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Aroyl hydrazones have been intensively investigated over the last decades due to their various biological properties such as anticancer, antibacterial and antimicrobial effects. Herein, we examine the anti-proliferative effect of two new aroyl hydrazones used in a combination with AVPI- and RGD -- peptides. The anti-proliferative activity is checked by MTT assay after 72h of treatment on MDA-MB-231 breast cancer cells. Though the aroyl hydrazone derivatives used as single agents shows a high activity, the combination is found not beneficial. [ABSTRACT FROM AUTHOR]

One of the potent somatostatin analogs, BIM-23052 (DC-23-99) d-Phe-Phe-Phe-d-Trp-Lys-Thr-Phe-Thr-NH2, has established in vitro growth hormone inhibitory activity in nM concentrations. It is also characterized by high affinity to some somatostatin receptors which are largely distributed in the cell membranes of many tumor cells. Herein, we report the synthesis of a series of analogs of BIM-23052 containing halogenated Phe residues using standard solid-phase peptide method Fmoc/OtBu-strategy. The cytotoxic effects of the compounds were tested in vitro against two human tumor cell lines—breast cancer cell line and hepatocellular cancer cell line, as well as on human non-tumorigenic epithelial cell line. Analogs containing fluoro-phenylalanines are cytotoxic in μM range, as the analog containing Phe (2-F) showed better selectivity against human hepatocellular cancer cell line. The presented study also reveals that accumulation of halogenated Phe residues does not increase the cytotoxicity according to tested cell lines. The calculated selective index reveals different mechanisms of antitumor activity of the parent compound BIM-23052 and target halogenated analogs for examined breast tumor cell lines. All peptides tested have high antitumor activity against the HepG2 cell line (IC50 ≈ 100 μM and SI > 5) compared to breast cells. This is probably due to the high permeability of the cell membrane and the higher metabolic activity of hepatocytes. In silico docking studies confirmed that all obtained analogs bind well with the somatostatin receptors with preference to ssrt3 and ssrt5. All target compounds showed high hydrolytic stability at acid and neutral pH, which mimic physiological condition in stomach and human plasma. [ABSTRACT FROM AUTHOR]

AVPI-(Ala-Val-Pro-Ile) and RGD-(Arg-Gly-Asp) peptides have recently attracted a growing interest in the anticancer drug design and development. Following the concept of combining two fragments with different functionalities in order to achieve increased effects, we present herein the synthesis of two AVPI-RGD peptides. The impact of the performed chemical modifications on the anti-proliferative activity of these peptides was evaluated at MDA-MB-231 cancer cells. It was found that the conjugated peptide with modifications at proline and arginine residues showed a higher anti-proliferative effect than the parent AVPI-RGD molecule. Furthermore, it was observed that the effect of AVHypI-AgbGD vs. that of its co-administrated structural subunits was higher. The results obtained in this work suggested that the introduced substitutions and the conjugation of the two functional motifs benefit the anti-proliferative activity of the parent peptides. [ABSTRACT FROM AUTHOR]

Peptides have been developed during the last decade as an alternative for delivery and targeting of drugs, and for the visualization of tumors. In contrast to the antibodies, the peptides are smaller and can be delivered to the cytoplasm by various mechanisms. RGD peptides have been developed as potent integrin ligands and antagonists that inhibit the adhesion and formation of tumor metastases or directly induce apoptosis by activating caspases. A series of short RGD mimetics and their conjugates are synthesized and their cytotoxic activity against four cancer cell lines is examined. RGD peptides modified by shorter homologues of with arginine (α-amino-4-guanidinobutyric acid (Agb) and α-amino-3-guanidino-propionic acid (Agp)) show an increase of the cytotoxic effect compared to that of the parent RGD peptide. [ABSTRACT FROM AUTHOR]

