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1.
Int J Pept Res Ther ; 23(2): 235-245, 2017.
Article in English | MEDLINE | ID: mdl-28491013

ABSTRACT

Fifteen new peptide derivatives of ɛ-aminocaproic acid (EACA) containing the known fragment -Ala-Phe-Lys- with an affinity for plasmin were synthesised in the present study. The synthesis was carried out a solid phase. The following compounds were synthesised: H-Phe-Lys-EACA-X, H-d-Ala-Phe-Lys-EACA-X, H-Ala-Phe-Lys-EACA-X, H-d-Ala-Phe-EACA-X and H-Ala-Phe-EACA-X, where X = OH, NH2 and NH-(CH2)5-NH2. All peptides, except for those containing the sequence H-Ala-Phe-EACA-X, displayed higher inhibitory activity against plasmin than EACA. The most active and selective inhibitor of plasmin was the compound H-d-Ala-Phe-Lys-EACA-NH2 which inhibited the amidolytic activity of plasmin (IC50 = 0.02 mM), with the antifibrinolytic activity weaker than EACA. The resulting peptides did not affect the viability of fibroblast cells, colon cancer cell line DLD-1, breast MCF-7 and MDA-MB-231 cell lines.

2.
Perspect Medicin Chem ; 6: 73-80, 2014.
Article in English | MEDLINE | ID: mdl-25374459

ABSTRACT

Antimicrobial peptides (AMPs) are an essential part of innate immunity. These compounds have been considered as potential therapeutics because of their broad-spectrum activities and proven ability to avoid antimicrobial resistance, but their clinical and commercial developments have some limitations, such as susceptibility to proteases and a high cost of peptide production. To overcome these problems, many researchers have tried to develop short active peptides, their modifications and mimics with better properties while retaining their basic features of natural AMPs such as cationic charge and the amphipathic structure.

3.
Acta Pol Pharm ; 70(3): 431-4, 2013.
Article in English | MEDLINE | ID: mdl-23757933

ABSTRACT

Effects of eight short peptides containing lysine and epsilon-aminocaproic acid (EACA) on prolongation of the clot lysis time, as well as hemolytic and antibacterial activities were investigated. Interaction with plasmids pBR322 and pUC19 with the use of ethidium bromide assay and determination of influence on the activity of topoisomerase I and II were also tested. Examined compounds inhibited fibrinolytic activity of plasmin and five of them were more active than EACA. Amides of dipeptides were most active antifibrinolytics (IC50 < 0.2 mM). According to the obtained data, the significant inhibition of fibrinolytic activity of plasmin was not associated with hemolytic effects. Examined compounds did not show antibacterial activity (MIC > 512 mg/L). DNA binding effects determined with the use of ethidium bromide were weak for all peptides and similar to those observed with EACA. Six compounds inhibited topoisomerase II action on supercoiled DNA.


Subject(s)
Aminocaproic Acid/pharmacology , Antifibrinolytic Agents/pharmacology , DNA, Superhelical/metabolism , Fibrinolysin/antagonists & inhibitors , Lysine/pharmacology , Peptides/pharmacology , Topoisomerase II Inhibitors/pharmacology , Anti-Bacterial Agents/pharmacology , Hemolysis/drug effects
4.
J Enzyme Inhib Med Chem ; 28(3): 639-43, 2013 Jun.
Article in English | MEDLINE | ID: mdl-22299583

ABSTRACT

Eight peptides of the general H-D-Ser-AA-Arg-OH formula, where AA = phenylglycine, phenylalanine, homophenylalanine, cyclohexylglycine, cyclohexylalanine, homocyclohexylalanine, α-methylphenylalanine and 1-aminocyclohexyl carboxylic acid were obtained and tested for their effect on the amidolytic activities of urokinase, thrombin, trypsin, plasmin, t-PA and kallikrein. We tested the hemolytic activity of the peptides against porcine erythrocytes and the antitumor activity against the human breast cancer cells, standard MCF-7 and estrogen-independent MDA-MB-231. The most active compounds were H-D-Ser-Chg-Arg-OH towards thrombin and H-D-Ser-Phg-Arg-OH towards plasmin with K(i) value 5.02 µM and 5.7 µM, respectively.


