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The ultrastructure of Phanerochaete chrysosporium hyphae from pellets in submerged liquid cultures was investigated in order to learn more about the interrelation between fungal architecture and manganese peroxidase (MnP) production. At day 2 of cultivation, some subapical regions of hyphae in the outer and middle zones of the pellet initiated differentiation into intercalary thick-walled chlamydospore-like cells of about 10 [micro]m diameter. At the periphery of the cytoplasm of these cells, a large number of mitochondria and Golgi-like vesicles were observed. The sites of MnP production were Iocalized at different stages of cultivation by an immunolabelling procedure. The immunomarker of MnP was mainly concentrated in the chlamydospore-like cells and principally distributed in Golgi-like vesicles Iocated at the periphery of the cytoplasm. The apices of hyphae in the outer layer of the pellets were apparently minor sites of MnP production. Maximal MnP release into the culture supernatant coincided with apparent autolysis of the chlamydospore-like cells. Production of extracellular autolytic chitinase and protease coincided with the disappearance of these structures from the pellets. The chlamydospore-like cells observed in the mycelial pellets of P. chrysosporium could be metabolically active entities operating as an enzyme reservoir, delivering their content into the surrounding medium possibly by an enzyme-mediated autolytic process.

Protoplast formation, stabilization and regeneration was improved for 4 strains (erythromycin producers) of Saccharopolyspora erythraea. A modified medium was developed for protoplast regeneration. Parental and protoplast-regenerated strains exhibited changes in morphology, ultrastructure, and antibiotic production. [ABSTRACT FROM AUTHOR]

Noise can be defined as an undesirable sound that pollutes the environment. If noise is continuous and exceeds certain levels, negative effects on health can be observed. In recent years, the impact of environmental noise (road traffic noise, railway traffic noise, air traffic noise and industrial noise) on human health has come under increasingly intense scrutiny. Noise can cause a number of negative effects on health that directly or indirectly affect humans. The occurrence of some certain and harmful health effects drives the onset of others and may contribute to the development of various diseases. Health is not only a state of physical well-being, but also mental well-being. Mental health primarily depends on the quality of life, which can be affected by various environmental factors, such as noise. An important aspect of fighting noise is the most effective protection of the population by avoiding sources of noise and reducing it. This can be achieved by introducing new technical solutions and new technologies, including devices that generate less noise. Another important measure is educating the society and influencing the change of individual and collective behavior, which may contribute to reducing the harmful factor, which is noise in human life, and minimize the resulting negative effects on health., Competing Interests: The authors declare no conflict of interest, (© Copyright by the National Institute of Public Health - National Institute of Hygiene.)

Cancers are the leading cause of deaths worldwide. In 2018, an estimated 18.1 million new cancer cases and 9.6 million cancer-related deaths occurred globally. Several previous studies have shown that the enzyme, leucine aminopeptidase is involved in pathological conditions such as cancer. On the basis of the knowledge that isoquinoline alkaloids have antiproliferative activity and inhibitory activity towards leucine aminopeptidase, the present study was conducted a study which involved database search, virtual screening, and design of new potential leucine aminopeptidase inhibitors with a scaffold based on 3,4-dihydroisoquinoline. These compounds were then filtered through Lipinski's "rule of five," and 25 081 of them were then subjected to molecular docking. Next, three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed for the selected group of compounds with the best binding score results. The developed model, calculated by leave-one-out method, showed acceptable predictive and descriptive capability as represented by standard statistical parameters r 2 (0.997) and q 2 (0.717). Further, 35 compounds were identified to have an excellent predictive reliability. Finally, nine selected compounds were evaluated for drug-likeness and different pharmacokinetics parameters such as absorption, distribution, metabolism, excretion, and toxicity. Our methodology suggested that compounds with 3,4-dihydroisoquinoline moiety were potentially active in inhibiting leucine aminopeptidase and could be used for further in-depth in vitro and in vivo studies.