Myosmine, 3-(1-pyrroline-2-yl) pyridine is a minor tobacco alkaloid that has also been found in various widely used foods. Recently, this phytochemical has been gaining an increasing interest as a potential risk factor for the development of oesophageal adenocarcinoma. This study aimed to examine the effects of myosmine on the cell viability and proliferative activity of erythroleukemia and hepatocellular carcinoma cells and to obtain additional information about the mechanisms underlying its cytotoxic activity. The in vitro cytotoxic effect of myosmine on the HepG2 and MEL tumour cell lines was assessed by MTT dye reduction and trypan blue dye exclusion assays. The alterations in the tumour cell morphology induced by myosmine were analysed by fluorescent microscopy after staining with acridine orange (AO)/ethidium bromide (EtBr) and 4′,6-diamidine-2′-phenylindole dihydrochloride (DAPI). Annexin V-FITC/propidium iodide (PI) staining was used to assess the apoptosis-inducing ability of myosmine. The modulating action of antioxidant treatment on myosmine-induced cytotoxicity against the HepG2 tumour cell line was also examined. The cell viability tests indicated that myosmine induced a significant dose-dependent reduction of the viability and proliferative activity of both tumour cell lines. Fluorescent microscopy studies revealed marked alterations in the morphology of myosmine-treated tumour cells with signs of cell cycle arrest and apoptosis. The results of the simultaneous treatment with myosmine and vitamin C showed modulating activity of vitamin C on the cytotoxic effect of myosmine with concentration- and time-dependent variations. The presented results could contribute to the assessment of the potential health risks associated with the dietary myosmine exposure. Abbreviations AO: acridine orange; DAPI: 4',6-diamidine-2'-phenylindole dihydrochloride; DMEM: Dulbecco's modified Eagle medium; DMSO: dimethyl sulfoxide; EtBr: ethidium bromide; FITC: fluorescein isothiocyanate; GERD: gastroesophageal reflux disease; MEL: murine erythroleukemia; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NNN: N'-nitrosonornicotine; PBS: phosphate buffered saline; PI: propidium iodide [ABSTRACT FROM AUTHOR]

Hydrazones have versatile properties that make them promising for a range of possible applications. In this study, we examined a library of 17 aroylhydrazones derived from nicotinic acid hydrazide (1-12) and isonicotinic acid hydrazide (A-E) created by us for their biological activity. The antiproliferative activity of the compounds was investigated on non-tumour MCF-10A cells and cancer cell lines, MCF-7 and MDA-MB-231. Four compounds were selected as most active in cell growth inhibition of the tumour cell lines. These compounds, 5, 11, C and E, were tested on four additional cell lines: non-tumour BJ and cancer cell lines, HeLa, HepG2 and HT-29. Compounds 5 and E exhibited the highest selectivity index on cancer cell lines MDA-MB-231, HeLa and HepG2. High selectivity to MCF-7 cells was demonstrated with compound 5. Compound C was very selective to HepG2 cells as well as to MDA-MB-231 but to a lesser degree. Compound 11 showed selectivity against MDA-MB-231. The obtained results allow assessing the structure–activity relationship of the compounds and provide insight into the further development of this group of aroylhydrazones as more potent and selective anti-neoplastic agents. [ABSTRACT FROM AUTHOR]

Close functional and anatomical interactions between the neurotensin (NT) and dopamine (DA) systems suggest that NT could be associated with Parkinson's Disease (PD). However, clinical use of NT is limited due to its rapid degradation. This has led to the synthesis of a number of new NT fragment 8-13 [NT(8-13)] analogues, such as NT2 and NT4, to avoid the fast biodegradation of NT. The aim of this study was to investigate the neuroprotective effects of NT2 and NT4 on an experimental model of Parkinson's disease in rats induced with 6-hydroxydopamine (6-OHDA) treatment, producing striatal lesions. Wistar male rats were divided into different groups: a sham-operated (SO) group, a striatal 6-OHDA-lesioned control group, two groups of 6-OHDA-lesioned rats treated for 5 days with NT2 or NT4 (10 mg/kg, intraperitoneally) and a NT-treated group as reference. During the first and second week post lesion the animals were subjected to a number of behavioral tests (apomorphine-induced rotations, rotarod, passive avoidance test), and brain tissue was evaluated histologically and also assessed for DA levels. The results showed that both the number of apomorphine-induced rotations and falls (rotarod test) increased in the 6-OHDA group relative to the SO group. At the same time, the 6-OHDA-treated group showed significant memory impairment, based on the to step-through test, compared to the SO group. Treatment with NT2 and NT4 significantly decreased the number of apomorphine-induced rotations and improved the memory of lesioned animals, with these NT analogues demonstrating better neuroprotective and neuromodulatory effects than NT. DA content in the brain of the PD rats treated with NT2 and NT4 increased, possibly due to attenuation of the loss of DA-ergic neurons. NT2 and NT4 were found to easily penetrate the blood-brain barrier and they showed a better stability than the reference NT neuropeptide. In conclusion, the NT approach represents an attractive strategy for the treatment of neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Melanocyte-inhibiting factor (MIF-1) is the first hypothalamic tripeptide which has been demonstrated to act not only in the brain but also in the pituitary. Tyr-MIF-1 acts as an opiate agonist. It binds selectively and with a high affinity to the μ-opioid receptor when compared with the δ-and κ-opioid receptors. A large number of analogues of MIF-1 and Tyr-MIF-1, containing various modifiers in their structures, have been synthesized and their analgesic effect was determined by various in vivo tests. The aim of current study was: (1) to synthesize new MIF-1 and Tyr-MIF-1 analogues containing sulfoarginine (sArg) and norsulfoarginine (NsArg) in the second and third position, respectively; (2) with the help of docking procedures to find the relationship between structure and biological activity of MIF-1 and Tyr-MIF-1 analogues previously synthesized and biologically tested; (3) using found correlation to predict the biological effect of newly synthesized analogues. New analogues of MIF-1 and Tyr-MIF-1 were synthesized using methods of peptide synthesis in solution. Docking was performed with GOLD 5.0 and a correlation between the obtained docking data and the values from in vivo test was found. Some structure-activity relationships were determined. According to the correlation, we made assumptions about the biological effect of sArg and NsArg containing MIF-1 and Tyr-MIF-1. A computational approach could be very useful in the elucidation of the structure-activity relationship and in the design of new analogues with desired biological effect. [ABSTRACT FROM AUTHOR]