Subject(s)
Oligopeptides/chemistry , Oligopeptides/pharmacology , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Erythrocytes/drug effects , Female , Fibrinolysin/antagonists & inhibitors , Humans , Kallikreins/antagonists & inhibitors , Swine , Thrombin/antagonists & inhibitors , Tissue Plasminogen Activator/antagonists & inhibitors , Trypsin Inhibitors/chemistry , Trypsin Inhibitors/pharmacology , Urokinase-Type Plasminogen Activator/antagonists & inhibitors
5.
Acta Pol Pharm ; 69(1): 63-73, 2012.
Article in English | MEDLINE | ID: mdl-22574508

ABSTRACT

The amino analogues of pentamidine with a polymethylene (n = 3 - 6) chain and their chlorambucil derivatives were synthesized. The obtained compounds revealed cytotoxic effect on MCF-7 human breast cancer cell line (IC50 = 22 - 95 +/- 2 pM), mainly by the induction of apoptosis. The topoisomerase I/II inhibition assay and the ethidium displacement assay with the use of pBR322 plasmid DNA were used to the study of mechanism by which the obtained compounds could act. All the compounds are able to bind with DNA and interfere in vitro with the activity of topoisomerase (I and II). The determination of association constants with the use of calf thymus DNA, T4 coliphage DNA, poly(dA-dT)2 and poly(dG-dC)2 showed that the tested compounds bind within minor groove of B-DNA, but not selectively. The alkylating activity of chlorambucil derivatives determined in vitro using a Preussmann test was similar to the activity of chlorambucil. The influence of all the compounds on the amidolytic activity of plasmin and trypsin was also examined. The plasmin activity was inhibited by pentamidine, chlorambucil and aromatic bis-amines (IC50 = 0.1 - 8 mM), whereas the trypsin activity was influenced only by pentamidine.


Subject(s)
Antifibrinolytic Agents , Antineoplastic Agents, Alkylating , Chlorambucil , Pentamidine , Topoisomerase I Inhibitors , Topoisomerase II Inhibitors , Trypsin Inhibitors , Antifibrinolytic Agents/chemical synthesis , Antifibrinolytic Agents/pharmacology , Antineoplastic Agents, Alkylating/chemical synthesis , Antineoplastic Agents, Alkylating/pharmacology , Apoptosis/drug effects , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Chlorambucil/analogs & derivatives , Chlorambucil/chemical synthesis , Chlorambucil/pharmacology , DNA/drug effects , DNA/metabolism , Dose-Response Relationship, Drug , Female , Humans , Inhibitory Concentration 50 , Molecular Structure , Pentamidine/analogs & derivatives , Pentamidine/chemical synthesis , Pentamidine/pharmacology , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/pharmacology , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/pharmacology
6.
Protein Pept Lett ; 17(10): 1300-4, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20594155

ABSTRACT

Twelve peptides of the general X-SO(2)-D-Ser-Ala-Arg-OH formula (where X = methyl, phenyl, α-tolyl, p-tolyl, 4-methylbenzyl, 1-naphtyl, 2-naphtyl, 4-chlorophenyl, 4-bromophenyl, 2-mesityl, 2,4,6-triisopropylphenyl, 4-acetamidophenyl) were obtained and tested for their effect on the amidolytic activities of urokinase, thrombin, trypsin, plasmin, t-PA and kallikrein. 2,4,6-triisopropylphenyl-SO(2)-D-Ser-Ala-Arg-OH was the most selective inhibitor of urokinase and α-tolyl-SO(2)-D-Ser-Ala-Arg-OH was the most active inhibitor of uPA with K(i) value 24 µM. The compounds were tested for their in vitro antitumour activity in the following human breast cancer cells: standard MCF-7 and estrogen-independent MDA-MB-231. Four of the synthesized peptides showed cytotoxic effects against MDA-MB-231 cell lines in the range from 2.9 to 8.5 µM. The examined compound did not influence to MCF-7 cancer cells. The synthesized peptides were nontoxic to pig's erythrocytes.