Radiofrequency electromagnetic radiation emitted from Wi-Fi devices is nonionizing radiation. The frequencies used in wireless technology are similar to those applied in mobile telephony. Due to the much lower output power of devices using Wi-Fi compared to mobile phones, the degree of exposure to radiation is also lower. Most of the research on Wi-Fi has been carried out in less favorable or adverse conditions, involving higher power values of devices (peak values instead of average values) and smaller distances of working devices from measuring points. None of the studies conducted so far have indicated that there were the exceedances of the permissible values of radiofrequency electromagnetic radiation contained in the Polish and global legal regulations. Similar to the research related to the impact of mobile telephony on human health, the studies conducted until now focusing on exposure to Wi-Fi are considered ambiguous as they do not give a definitive answer on the possible negative (including carcinogenic) effects on human health. Because of the continuous development of wireless networks, there is a need for further research on this topic. Moreover, due to the high popularity of devices using Wi-Fi among children and adolescents, whose period of exposure to electromagnetic radiation is longer compared to adults, it is necessary to continuously observe these populations and subject them to careful analysis., Competing Interests: The authors declare no conflict of interests, (© Copyright by the National Institute of Public Health - National Institute of Hygiene.)

Chemical composition, organoleptic and physicochemical properties of natural groundwaters are varied and dependent on their geological environment. Determining the basic organoleptic properties - such as colour, taste, odour - as well as physical properties - such as electrical conductivity or redox potential - allow us to assess the stability of water chemical composition. Based on their origin, groundwaters can be divided into infiltration, as well as condensation, juvenile, metamorphic and relic groundwaters, which are currently of lesser value. Groundwaters sourced in Poland belong to various chemical types and play an important role in balneotherapy and the bottling industry. Of particular importance are thermal, bicarbonate, chloride or sulphate type waters. There is also a growing interest in humic waters found in the Wielkopolska region., Competing Interests: The authors declare no conflict of interest., (© Copyright by the National Institute of Public Health - National Institute of Hygiene.)

Natural medicinal resources are a country’s natural wealth. Natural medicinal waters, medicinal gases, and peloids have many properties that enable their use in the treatment of gastrointestinal, circulatory, respiratory, bone and joint, and skin and soft tissue disorders. Balneotherapy can be also applicable in prevention of many diseases and rehabilitation. At present, because there are several chemicals of synthetic origin, there is a need to search for nonpharmacological approaches and explore natural healing sources, which better fit the human body. Compared to synthetic drugs, these resources rarely show side effects, which increases the comfort of therapy. The use of natural medicinal resources in the form of treatments in health resort medicine centers under the supervision of balneologists, combined with the healing properties of the climate, contributes not only to the reduction of treatment time for many diseases but also to improvement of therapy’s results. The article discusses natural medicinal resources and some of their therapeutic applications., Competing Interests: The authors declare no conflict of interest, (National Institute of Public Health - National Institute of Hygiene)

In recent years, there has been a rapid increase in the number of electromagnetic radiation sources such as mobile phones and base stations of mobile telephony. This radiation has been classified by the International Agency for Research on Cancer as a possible human carcinogen (group 2B). For this reason, many studies have been carried out on the impact of mobile telephony on human health. The largest of the experiments were carried out on animals. Due to the divergent results of many studies, there was no clear answer on the possible carcinogenic effects of this type of radiation on health. Detection of cancer shortly after an exposure is the most difficult task in analyzing the results. Some of the studies require repetition and verification of the results. In the case of negative effects of electromagnetic fields on brain activity, sleep, heart rate, cognitive function and blood pressure, no consistent evidence has been obtained either. In view of the increasing popularity of mobile phones, their location at short distances from the body (mainly the head) and the development of mobile phone technologies (which entails an increase in the number of base stations), further research, especially among young people, is needed. The duration of human exposure to electromagnetic radiation is subject to an increase and only further research can provide an answer on the possible negative effects of mobile phones and base stations., (Copyright by the National Institute of Public Health - National Institute of Hygiene)

Evolution-derived natural compounds have been inspirational for design of numerous pharmaceuticals, e.g., penicillins and tetracyclines. Herein, we present a bioinspired strategy to design peptide dendrimers for the effective therapy of E. coli infections where the selection of appropriate amino acids and the mode of their assembly are based on the information gained from research on membranolytic natural antimicrobial peptides (AMP's). On the molecular level two opposite effects were explored: the effect of multiple positive charges necessary for membrane disintegration was equilibrated by the anchoring role of tryptophanes. Indeed, a series of Trp-terminated dendrimers exhibited high potency against clinical isolates of antibiotic resistant ESBL E. coli strains, stability in human plasma along with very low hemo- and genotoxicity. Investigation of the underlying antimicrobial mechanism indicated that the dendrimers studied at minimal inhibitory concentration showed weak permeability toward membranes. Solid-state 2D NMR studies revealed their presence on and inside the model membranes. Therefore, their biological properties might be explained by targeting of extra- or intracellular receptors. Our results point to a new approach to design novel branched antimicrobials with high therapeutic index.