Leu-Arg is a kyotorphin receptor antagonist. It is very important to control antinociception and this could be achieved by modifications in agonist's or antagonist's molecules. Two analogues of Leu-Arg were synthesized, their IR- spectral characteristics were defined, and preliminary docking studies were performed. The results show that new analogues bind receptor thus they could be used for further analysis and their biological activity could be tested in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Kyotorphin (KTP; Tyr-Arg) an endogenous neuropeptide is potently analgesic when delivered directly to CNS. An effort to enhance the potency, enzymatic stability and improving bioavailability of KTP is the modification with unnatural amino acids. The aims of presented study were: (1) To synthesize new analogues of kyotorphin containing unnatural amino acids: norcanavaine (NCav) and norcanaline (NCan), structural analogues of arginine and ornithine, respectively; (2) To understand the influence of the arginine mimetics on the pharmacological properties of KTP analogues, through examination their effects on the paw pressure nociceptive threshold; (3) To find relationship between the structure and obtained biological effects of the all synthesized kyotorhin analogues, by molecular docking with μ-opioid receptor. As a result of our work four new kyotorphin analogues containing NCan and NCav were obtained. A correlation between the data from the in vivo test and docking results was found. This allows a better elucidation of the ligand-receptor interactions, the prediction of biological activity of the newly synthesized compounds, and to generate compounds with increased biological effects. [ABSTRACT FROM AUTHOR]

Arginine residues are very important for the structure of proteins and their action. Arginine is essential for many natural processes because it has unique ionizable group under physiological conditions. Numerous mimetics of arginine were synthesized and their biological effects were evaluated, but the mechanisms of actions are still unknown. The aim of this study is to see if oxy- and sulfoanalogues of arginine can be recognized by human arginyl-tRNA synthetase (HArgS) -- an enzyme responsible for coupling of L-arginine with its cognate tRNA in a two-step catalytic reaction. We make use of modeling and docking studies of adenylate kinase (ADK) to reveal the effects produced by the incorporation of the arginine mimetics on the structure of ADK and its action. Three analogues of arginine, L-canavanine (Cav), L-norcanavanine (NCav), and L-sulfoarginine (sArg), can be recognized as substrates of HArgS when incorporated in different peptide and protein sequences instead of L-arginine. Mutation in the enzyme active center by arginine mimetics leads to conformational changes, which produce a decrease the rate of the enzyme catalyzed reaction and even a loss of enzymatic action. All these observations could explain the long-lasting nature of the effects of the arginine analogues. [ABSTRACT FROM AUTHOR]

Methionine aminopeptidase, known to be encoded by single genes in prokaryotes, is a cobalt-dependent enzyme that catalyzes the removal of N-terminal methionine residues from nascent polypeptides. Three ORFs encoding putative methionine aminopeptidases from the genome of cyanobacterium Synechocystis sp. strain PCC6803, designated as slr0786 (map-1), slr0918 (map-2) and sll0555 (map-3) were cloned and expressed in Escherichia coli. The purified recombinant proteins encoded by map-1 and map-3 had much higher methionine aminopeptidase activity than the recombinant protein encoded by map-2. Comparative analysis revealed that the three recombinant enzymes differed in their substrate specificity, divalent ion requirement, pH, and temperature optima. The broad activities of the iso-enzymes are discussed in light of the structural similarities with other peptidase families and their levels of specificity in the cell. Potential application of cyanobacterial MetAPs in the production of recombinant proteins used in medicine is proposed. This is the first report of a prokaryote harboring multiple methionine aminopeptidases. [ABSTRACT FROM AUTHOR]