Subject(s)
Blood Proteins/chemical synthesis , Blood Proteins/pharmacology , Erythrocytes/drug effects , Peptides/chemical synthesis , Peptides/pharmacology , Amides/chemical synthesis , Amides/chemistry , Animals , Blood Proteins/chemistry , Breast Neoplasms/drug therapy , Cell Line, Tumor , Female , Humans , Peptides/chemistry , Sulfur , Swine
7.
J Enzyme Inhib Med Chem ; 25(5): 629-34, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20429779

ABSTRACT

The biological evaluation of carbocyclic minor groove binders 1-6 is described. The cytotoxicity of the obtained compounds was tested on MDA-MB-231 breast cancer cells. The mechanism of action of compounds 1-6 was studied employing the topoisomerase I/II inhibition assay and ethidium displacement assay using pBR322. Determination of association constants was done using calf thymus DNA, T4 coliphage DNA, poly(dA-dT)(2), and poly(dG-dC)(2). The effect of compounds 1-6 on the amidolytic activity of plasmin, trypsin, thrombin, and urokinase was also examined.


Subject(s)
Aniline Compounds/metabolism , Aniline Compounds/pharmacology , Benzamides/metabolism , Benzamides/pharmacology , DNA/metabolism , Serine Proteinase Inhibitors/metabolism , Serine Proteinase Inhibitors/pharmacology , Topoisomerase I Inhibitors/metabolism , Topoisomerase I Inhibitors/pharmacology , Topoisomerase II Inhibitors/metabolism , Topoisomerase II Inhibitors/pharmacology , Bacteriophage T4 , Binding, Competitive , Cell Line, Tumor , Cell Proliferation/drug effects , DNA, Superhelical/metabolism , DNA, Viral/metabolism , Drug Design , Ethidium/metabolism , Humans , Inhibitory Concentration 50 , Kinetics , Plasmids , Polydeoxyribonucleotides/metabolism
8.
Acta Pol Pharm ; 67(2): 201-4, 2010.
Article in English | MEDLINE | ID: mdl-20369798

ABSTRACT

The effect of H-EACA-L-Cys(S-Bzl)-OH, H-EACA-L-Leu-OH, H-EACA-L-Nle-OH and EACA on the viability of MCF-7 and fibroblast cells was examined. The antibacterial activity of these compounds was also tested. H-EACA-L-Leu-OH and H-EACA-L-Nle-OH showed cytotoxic activity against MCF-7 and fibroblast cell lines, particularly in the highest studied 20 mM concentration. None of the examined dipeptides showed antibacterial activity.


Subject(s)
Aminocaproic Acid/pharmacology , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Fibroblasts/drug effects , Antifibrinolytic Agents/pharmacology , Breast Neoplasms/pathology , Cell Line , Female , Humans
9.
J Enzyme Inhib Med Chem ; 25(1): 139-42, 2010 Feb.
Article in English | MEDLINE | ID: mdl-20030517

ABSTRACT

Eleven peptides of the general formula H-d-Ser-Ala-Arg-NH-X, where X = (CH2)n-NH2, n = 2-9, (CH2)m-OH, m = 2-4, were obtained and tested for their effect on the amidolytic activities of urokinase, thrombin, trypsin, plasmin, t-PA, and kallikrein. H-D-Ser-Ala-Arg-NH-(CH2)5-NH2 inhibited urokinase with a Ki value of 6.3 microM.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Urokinase-Type Plasminogen Activator/antagonists & inhibitors
10.
Acta Pol Pharm ; 66(1): 37-40, 2009.
Article in English | MEDLINE | ID: mdl-19226966

ABSTRACT

The effect of epsilon-aminocaproyl-S-benzyl-L-cysteine on the activation of plasminogen by t-PA. streptokinase and urokinase has been examined using fibrinolytic method. The obtained results have been compared with the obtained results for epsilon-aminocaproic acid and trans-4-(aminomethyl)cyclohexanecarboxylic acid. The inhibition of the plasminogen activation determined with the use of epsilon-aminocaproyl-S-benzyl-L-cysteine was weaker than the inhibition determined by using antifibrinolytic aminoacids.


