Impact of functional satellite groups on the antimicrobial activity and hemocompatibility of telechelic poly(2-methyloxazoline)s

Polyoxazolines with a biocidal quarternary ammonium end-group are potent biocides. Interestingly, the antimicrobial activity of the whole macromolecule is controlled by the nature of the group at the distal end. These nonreactive groups are usually introduced via the initiator. Here we present a study with a series of polymethyloxazolines with varying satellite groups introduced upon termination of the polymerization reaction. This allowed us to introduce a series of functional satellites, including hydroxy, primary amino, and double-bond-containing groups. The resulting telechelic polyoxazolines were explored regarding their antimicrobial activity and toxicity. It was found that the functional satellite groups greatly controlled the minimal inhibitory concentrations against the bacteria Staphylococcus aureus and Escherichia coli in a range of 10 to 2500 ppm. Surprisingly, the satellite groups also controlled the hemotoxicity but in a different way than the antimicrobial efficiency.     

Synthesis of new sulfonamide inhibitors of carbonic anhydrase

Four different derivatives of aromatic sulfonamides have been synthesized: 1,2-bis[(4-sulfonamidobenzamide)ethoxy]ethane (SBAM), 1,2-bis[(4-sulfonamidobenzoate)ethoxy]ethane, 1,2-bis[(2,4-dichloro-5-sulfonamidobenzamide)ethoxy]ethane, and 1,2-bis[(2,4-dichloro-5-sulfonamidobenzoate)ethoxy]ethane. SBAM is a most potent inhibitor on ciliary epithelium carbonic anhydrase and is approximately 13 times more active against carbonic anhydrase isoform II than against isoform I.     

Bis‐ and Tetrakis(carboxylato)platinum(IV) Complexes with Mixed Axial Ligands – Synthesis,Characterization, and Cytotoxicity

A series of twelve novel diamminetetrakis(carboxylato)platinum(IV) and 18 novel bis(carboxylato)dichlorido(ethane‐1,2‐diamine)platinum(IV) complexes with mixed axial carboxylato ligands was synthesized and characterized by multinuclear ¹H‐, ¹³C‐, ¹⁵N‐, and ¹⁹⁵Pt‐NMR spectroscopy. Their cytotoxic potential was evaluated (by MTT assay) against three human cancer cell lines derived from ovarian teratocarcinoma (CH1/PA‐1), lung (A549), and colon carcinoma (SW480). In the cisplatin‐sensitive CH1/PA‐1 cancer cell line, diamminetetrakis(carboxylato)platinum(IV) complexes showed IC₅₀ values in the low micromolar range, whereas, for the most lipophilic compounds of the bis(carboxylato)dichlorido(ethane‐1,2‐diamine)platinum(IV) series, IC₅₀ values in the nanomolar range were found.     

Antimicrobial efficiency of some N,N′-bis(alkymethyl)-1,2-ethanediamine dioxides and N,N′-bis(alkylmethyl)-1,2-propanediamine dioxides

Ten dioxide species derived from N,N′-bis(alkylmethyl)-1,2-ethanediamine and N,N′-bis(alkylmethyl)-1,2-propanediamine were tested for their activity withStaphylococcus aureus, Escherichia coli andCandida albicans. A relation between the length of the alkylchain, and/or the molecule asymmetry, and the antimicrobial activity was found. Part V of the series Amine Oxides; part IV: Mlynarciket al.: Folia Microbiol. 24, 188 (1979).     

Guanidine Derivatives: Conformation, Capability for Chelation, Study as Reversible Inhibitors of Cholinesterases of Different Origin

Study of spatial structure of biologically active guanidine derivatives by the method of molecular mechanics has shown that in an anticoccidial drug, 1,3-bis ( p-chlorobenzylidenamino)guanidine (Cl-BAG) the most preferable are convolute conformations, in which the chlorine atoms that are distant in the valent chain are approached to each other at a distance of 3.7 . This indicates predisposition of the optimal conformations to form chelate complexes with ions of metals, which is confirmed by comparative spectrophotometric studies of the second derivative of differential UV-spectra of Cl-BAG in the presence and absence of calcium ions. Its derivative without chlorine (BAG) is unable to bind Ca²⁺ and has been shown to have no anticoccidial action, which associates the biological potency with the presence of calcium-binding ability of the compounds. The capability of Cl-BAG for chelation depends essentially on nature of the chelated metal ion. The antienzyme testing of inhibiting action of the guanidine derivatives toward cholinesterases of human erythrocytes, horse blood serum, mink brain and serum, optic ganglia of the Pacific squid Todarodes pacificus has revealed difference between the enzymes due to possibility of redistribution of the positive charge between the guanidinium fragment and amino groups and a change of the degree of charge delocalization.     