A new metabolite, cyclic dipeptide, cis-(3S,8aS)-3-(3,4-dihydroxybenzyl)hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, named JS-3 was isolated from Streptomyces sp. 8812 fermentation broth. Its chemical structure was established by means of spectroscopic analysis. A wide-range-screening study, which included inhibition assay of DD-carboxypeptidase/transpeptidase activity, determination of antibacterial, antifungal, and antiproliferative activities as well as free-radical scavenging was performed. To authors knowledge, this is the first isolation of such compound from natural sources and the first one from bacteria, Streptomyces.

Comparative of studies of genomes of invertebrates and humans shows that in invertebrates including insects there are numerous homologues of human’s genes coding proteins involved in recognition pathogens or transduction of the expression signal. Thanks this features, insects such as Drosophila melanogaster M., Blattella germanica L., Culex quinquefasciatus S., Bombyx mori L. and Galleria mellonella L. are used in studies on virulence, host resistance or in assessing the in vivo efficacy of antibiotics, fungicides and other biologically active substances. G. mellonella (greater wax moth) are rapid growth, high fertility, size and short life cycle insects- these are features that should be met by good model organisms; therefore the number of researches with larvae of wax moth as the model organism for pathogens assays grows from year to year. This is showing by number of scientific publications about infection’s model of G. mellonella. An obstacle in the wide use of G. mellonella caterpillars as a model in biomedical research is the lack of standardized breeding of these insects, which would guarantee the reproducibility of the obtained results and lack of procedures and standards according to which biomedical research will be carried out. Despite this, the G. mellonella model can be used in the initial analysis before conventional in vivo tests and to reduce the number of tests performed on mammals.

The growing resistance of microorganisms towards antibiotics has become a serious global problem. Therapeutics with novel chemical scaffolds and/or mechanisms of action are urgently needed to combat infections caused by multidrug resistant pathogens, including bacteria, fungi and viruses. Development of novel antimicrobial agents is still highly dependent on the discovery of new natural products. At present, most antimicrobial drugs used in medicine are of natural origin. Among the natural producers of bioactive substances, Actinobacteria continue to be an important source of novel secondary metabolites for drug application. In this review, the authors report on the bioactive antimicrobial secondary metabolites of Actinobacteria that were described between 2011 and April 2018. Special attention is paid to the chemical scaffolds, biological activities and origin of these novel antibacterial, antifungal and antiviral compounds. Arenimycin C, chromopeptide lactone RSP 01, kocurin, macrolactins A1 and B1, chaxamycin D as well as anthracimycin are regarded as the most effective compounds with antibacterial activity. In turn, the highest potency among selected antifungal compounds is exhibited by enduspeptide B, neomaclafungins A-I and kribelloside D, while ahmpatinin i Bu, antimycin A1a, and pentapeptide 4862F are recognized as the strongest antiviral agents., (© 2018 Katarzyna Jakubiec-Krzesniak et al.)