Subject(s)
Aminocaproates , Antifibrinolytic Agents/pharmacology , Cysteine/analogs & derivatives , Fibrinolytic Agents/pharmacology , Plasminogen/drug effects , Aminocaproic Acid/pharmacology , Cysteine/pharmacology , Plasminogen/metabolism , Streptokinase/pharmacology , Tissue Plasminogen Activator/pharmacology , Tranexamic Acid/pharmacology , Urokinase-Type Plasminogen Activator/pharmacology
12.
Arch Pharm (Weinheim) ; 342(2): 87-93, 2009 Feb.
Article in English | MEDLINE | ID: mdl-19173336

ABSTRACT

Eight of analogues of distamycin, potential minor-groove binders, were synthesized and tested for in-vitro cytotoxicity towards human breast cancer cells MCF-7 and MDA-MB-231. The method of synthesis is simple and convenient. All of the compounds 1-8 showed antiproliferative and cytotoxic effects against both cell lines in the range 3.47 to 12.53 microM for MDA-MB-231 and 4.35 to 12.66 microM for MCF-7. All compounds demonstrated activity against DNA topoisomerases I and II at a concentration of 50 microM. The ethidium bromide assay showed that these compounds bind to plasmid pBR322, yet weaker than distamycin. Further investigations concerning the mechanism of cytotoxicity are now in progress, but the IC(50) values suggest that synthetic distamycin analogues with a free amino group, 3-4 and 7-8, can serve as potential carriers of strong acting elements, e. g. alkylating groups.


Subject(s)
Antineoplastic Agents/chemical synthesis , Distamycins/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Distamycins/chemistry , Distamycins/pharmacology , Dose-Response Relationship, Drug , Humans , Molecular Structure , Structure-Activity Relationship , Topoisomerase I Inhibitors , Topoisomerase II Inhibitors
13.
Acta Pol Pharm ; 66(6): 633-8, 2009.
Article in English | MEDLINE | ID: mdl-20050527

ABSTRACT

Six new aromatic oligopeptides were synthesized and evaluated for their activity in the standard cell line of the mammalian tumor MCF-7 as well as in a cell-free system employing the topoisomerase I/II inhibition assay.


Subject(s)
Antineoplastic Agents/chemical synthesis , Distamycins/chemical synthesis , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Distamycins/pharmacology , Humans , Topoisomerase Inhibitors
14.
Acta Pol Pharm ; 65(2): 213-5, 2008.
Article in English | MEDLINE | ID: mdl-18666427

ABSTRACT

Inhibitory effects of nine carbocyclic DNA minor groove binders on amidolytic activities of plasmin, trypsin and urokinase were examined. Some of the studied compounds affected plasmin or trypsin activity, but not urokinase activity. One of the pentamidine analogues (5) and two bis-netropsin like compounds (6, 8) were potent inhibitors of plasmin (IC50 equals 90 and 100 microM), whereas an analogue of netropsin (2) was trypsin inhibitor (IC50 = 100 microM).


Subject(s)
Amines/pharmacology , Fibrinolysin/antagonists & inhibitors , Netropsin/analogs & derivatives , Pentamidine/analogs & derivatives , Trypsin Inhibitors/pharmacology , Urokinase-Type Plasminogen Activator/antagonists & inhibitors , Netropsin/pharmacology , Pentamidine/pharmacology , Structure-Activity Relationship
15.
Acta Pol Pharm ; 65(3): 377-81, 2008.
Article in English | MEDLINE | ID: mdl-18646558

ABSTRACT

Five substituted amides of lysine with the general formula: X-Lys-NH-Y, where X= acetyl or ethoxycarbonyl, Y= cyclohexyl, benzyl, hexyl or cadaverine residue were synthesised and their effects on fibrinolytic activity of plasmin, clotting activity of thrombin and amidolytic activities of both enzymes were examined.


