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1

Synthesis of HYNIC- and DOTA-Conjugates with mi-Opioid Receptor Ligands: Morphiceptin and Endomorphin-2

Fichna J., Janecka A., Kosson P., Maecke H.

Polish Journal of Chemistry

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2004

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Vol. 78 / nr 7

951-959

EN

Opioid peptides recently attracted much attention as low molecular weight compounds, which can target malignant cells expressing opioid receptors on their cell surface. Therefore opioid peptides have a potential to be introduced as radiopharmaceuticals. In this paper, we describe the method of conjugation of two bifunctional chelating agents (BFCAs), hydrazinopyridine-3-carboxylic acid (HYNIC) and 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid (DOTA), to the N-terminal amino group of morphiceptin, endomorphin-2, and two of their analogs modified in position 3. GABA was used as a spacer molecule. mi-Opioid binding affinities of the peptides were compared with the binding affinities of BFCA-GABA-peptide conjugates. It was shown that the introduction of HYNIC to mi-opioid ligands causes only a slight decrease of -opioid receptor affinity, while DOTA-conjugates loose their affinity for mi-receptors completely.

2

Statherin SV2 and Its Analogue. Synthesis and Evaluation of Antimicrobial Activity

Kamysz W., Kochańska B., Kędzia A., Ochocińska J., Maćkiewicz Z., Kupryszewski G.

Polish Journal of Chemistry

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2002

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Vol. 76 / nr 6

801-806

EN

Statherins are natural peptides derived from human saliva. They may take part in transport of calcium and phosphate and most probably are partly responsible for protection and recalcification of tooth enamel. The solid phase synthesis of statherin SV2 and its dephosphorylated analogue, their purification by solid phase extraction (SPE), as well as the evaluation of their antibacterial activity are presented.

3

Analogues of Ecballium elaterium Trypsin Inhibitor II (EETI-II) with L-Cysteine Residues Substituted by L-Penicillamine (Pen) and L-Homocysteine (Hcy) in Positions 19, 21 and 27

Frąszczak P., Kaźmierczak K., Stawikowski M., Jaśkiewicz A., Kupryszewski G., Rolka K.

Polish Journal of Chemistry

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2002

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Vol. 76 / nr 10

1441-1446

EN

Two analogues of peptidic trypsin inhibitor isolated from seeds of Ecballium elaterium (EETI-II): [Pen19,21,27] EETI-II (1) and [Hcy19,21,27] EETI-II (2) were synthesized by the solid-phase method using the Fmoc/But procedure. Their inhibitory activity was determined by the calculation of association equilibrium constants (Ka) with bovine _-trypsin. In comparison with the parent compound, both analogues showed reduced trypsin inhibitory activity more than 7 and 18 times, respectively. We postulate that the observed differences may reflect the role of disulfide bridges in the interaction of inhibitors with trypsin or the introduced modifications change the conformational equilibrium of the analogues synthesized towards conformation(s) less favorable for the interaction with the enzyme.

4

Synthesis and Biological Activity of New Octapeptide Analogues of Somatostatin with N-Terminal Modifications

Janecka A., Zubrzycka M.

Polish Journal of Chemistry

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2001

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Vol. 75, nr 12

1877-1880

EN

Five new octapeptide analogues of somatostatin, based on RC-160, D-Phe-c(Cys-Tyr-D-Trp-Lys-Val-Cys)-Thr-NH2, containing N-terminal modifications have been syn-thesized. N-terminal, exocyclic D-Phe was replaced by aromatic unnatural amino acids: D-Nal, D-3(2-naphthyl)alanine; D-Pal, D-3-(3-pyridyI)aIanine; D-Qal, D-3-(3-quino-lyl)alanine; D-Cl-Phe, D-3-(4-chIorophenyl)alanine, and D-Cl2-Phe, D-3-(3,4-dichIoro-phenyl)alanine. The inhibitory effect of these new analogues on growth hormone (GH) release in rats was measured. It was found that the analogues with bicyclic D-Nal and D-Qal were less potent than RC-160 in inhibiting GH release in vivo, while all the analogs with aromatic, monocyclic amino acids in position l were morę potent than RC-160. The best results were obtained for the analogue containing hydrophilic D-Pal in position 1. This analogue was 8.4 times more potent than RC-160.

5

Cyclic Analogue of Human Heat Shock Protein 70(29-42) Fragment. Synthesis, Conformational Studies and Evaluation of Its Immunogenicity

Karawajczyk B., Wirkus-Romanowska I., Wysocki J., Rolka K., Maćkiewicz Z., Głośnicka R., Kupryszewski G.

Polish Journal of Chemistry

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2001

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Vol. 75, nr 2

265-273

EN

The cyclic hexadecapeptide containing human heat shock protein 70(29-42) fragment cyclized by the disulfide bridge between two L-cysteine residues introduced at the N- and C-termini was synthesized by the solid phase method. It was established that the cyclic analogue, contrary to its linear counterpart, had much lower ability to generate immune response in rabbits. Conformational studies of cyclic peptide performed using 1D and 2D 1H-NMR spectroscopy in conjunction with theoretical conformational analysis revealed that the cyclization constrained the 3D structure of this peptide, reflected by the observed rate of cis/trans isomerization of Arg9-Thr10 peptide bond and the presence of Gly7-Asn8 peptide bond in cis geometry.We, therefore, postulate that the conformational flexibility in the case of Human Heat Shock Protein fragments is a key element for their immunogenicity.

6

New Analogues of Proline-Rich Protein Fragments : Synthesis and Their Effect on Resistance of Murine Thymocytes to Hydrocortisone

Wirkus-Romanowska I., Miecznikowska H., Janusz M., Szymaniec S., Fortuna W., Międzybrodzki R., Zablocka M., Lisowski J., Kupryszewski G.