The synthesis of four cymantrene-5-fluorouracil derivatives ( 1 - 4 ) and two cymantrene-adenine derivatives ( 5 and 6 ) is reported. All of the compounds were characterized by spectroscopic methods and the crystal structure of two derivatives ( 1 and 6 ), together with the previously described cymantrene-adenine compound C was determined by X-ray crystallography. While the compounds 1 and 6 crystallized in the triclinic P-1 space group, compound C crystallized in the monoclinic P 2₁/ m space group. The newly synthesized compounds 1 - 6 were tested together with the two previously described cymantrene derivatives B and C for their in vitro antiproliferative activity against seven cancer cell lines (MCF-7, MCF-7/DX, MDA-MB-231, SKOV-3, A549, HepG2m and U-87-MG), five bacterial strains Staphylococcus aureus (methicillin-sensitive, methicillin-resistant and vancomycin-intermediate strains), Staphylococcus epidermidis , and Escherichia coli , including clinical isolates of S. aureus and S. epidermidis , as well as against the protozoan parasite Trypanosoma brucei . The most cytotoxic compounds were derivatives 2 and C for A549 and SKOV-3 cancer cell lines, respectively, with 50% growth inhibition (IC 50 ) values of about 7 µM. The anticancer activity of the cymantrene compounds was determined to be due to their ability to induce oxidative stress and to trigger apoptosis and autophagy in cancer cells. Three derivatives ( 1 , 4 and 5 ) displayed promising antitrypanosomal activity, with GI 50 values in the low micromolar range (3-4 µM). The introduction of the 5-fluorouracil moiety in 1 enhanced the trypanocidal activity when compared to the activity previously reported for the corresponding uracil derivative. The antibacterial activity of cymantrene compounds 1 and C was within the range of 8-64 µg/mL and seemed to be the result of induced cell shrinking., Competing Interests: The authors declare no conflict of interest.

A series of six novel metallocenyl-7-ADCA (metallocenyl = ferrocenyl or ruthenocenyl; 7-ADCA = 7-aminodesacetoxycephalosporanic acid) conjugates were synthesized and their antibacterial properties evaluated by biochemical and microbiological assays. The ruthenocene derivatives showed a higher level of inhibition of DD-carboxypeptidase 64-575, a Penicillin Binding Protein (PBP), than the ferrocene derivatives and the reference compound penicillin G. Protein X-ray crystallographic analysis revealed a covalent acyl-enzyme complex of a ruthenocenyl compound with CTX-M β-lactamase E166A mutant, corresponding to a similar complex with PBPs responsible for the bactericidal activities of these compounds. Most interestingly, an intact compound was captured at the crystal-packing interface, elucidating for the first time the structure of a metallocenyl β-lactam compound that previously eluded small molecule crystallography. We propose that protein crystals, even from biologically unrelated molecules, can be utilized to determine structures of small molecules., Competing Interests: Notes The coordinates and structure factors have been deposited in the Protein Data Bank (PDB), www.rcsb.org, with the accession code PDB ID: 5UJO. The authors declare no competing financial interest.

We report a study of a series of isoquinoline derivatives, including their synthesis, in vitro microsomal leucine aminopeptidase (LAP) inhibition and antiproliferative activity on cancer cell lines. Among fourteen tested compounds, one (compound 3b) was determined to have good activity against LAP and significant antiproliferative activity against HL-60 human promyelocytic leukemia, Burkitt's lymphoma Raji, camptothecin resistant CEM/C2 leukemia cells with mutated catalytic site of topoisomerase I, its parental cell line CCRF/CEM and LoVo colon cancer. Its influence on the cell cycle was also observed. Moreover, we have confirmed that antiproliferative activity towards cancer cells is due to LAP inhibition. Docking simulation based on positioning compound 3b into the LAP active site was performed to explore the possible binding mode. The compound was able to form hydrogen bonds with Gly362 and coordinate zinc ions, which was previously suggested to be essential for inhibitory activity. Compound 3b was also characterized with a good selectivity index for cancer versus normal mammalian cells. Toxicological studies involving examination of skin sensitization, acute skin irritation/corrosion, acute dermal toxicity, acute oral toxicity and acute eye irritation/corrosion established that compound 3b is safe for use., (Copyright © 2016. Published by Elsevier Ltd.)

This study is a continuation of a research program aimed at identifying potent drugs against bacterial infections, in which a series of organic compounds: dicarboxylic acid imides and thioimides, isoquinoline derivatives and open chain compounds, were examined for antimicrobial properties against Staphylococcus auneus and Escheiichia coli. In effect of this investigation, the most active compounds (35-40, 47) were selected for in vitiv tests against fourteen clinically important pathogenic isolates, the methicillin resistant Staphylococcus aueus (MRSA) and several reference Gram-negative bacteria: Prteus vulgaris, Pseudomonas aeruginosa, Klebsiella pneumonia, Stenonophoinonas inaltophilia, and Acinetobacter baumannii. The obtained data revealed that seven compounds (three dithioimides, 35, 39, 47, and four thioimides, 36-38, 40) exhibit effective antibacterial activity against the tested Staphylococcus auirus MSSA and MRSA strains. Among them, dicarboxylic acid thioimides 37 and 38 were proven to be the most active.