Protein stabilization and destabilization by guanidinium salts

Preferential interactions of bovine serum albumin were measured with guanidine sulfate, guanidine acetate, and guanidine hydrochloride. The results showed an increasing preferential hydration with increasing salt concentration for the sulfate, positive preferential salt binding for the hydrochloride, and an intermediate situation for the acetate. These results correlate well with the known effects of the three salts on protein stability, namely, the stabilizing effect of guanidine sulfate and the denaturing effect of guanidine hydrochloride. Comparison of guanidinium and magnesium salts indicated that the substitution of guanidinium ion for Mg2+ decreases the preferential hydration and increases the preferential salt binding, suggesting that the perturbation by guanidinium ion binding of the surface free energy is greater than that by Mg2+ ion. It was concluded that guanidine salts are not a special class, but their activity toward proteins is modulated by the same fine balance between hydration and salt binding to protein as in the case of other salts, with the second factor being stronger in guanidine salts.     

Interactions of biocidal guanidine hydrochloride polymer analogs with model membranes: a comparative biophysical study

Four synthesized biocidal guanidine hydrochloride polymers with different alkyl chain length, including polyhexamethylene guanidine hydrochloride and its three new analogs, were used to investigate their interactions with phospholipids vesicles mimicking bacterial membrane. Characterization was conducted by using fluorescence dye leakage, isothermal titration calorimetry, and differential scanning calorimetry. The results showed that the gradually lengthened alkyl chain of the polymer increased the biocidal activity, accompanied with the increased dye leakage rate and the increased binding constant and energy change value of polymer-membrane interaction. The polymer-membrane interaction induced the change of pretransition and main phase transition (decreased temperature and increased width) of phospholipids vesicles, suggesting the conformational change in the phospholipids headgroups and disordering in the hydrophobic regions of lipid membranes. The above information revealed that the membrane disruption actions of guanidine hydrochloride polymers are the results of the polymer's strong binding to the phospholipids membrane and the subsequent perturbations of the polar headgroups and hydrophobic core region of the phospholipids membrane. The alkyl chain structure significantly affects the binding constant and energy change value of the polymer-membrane interactions and the perturbation extent of the phospholipids membrane, which lead to the different biocidal activity of the polymer analogs. This work provides important information about the membrane disruption action mechanism of biocidal guanidine hydrochloride polymers.     

Synthesis, characterization, and antitumor activity of 1,2-bis(diphenylphosphino) ethane platinum(II) and palladium(II) complexes

A number of 1,2-bis(diphenylphosphino)ethane monomeric platinum(II) and palladium(II) complexes have been synthesized in light of their potential antitumor activity. The metal center is coordinated with a number of carboxylate anions in the cis-configuration. These complexes have been characterized by elemental analysis, conductivity measurement, and various spectroscopic techniques [IR and 195Pt NMR]. In vivo screening tests for activity of these complexes were performed against the L1210/0 murine leukemia cancer model, but none displayed a significant level of antitumor activity.     

Structure-activity examination of poly(glycoamidoguanidine)s: glycopolycations containing guanidine units for nucleic acid delivery