Polish Journal of Chemistry

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2000

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Vol. 74, nr 7

979-984

EN

New analogues of proline-rich protein (PRP) fragment were synthezed by the solid phase method using Boc/Bzl procedure. Dimer of the nonapeptide as well as dimer, trimer and tetramer of hexapeptide fragments of PRP possesing immunotropic activity were obtained.

7

Fragments of a Proline-Rich Polypeptide Settled on a Hexapeptide Carcass Constructed of Glycine and L-Lysine Residues : Synthesis and Biological Properties

Wirkus-Romanowska I., Miecznikowska H., Zablocka M., Rybka K., Fortuna W., Międzybrodzki R., Szymaniec S., Janusz M., Lisowski J., Kupryszewski G.

Polish Journal of Chemistry

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2000

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Vol. 74, nr 2

219-225

EN

Proline-rich polypeptide fragments settled on a hexapeptide constructed od L-lysine and glycine residues were synthesized by the solid phase method: X-Lys(X)-Gly-Lys(X)-Gly-Lys(X)-Gly-OH, X= Tyr-Val-Pro-Leu-Phe-Pro and Y-Lys(Y)-Gly-Lys(Y)-Gly-Lys(Y)-Gly-OH, Y=Val-Glu-Ser-Tyr-Val-Pro-Leu-Phe-Pro. Imunotropic activity of the analogues was determined in a murine syste using resistance to hydrocortisone and in human cell cultures using induction of cytokines as indicators.

8

Synthesis of human heat shock protein 70 (29-42) fragment and evaluation of its immunogenicity

Karawajczyk B., Wysocki J., Kunikowska D., Maćkiewicz Z., Głośnicka R., Korzeniowski A., Górski J., Kupryszewski G.

Polish Journal of Chemistry

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1998

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Vol. 72, nr 6

1017-1020

EN

The 29-42 fragment of human heat shock protein 70 (hsp 70) was synthesized by the solid phase method. As determined by enzyme-linked immunosorbent assay (ELISA), the synthetic hsp 70(29-42) peptide generated relatively strong immune response in immunized rabbits. Antibody titers were comparable with anti hsp 70 antibody serum level that was induced by immunization with recombinant protein (hsp 70). It was established that antibodies directed against hsp 70(29-42) peptide could be applied in ELISA for detecting hsp 70 in body fluids and tissues.

9

Synthesis of flagellin fragments and studies of their interactions with antibodies. Part 1

Klugmann K., Kunikowska D., Głośnicka R., Maćkiewcz Z.

Polish Journal of Chemistry

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1998

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Vol. 72, nr 9

2093-2097

EN

Three polypeptide fragments of flagellin protein were synthesized using the solid-phase method. The immunogenicity of the peptides was tested. All the peptides exhibit high immunonological activity.

10

Statherin and its shortened analogues

Wojciechowska I., Kochańska B., Stelmańska E., Knap N., Maćkiewicz Z., Kupryszewski G.

Polish Journal of Chemistry

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1998

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Vol. 72, nr 9

2098-2102

EN

Statherin is a 43-amino acid residue phosphominiprotein present in human parotid and submandibular saliva. It may take part in transport of calcium and phosphate and most probably is partly responsible for the protection and recalcification of tooth enamel. The solid phase synthesis of statherin and its three shorttened analoques: (1-15)statherin, [Ser(2), Ser(3)](1-15) statherin and [Asp(2), Asp(3)](1-15) statherin is presented. It was established that polyclonal antibodies directed against three shortened analoques showed affinity to synthetic statherin and statherin in saliva.

11

Cyclic analogues of proline-rich protein fragments. Part 1. Synthesis and evaluation of immunotropic activity

Wirkus-Romanowska I., Ciurak M., Miecznikowska H., Rolka K., Janusz M., Szymaniec S., Krukowska K., Lisowski J., Kupryszewski G.

Polish Journal of Chemistry

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1998

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Vol. 72, nr 11

2394-2398

EN

Proline-rich protein (PRP), isolated from ovine colostrum, possesses strong immunotropic activity. The nonapeptide (Val-Glu-Ser-Tyr-Val-Pro-Leu-Phe-Pro) and the hexapeptide (Tyr-Val-Pro-Leu-Phe-Pro) PRP fragments reveled biological activity similar to that of the native protein. Seeking for analogues of PRP fragments with costrained structure, two cyclic peptides were synthesized by the solid phase method: Cys-Val-Glu-Ser-Tyr-Val-Pro-Leu-Phe-Pro-Cys and Ac-Glu-Tyr-Val-Pro-Leu-Phe-Pro-Lys-NH2. Immunotropic activity of both peptides in murine system was the same as for linear nonapeptide, whereas all three peptides were practically inactive in human system, where resistance to hydrocortisone and induction of two cytokinins IFN and TNF were used as indicators, respectively.

12

Analogue of Cucurbita maxima trypsin inhibitor III (CMTI-III) with AII L-cysteine residues substituted by L-penicillamine (Pen). Synthesis and evaluation of trypsin inhibitory activity

Jaśkiewicz A., Lesner A., Różycki J., Kupryszewski G., Rolka K.

Polish Journal of Chemistry

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1998

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Vol. 72, nr 12

2537-2540

EN

A 29-peptide, [ Pen(3,10,16,20,22,28) ] CMTI-III, an analogue of Cucurbita maxima trypsin inhibitor from squash seeds was synthesized by the solid phase method using the Fmoc chemistry. The inhibitory activity of the analogue, as measured by the association equilibrium constant (K-a) with bovine beta-trypsin, is of the same order of magnitude as that for the wild CMTI-III.