = 122.70 (1) degree, V = 1858.2 (9) A3, Z = 4, D chi = 1.21 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 1.83 cm-1, F(000) = 728, T = 295 K. The final R value for 1466 independent observed reflections is 0.075. The thiomethylene dipeptide analogue possesses a C alpha i...C alpha i+1 distance somewhat smaller than in the extended amide counterpart due to a partially folded structure, especially in the C-terminal region. Pairs of molecules are held together by O-H...O = C (carboxylic acid) hydrogen bonds.

Dipeptides↗
PubMed1988

Long, chiral polypeptide 3(10)-helices at atomic resolution.

The crystal-state preferred conformation of the terminally blocked hepta- and octapeptides with the general formula -(Aib)n L-Leu-(Aib)2- (n = 4 and 5, respectively), determined by X-ray diffraction, was found to be a right-handed 3(10)-helix stabilized by five and six consecutive intramolecular NH...O = C H-bonds of the C(10)-III type, respectively. The octapeptide structure represents the first observation at atomic resolution of a regular, chiral 3(10)-helix larger than two complete turns. In both cases the right handed screw sense of the helix is dictated by the presence of the single, internal L-residue. This study confirms the propensity of short peptides rich in Aib, the prototype of the amino acid residues dialkylated at the alpha carbon, to adopt a 3(10)-helical structure and is expected to help our understanding of the conformational preferences of the membrane-active, channel-forming, ion-transporting peptaibol antibiotics.

Butyrates↗
PubMed1987

Conformational preferences and self-association modes of two diastereomeric statine derivatives.

The conformational preferences and self-association modes of the two diastereomeric N-acetyl, methylamides of 3-hydroxy, 4-amino, 6-methylheptanoic acid (statine) with (R, S) and (S, S) configurations at the 3-hydroxy and 4-amino carbons, respectively, have been determined in solution as well as in the solid state by infrared absorption, 1H nuclear magnetic resonance, and X-ray diffraction. Conformational energy computations have also been performed in parallel. In the crystal state, the change in chirality of the hydroxyl group induces different intermolecular H-bonding schemes in the (R, S) isomer compared to the two structurally distinct molecules in the asymmetric unit of the (S, S) isomer. Different propensities to self-aggregate are seen in solvents of low polarity. In solvents of high polarity, however, the molecules of both isomers are largely solvated, while still keeping some local conformational restriction. Conformational energy computations indicate that in vacuo the two diastereomers exhibit different flexibility, and a preferred conformation with a different type of intramolecular H-bond.

Amino Acids↗
PubMed1987

Self-association and solubility of peptides. A solvent titration study of the 28-31 segment of corticotropin releasing factor.

Self-association of peptides related to the 28-31 sequence of corticotropin releasing factor in methylene chloride was disrupted by adding a variety of polar organic solvents in increasing amounts. This structural transition was monitored by the disappearance of either the amide-1 C = O stretching band (1635 cm-1) or the amide-A N-H stretching band (3300 cm-1) of strongly intermolecularly H-bonded molecules in the infrared absorption spectra. The effects induced by main-chain length, protection of the C-terminal group, nature of solvent, and peptide concentration were assessed. The increasing propensity to aggregate displayed by these peptides is paralleled by a decrease in their solubility.

Chemical Phenomena↗