Peptides with 6-Aminohexanoic Acid: Synthesis and Evaluation as Plasmin Inhibitors.

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, NH and NH-(CH)-NH.

Antimicrobial peptides and their analogs: searching for new potential therapeutics.

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.

Effect of short peptides containing lysine and epsilon-aminocaproic acid on fibrinolytic activity of plasmin and topoisomerase II action on supercoiled DNA.

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.

Amino and chlorambucil analogues of pentamidine--synthesis and biological examinations.

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.

Tripeptides with non-code amino acids as potential serine proteases inhibitors.

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.

Synthesis and activity of N-sulfonylamides of tripeptides as potential urokinase inhibitors.

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.

Carbocyclic potential DNA minor groove binders and their biological evaluation.

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.

Cytotoxic activity of epsilon-aminocaproylamino acids in breast cancer MCF-7 and fibroblast cell lines.

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.

Analogues of distamycin--synthesis and biological evaluation of new aromatic oligopeptides, potential anticancer agents.

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.

Synthesis and activity of amides of tripeptides as potential urokinase inhibitors.

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.

Synthesis and antibacterial activity of DL-threo-1-(1-methylsulfonylpyrrole-3-yl)-2-difluoroacetamidopropane-1,3-diol.

The three-stage synthesis of a pyrrole analogue of chloramphenicol (5) was described. It is inactive.

Effect of epsilon-aminocaproyl-S-benzyl-L-cysteine on the activity of plasminogen activators.

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.

Synthesis and biological evaluation of distamycin analogues - new potential anticancer agents.

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.

Effects of netropsin and pentamidine amino analogues on the amidolytic activity of plasmin, trypsin and urokinase.

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).

Biological activity of amide derivatives of lysine.

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.

Low molecular peptides as potential inhibitors of plasmin.

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.

Carbocyclic analogues of lexitropsin--DNA affinity and endonuclease inhibition.

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.

Synthesis of alkylamides of dipeptides as potential plasmin inhibitors.

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.

Effect of epsilon-aminocaproylamino acids on fibrin formation.

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.

Aromatic benzotriazole amides--synthesis and biological evaluation.

Four derivatives of benzotriazole-5-carboxylic acid were synthesized as potential UV-light dependent DNA cleaving agent. The effect of these compounds on phiX174 RF1 phage DNA and pBR322 plasmid DNA was investigated with and without UV exposure. It has been found that the two compounds exert the influence on topological forms of DNA.

Effects of epsilon-aminocaproiloaminoacids on the amidolytic activity of tissue plasminogen activator, urokinase and kallikrein.

Effect of three epsilon-aminocaproylaminoacids with a significant antifibrinolytic activity on amidolytic activity of tissue plasminogen activator (t-PA), urokinase and kallikrein was examined. epsilon-Aminocaproyl-S-benzyl)-L-cysteine and epsilon-aminocaproyl-L-norleucine were weak inhibitors of kallikrein. Weak activation of t-PA activity was observed at high concentration of the tested compounds.

The effect of some epsilon-aminocaproic acid derivatives on platelet responses.

epsilon-Aminocaproic acid (EACA) is a synthetic low molecular drug with antifibrinolytic activity. However, treatment with this drug can be incidentally associated with an increased thrombotic tendency. The aim of the present work was to test synthetic EACA derivatives for their antiplatelet activities.

Synthesis and cytotoxic effect of carbocyclic potential minor groove binders.

New carbocyclic potential minor groove binders were synthesised, using 3-nitrobenzoyl chloride and aliphatic alpha,omega-diamines with three, four and five methylene fragments. The half structures, compounds IV-VI can be compared to bis-amidines, compounds X-XII to bis-netropsin. All of the compounds were investigated antiproliferative and cytotoxic effects in the standard cell line of mammalian tumour MCF-7.

Aromatic analogues of DNA minor groove binders--synthesis and biological evaluation.

Nine carbocyclic analogues of mono- and bis-lexitropsins and two analogues of pentamidine with unsubstituted N-terminal amine group were synthesized. We have investigated the cytotoxic activity of new aromatic analogues of DNA binding ligands in MCF-7 breast cancer cells and assessed their ability to act as inhibitors of topoisomerase I and II. These studies indicate that aromatic analogues of bis-netropsin contain two identical units tethered by alkyloxyl chains are a potent catalytic inhibitor of both topoisomerases and exhibit moderate cytotoxicity in MCF-7 breast cancer cells.