The aim of this study was to determine the antioxidant properties of 6,7-dihydroxy-3,4-dihydroiso- quinoline-3-carboxylic acid (1) and its derivatives in living cells against reactive forms of oxygen and nitrogen, i.e., hydrogen peroxide and nitric oxide. Four of tested compounds scavenged the reactive form of nitrogen more efficiently or similarly to Trolox (EC50 = 55.80 µM). Two compounds exhibited antioxidant activity against reactive oxygen species better than Trolox (EC50 = 51.88 µM). The most active derivative of 1 was the compound containing an iodine atom at position 8 (6,7-dihydroxy-8-iodo-3,4-dihydroisoquinoline-3-carboxylic acid). Our studies showed that some of the derivatives had the ability to cross the cell membrane and scavenge free radicals inside living cells. Thus, they are able to protect DNA and other cellular structures from the dam- aging effects of reactive oxygen and nitrogen species. In addition, some molecular descriptors of the tested compounds were determined with the use of ICM Pro (Molsoft L.L.C.).

Cancers are the leading cause of deaths all over the world. Available anticancer agents used in clinics exhibit low therapeutic index and usually high toxicity. Wide spreading drug resistance of cancer cells induce a demanding need to search for new drug targets. Currently, many on-going studies on novel compounds with potent anticancer activity, high selectivity as well as new modes of action are conducted. In this work, we describe in details three enzyme groups, which are at present of extensive interest to medical researchers and pharmaceutical companies. These include receptor tyrosine kinases (e.g. EGFR enzymes) and non-receptor tyrosine kinases (Src enzymes), type A, B and C Aurora kinases and aminopeptidases, especially leucine aminopeptidase. We discuss classification of these enzymes, biochemistry as well as their role in the cell cycle under normal conditions and during cancerogenesis. Further on, the work describes enzyme inhibitors that are under in vitro, preclinical, clinical studies as well as drugs available on the market. Both, chemical structures of discovered inhibitors and the role of chemical moieties in novel drug design are discussed. Described enzymes play essential role in cell cycle, especially in mitosis (Aurora kinases), cell differentiation, growth and apoptosis (tyrosine kinases) as well as G1/S transition (leucine aminopeptidase). In cancer cells, they are overexpressed and only their inhibition may stop tumor progression. This review presents the clinical outcomes of selected inhibitors and argues the safety of drug usage in human volunteers. Clinical studies of EGFR and Src kinase inhibitors in different tumors clearly show the need for molecular selection of patients (to those with mutations in genes coding EGFR and Src) to achieve positive clinical response. Current data indicates the great necessity for new anticancer treatment and actions to limit off-target activity.

The nutritional requirements and environmental conditions for a submerged culture of Streptomyces sp. 8812 were determined. Batch and fed-batch Streptomyces sp. 8812 fermentations were conducted to obtain high activity of secondary metabolites. In the study several factors were examined for their influence on the biosynthesis of the active metabolites-7-hydroxy-6-oxo-2,3,4,6-tetrahydroisoquinoline-3-carboxy acid (C10H9NO4) and N-acetyl-3,4-dihydroxy-L-phenylalanine (C11H13NO5): changes in medium composition, pH of production medium, various growth phases of seed culture, amino acid supplementation and addition of anion exchange resin to the submerged culture. Biological activities of secondary metabolites were examined with the use of DD-carboxypeptidase 64-575 and horseradish peroxidase. Streptomyces sp. 8812 mycelium was evaluated under fluorescent microscopy and respiratory activity of the strain was analyzed. Moreover, the enzymatic profiles of the strain with the use of Api ZYM test were analyzed and genetic analysis made. Phylogenetic analysis of Streptomyces sp. 8812 revealed that its closest relative is Streptomyces capoamus JCM 4734 (98%), whereas sequence analysis for 16S rRNA gene using NCBI BLAST algorithm showed 100% homology between these two strains. Biosynthetic processes, mycelium growth and enzyme inhibitory activities of these two strains were also compared.