Subject(s)
Amides/chemical synthesis , Fibrinolysin/antagonists & inhibitors , Lysine/analogs & derivatives , Thrombin/antagonists & inhibitors , Amides/pharmacology , Blood Coagulation/drug effects , Blood Coagulation/physiology , Fibrinolysis/drug effects , Fibrinolysis/physiology , Lysine/pharmacology , Structure-Activity Relationship
16.
Acta Pol Pharm ; 64(2): 115-9, 2007.
Article in English | MEDLINE | ID: mdl-17665860

ABSTRACT

A DNA-binding affinity and the effect on restriction enzymes activity of seven carbocyclic mono- and bis-lexitropsins and two analogues of pentamidine with unsubstituted N-terminal amine group were investigated. DNA association constants (Kapp) show that DNA affinity of mono-compounds is much weaker than netropsin and distamycin. Bis-analogues of netropsin bind DNA more strongly than mono-ligands, but without sequence-selectivity. Only pentamidine derivatives reveal preference to AT-rich sequence. The studied compounds can inhibit catalytical action of endonucleases recognizing sequence of four AT base pairs following one another.


Subject(s)
Acids, Carbocyclic/chemistry , DNA/chemistry , Endonucleases/metabolism , Netropsin/analogs & derivatives , Binding Sites/genetics , Binding, Competitive , Bisbenzimidazole/chemistry , DNA/genetics , DNA/metabolism , Distamycins/chemistry , Endonucleases/antagonists & inhibitors , Molecular Structure , Netropsin/chemistry , Netropsin/metabolism , Netropsin/pharmacology , Pentamidine/analogs & derivatives , Pentamidine/chemistry , Pentamidine/metabolism , Structure-Activity Relationship
17.
Acta Pol Pharm ; 64(4): 355-8, 2007.
Article in English | MEDLINE | ID: mdl-18536161

ABSTRACT

Ten peptides of the general formula A-Phe-Lys-X where A = H, H-D-Val, H-L-Val, H-D-Ala, H-L-Ala and X = OH, NH2 were obtained and tested for their antiplasmin activity with the use of amidolytic test.


Subject(s)
Fibrinolysin/antagonists & inhibitors , Peptides/pharmacology , Inhibitory Concentration 50 , Peptides/administration & dosage , Peptides/chemistry , Structure-Activity Relationship
19.
Acta Pol Pharm ; 63(2): 149-52, 2006.
Article in English | MEDLINE | ID: mdl-17514879

ABSTRACT

Effect of three epsilon-aminocaproylamino acids with significant antifibrinolytic activity on polymerization of fibrin monomer, clot retraction, fibrin structure, prothrombin consumption and thrombin activity was examined. epsilon-Aminocaproyl-L-norleucine and epsilon-aminocaproyl-L-leucine were weak inhibitors of thrombin activity and epsilon-aminocaproyl-L-norleucine slightly inhibited polymerization of fibrin monomers.


Subject(s)
Aminocaproic Acid/chemistry , Fibrin/chemistry , Aminocaproic Acid/pharmacology , Antifibrinolytic Agents/chemistry , Antifibrinolytic Agents/pharmacology , Blood Coagulation/drug effects , Dose-Response Relationship, Drug , Fibrinolysis/drug effects , Humans , Whole Blood Coagulation Time
20.
Acta Pol Pharm ; 63(1): 33-7, 2006.
Article in English | MEDLINE | ID: mdl-17515327

ABSTRACT

Four dipeptide alkylamides with general formula H-D-Phe-L-Lys-NH-X, where X = cyclohexyl, - (CH2)5NH2, -(CH2)2-OH and hexyl were obtained. Effect of these compounds on amidolytic and fibrinolytic activity of plasmin was examined.


Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Fibrinolysin/antagonists & inhibitors , Lysine/chemistry , Magnetic Resonance Spectroscopy , Structure-Activity Relationship , Thrombin/antagonists & inhibitors
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