Three gold(I) complexes of alkynyl chromones were synthesized and characterized. The single-crystal X-ray structure analysis of a dinuclear compound and of a flavone derivative exhibit a typical d10 gold(I)-alkynyl linear arrangement. All complexes were evaluated as anticancer and antibacterial agents against four human cancer cell lines and four pathogenic bacterial strains. All compounds show antiproliferative activity at lower micromolar range concentrations. Complex 4 showed a broad activity profile, being more active than the reference drug auranofin against HepG2, MCF-7 and CCRF-CEM cancer cells. The cellular uptake into MCF-7 cells of the investigated complexes was measured by atomic absorption spectroscopy (AAS). These measurements showed a positive correlation between an increased cellular gold content and the incubation time of the complexes. Unexpectedly an opposite effect was observed for the most active compound. Biological assays revealed various molecular mechanisms for these compounds, comprising: (i) thioredoxin reductase (TrxR) inhibition, (ii) caspases-9 and -3 activation; (iii) DNA damaging activity and (iv) cell cycle disturbance. The gold(I) complexes were also bactericidal against Gram-positive methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) bacterial strains, while showing no activity against the Gram-negative Escherichia coli bacterial strain.

We have determined a 1.18 Å resolution X-ray crystal structure of a novel ruthenocenyle-6-aminopenicillinic acid in complex with CTX-M β-lactamase, showing unprecedented details of interactions between ruthenocene and protein. As the first product complex with an intact catalytic serine, the structure also offers insights into β-lactamase catalysis and inhibitor design.

A series of 3,4-dihydroisoquinoline-3-carboxylic acid derivatives were synthesised and tested for their free-radical scavenging activity using 2,2-diphenyl-1-picrylhydrazyl radical (DPPH·), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radical (ABTS·+), superoxide anion radical (O2·-) and nitric oxide radical (·NO) assays. We also studied d-amino acid oxidase (DAAO), acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activity. Almost each of newly synthesised compounds exhibited radical scavenging capabilities. Moreover, several compounds showed moderate inhibitory activities against DAAO, AChE and BuChE. Compounds with significant free-radical scavenging activity may be potential candidates for therapeutics used in oxidative-stress-related diseases.

A series of new peptide dendrimers with amphiphilic surface, designed around a dendronized ornithine (Orn) core were synthesized and characterized by ESI-MS, ¹H-, ¹³C- NMR, and CD spectrometry. An improved antimicrobial potency against S. aureus and E. coli was detected as a result of an increased charge, higher branching and variable lipophilicity of the residues located at the C-terminus. Minimal inhibitory concentration (MIC) values indicated that the selected dendrimers were not sensitive to the physiological concentration of Na⁺ and K⁺ ions (100 mM), but expressed reduced potency at 10 mM concentration of Mg²⁺ and Ca²⁺ ions. Circular dichroism (CD) curves measured under various conditions revealed structure and solvent-dependent curve evolution. ESI-MS studies of gas-phase interactions between selected dendrimers and both anionic (DMPG) and neutral (DMPC) phospholipids revealed the presence of variously charged dendrimer/phospholipid aggregates with 1:1 to 1:5 stoichiometry. The collision-induced fragmentation (CID) of the most abundant [dendrimer/phospholipid]²⁺ ions of the 1:1 stoichiometry demonstrated that the studied dendrimers formed stronger complexes with anionic DMPG. Both phospholipids have higher affinity towards dendrimers with a more compact structure. Higher differences in CID energy necessary for dissociation of 50% of the complex formed by dendrimers with DMPG vs. DMPC (ΔCID₅₀) correlate with a lower hemotoxicity. Mass spectrometry results suggest that for a particular group of compounds the ΔCID₅₀ might be one of the important factors explaining selectivity of antimicrobial peptides and their branched analogs targeting the bacterial membrane. Both circular dichroism and mass spectrometry studies demonstrated that dendrimers of N(α)- and N(ε)-series possess a different conformation in solution and different affinity to model phospholipids, what might influence their specific microbicidal mechanism.

We report on the synthesis of ferrocenyl-ampicillin and ferrocenyl-6-aminopenicillinic acid bioconjugates. Title compounds were characterized by (1)H NMR, IR, MS and elemental analysis. These novel ferrocenyl-antibiotic conjugates were also investigated by cyclic voltammetry (CV). Ferrocenyl-ampicillin complexes revealed reversible uncomplicated oxidation whereas ferrocenyl-6-aminopenicillinic acid derivatives were found to exhibit adsorption waves in cathodic scans. Antibacterial activities of our ferrocenyl-antibiotic conjugates against Gram-positive methicillin-sensitive Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-resistant S. aureus (VRSA) and Staphylococcus epidermidis bacterial strains were determined. Our experiments show significant antibacterial activity of ferrocenyl-6-aminopenicillinic acid bioconjugates against the bacterial strains tested. Contrary to that ferrocenyl-ampicillin derivatives were inactive. The inhibitory effects on the dd-carboxypeptidase 64-575 II exerted by our ferrocenyl-6-aminopenicillinic acid bioconjugates were established in the low nanomolar range. The tumor cell growth inhibition of representative ferrocenyl-ampicillin and ferrocenyl-6-aminopenicillinic acid bioconjugates against MCF-7 breast adenocarcinoma and HT-29 colon carcinoma cell lines were studied in vitro. Similar to the antibacterial activity tests the assays in tumor cells revealed significant antiproliferative effects exerted by ferrocenyl-6-aminopenicillinic acid bioconjugates., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

A series of new cationic lipopeptides containing branched, amphiphilic polar head derived from (Lys)Lys(Lys) dendron and C(8) or C(12) chain at C-end were designed, synthesized and characterized. Antimicrobial in vitro activity expressed as minimal inhibitory concentration (MIC) was evaluated against Gram-positive and Gram-negative bacteria and yeasts from the Candida genus. A significant enhancement of antimicrobial potency along with increased selectivity against Candida reference strains was detected for derivatives with the C(12) residue. Several compounds were characterized by a low hemotoxicity. The antifungal activity of branched lipopeptides is multimodal and concentration dependent. Several compounds, studied in detail, induced potassium leakage from fungal cells, caused morphological alterations of fungal cells and inhibited activity of candidal β(1,3)-glucan synthase., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A novel antimicrobial agent labeled JS-1, being a member of isoquinoline alkaloids, of molecular formula C10H9NO4 was isolated from the culture broth of Streptomyces sp. 8812. In this study, we present the structure based on physicochemical and spectroscopic NMR investigations and on quantum chemical structure modeling. The structure of a molecule suggests the biosynthetic path starting from 3'-hydroxy tyrosine. The synthesis was undertaken and it resulted in NMR data that fully agree with the presented analysis.

A novel isoquinoline alkaloid of molecular formula C10H9NO4, labeled JS-1, was isolated from the culture broth of Streptomyces sp. 8812. It was purified by acetone protein precipitation from the culture supernatant, followed by anion exchange and C18 RP HPLC columns. JS-1 is an inhibitor of exocellular DD-carboxypeptidases/transpeptidases (DD-peptidases) 64-575 II from Saccharopolyspora erythraea 64-575 II, and R39 from Actinomadura R39. JS-1 exhibits activity against Gram-negative bacteria, such as Bordetella bronchiseptica, Stenotrophomonas maltophilia, Proteus vulgaris, P. mirabilis, Burkholderia cepacia and Acinetobacter baumanii, with MIC values 10-160 microg ml(-1), and against Gram-positive bacteria, such as Staphylococcus aureus, with MIC values 40-206 microg ml(-1).

Novel polyfunctional small amphiphilic peptide dendrimers characterized by incorporation of a new core compounds - tris-amino acids or tetrakis-amino alcohols that originated from a series of basic amino acids - were efficiently synthesized. These new core elements yielded molecules with multiple branching and (+5)/(+6) charge at the 1-st dendrimer generation. Dendrimers exhibited significant antimicrobial potency against Gram(+) and Gram(-) strains involving also multiresistant reference strains (S. aureus ATCC 43300 and E. coli ATCC BAA-198). In addition, high activity against fungi from the Candida genus was detected. More charged and more hydrophobic peptide dendrimers expressed hemolytic properties.

The 1,3-dipolar cycloaddition of the cyclic nitrone derived from tartaric acid and (S)-5-hydroxymethyl-2(5H)-furanone leads to the single adduct 7 which can be transformed into the 3-epi-1-homo-casuarine via a reaction sequence involving reduction of the lactone moiety and N-O bond hydrogenolysis, followed by intramolecular alkylation of the nitrogen atom. The adduct 7 can also be used in the synthesis of 1-methyl- or 3-methyl analogues of 3-epi-casuarine.

The 1,3-dipolar cycloaddition of cyclic nitrone derived from tartaric acid and (S)-5-hydroxymethyl-2(5H)-furanone leads to a single adduct which was transformed into 2,6-dihydroxyhastanecine via reaction sequence involving reduction of the lactone moiety, glycolic cleavage of the terminal diol, and the N-O hydrogenolysis followed by the intramolecular alkylation of the nitrogen atom.

Rearrangements initiating within the well-characterized break-point cluster region of the mixed lineage leukemia (MLL) gene on 11q23 are a hallmark of therapy-related leukemias following treatment with topoisomerase II poisons including etoposide. Hematopoietic stem cells (HSC) are believed to be the target cell for leukemia-initiating MLL rearrangement events. Although etoposide treatment is sufficient to induce readily detectable MLL rearrangements in primary human CD34+ cells, the majority of cells that gain translocations do not proliferate in culture possibly due to reduced proliferative capacity of most CD34+ cells during normal differentiation [Blood 2005;105:2124]. We characterized the impact of etoposide on primary human long-term repopulating HSC that represent only a minor portion of CD34+ cells. The proliferative capacity of HSC is dramatically increased following both a single and multiple exposures to etoposide as determined by their ability to engraft bone marrow of immune-deficient non-obese diabetic/severe combined immunodeficient mice and to initiate hematopoiesis in long-term initiating cultures. Similar to results in CD34+ cells, a significant proportion of etoposide-treated HSC-derived clones harbored stable MLL rearrangements, including duplications, inversions and translocations. These results indicate HSC are highly susceptible to etoposide-induced and potentially oncogenic rearrangements initiating within MLL, and these HSC are particularly proficient for continued long-term proliferation both in vivo and in vitro.

The [2+2]cycloaddition of chlorosulfonyl isocyanate to vinyl and (Z)-propenyl ethers derived from the 2-O-sulfonylated (R)- and (S)-1-(furyl-2')-1,2-ethanediols furnished the 4-alkoxy-azetidin-2-ones with a good to moderate stereoselectivity. The intramolecular alkylation of the beta-lactam nitrogen atom led to the corresponding 3-(furyl-2')- and 6-methyl-3-(furyl-2')-clavams. The transformation of the furyl residue into an alkoxycarbonyl group led to clavams related to the natural compounds. The synthesized clavams exhibited moderate inhibitory activities against DD-peptidase 64-575 and beta-lactamase (penase) as well as antifungal activities.

The 1,3-dipolar cycloaddition of a five-membered cyclic nitrone derived from malic acid and unsaturated D-threo-hexonolactone leads to a single adduct, which was transformed into 1-homoaustraline via a reaction sequence involving rearrangement of the six-membered lactone ring into the five-membered one, removal of the terminal carbon atom from the sugar chain, reduction of the lactone fragment into triol, protection of primary hydroxy groups, mesylation of the secondary one, cleavage of the N-O bond, and the intramolecular alkylation of the nitrogen atom.

The synucleins are a family of presynaptic proteins that are abundant in neurons and include alpha-, beta, and gamma-synuclein. Alpha-synuclein (ASN) is involved in several neurodegenerative age-related disorders but its relevance in physiological aging is unknown. In the present study we investigated the expression of ASN mRNA and protein in the different brain parts of the adult (4-month-old) and aged (24-month-old) rats by using RT-PCR technique and Western blot, respectively. Our results indicated that mRNA expression and immunoreactivity of ASN is similar in brain cortex, hippocampus and striatum but markedly lower in cerebellum comparing to the other brain parts. Aging lowers ASN mRNA expression in striatum and cerebellum by about 40%. The immunoreactivity of ASN in synaptic plasma membranes (SPM) from aged brain cortex, hippocampus and cerebellum is significantly lower comparing to adult by 39%, 24% and 65%, respectively. Beta-synuclein (BSN) was not changed in aged brain comparing to adult. Age-related alteration of ASN may affect the nerve terminals structure and function.