In this study we synthesized a new series of polymers known as poly(glycoamidoguanidine)s (PGAGs). These new polymer structures were synthesized by copolymerizing a carbohydrate monomer (diester; galatarate or tartarate) with a diamine incorporating guanidine or methylguanidine as a charge center to create a polyamide backbone. These materials were strategically designed and compared to our previously studied DNA delivery vehicles, poly(glycoamidoamine)s (PGAAs), which contain secondary amines as the charge groups along the polymer backbone to examine the effect of charge center type on the cellular delivery efficiency of plasmid DNA (pDNA). The guanidine moieties within the PGAGs facilitate electrostatic binding with the negatively charged phosphate backbone of plasmid DNA (pDNA). Stable polymer-pDNA complexes (polyplexes) with sizes in the range of 60-200 nm are formed at polymer/pDNA charge ratios (N/P) of 5 and above. When the PGAGs are complexed with Cy5-labeled pDNA (Cy5-pDNA) at N/P ratios of 10 and 25, between 80 and 95% of HeLa cells were positive for Cy5 fluorescence, indicating effective cellular internalization of the polyplexes. The toxicity of both PGAA and PGAG polyplexes was studied via MTT assays, and over 95% cell survival was observed at N/P ratios of 5, 10, 15, 20, 25, and 30 in HeLa cells. Transgene expression was examined via luciferase assays at various N/P ratios in the absence and presence of serum. In the absence of serum, the PGAG polyplexes revealed similar transgene expression when compared to polyplexes formed with their analogous PGAA structures. In the presence of serum, one analog (Gg) consisting of galactarate copolymerized with the guanidine monomer yielded gene expression similar to the positive control, Glycofect Transfection Reagent. This new series of guanidine-containing oligomers are promising as a new design strategy to incorporate an alternative charge center type within the backbone of glycopolymer-based nucleic acid delivery vehicles.     

Regioselective template synthesis, X-ray structure, and chiroptical properties of a topologically chiral sulfonamide catenane

The synthesis of a topologically chiral in,out-bis-sulfonamide catenane and its "dimer" are reported. The structures of the amide wheel and of the catenane were resolved by X-ray analysis. NMR-titration of the monosulfonamide-wheel yielded conclusive association constants supporting the proposed regioselective mechanism of the catenane formation. The enantioseparation of the catenane via chiral HPLC was successful. The enantiomers show pronounced Cotton effects in the aromatic region of the CD-spectrum. Since the template synthesis was carried out leading to the in-oriented sulfonamide-wheel blocked with an N-methyl group at its reactive sulfonamide functionality, the catenane represents the first monofunctional topologically chiral amide-based catenane. Reaction with 1,2-bis(2-iodoethoxy)ethane led to a bis-catenane containing two topological units. The meso- and the RR/SS-isomers represent a new type of topological diastereomers.     

An ab initio study of the guanidinium groups in saxitoxin

Quantum chemical (Hartree-Fock) calculations were performed on neutral and protonated saxitoxin in order to obtain optimum geometries, rotational energy barriers for the guanidinium ions and proton affinities. For comparison purposes, as model compounds, guanidinium systems in five and six membered rings were also investigated. In addition, DFT (B3LYP) calculations with the 6-31G** basis set were performed and the sodium affinities of the guanidinium groups in saxitoxin were obtained. It was concluded that the inhibition of the sodium channels by the saxitoxin is due to the interaction of the guanidinium group with carboxylate groups from the wall of the channel and not to the binding of the sodium ions. Figure Calculated structure of Compound 1, neutral saxitoxin. a Calculated structure of Compound 1a, saxitoxin protonated on the guanidine of the five-membered ring. b Calculated structure of Compound 1b, saxitoxin protonated on the guanidine of the six-membered ring     

Polyvinyl pyridine metal complex as permanent antimicrobial finishing for viscose fabric

Viscose fabrics were treated with polyvinyl pyridine (PVP) using padding technique, followed by oxidation with hydrogen peroxide or peracetic acid, which was prepared by the reaction of tetra acetyl ethylene diamine (TAED) with hydrogen peroxide. Peracetic acid gives higher oxidation of PVP than hydrogen peroxide. FTIR study proved the formation of N-oxide as a result of oxidation. Incorporation of copper and silver ion onto oxidized PVP was also proved by FTIR. The antimicrobial study emphasise that Cu/oxidized PVP and Ag/oxidized PVP have retarded the growth of bacteria significantly, and Ag/oxidized PVP has a far better biocidal activity. The antibacterial activity of both metal ions survived after washing 10 times.     

Synthesis of bioinorganic antimicrobial peptide nanoparticles with potential therapeutic properties

Amphiphilicity and cationicity are properties shared between antimicrobial peptides and proteins that catalyze biomineralization reactions. Merging these two functionalities, we demonstrate a reaction where a cationic antimicrobial peptide catalyzes self-biomineralization within inorganic matrices. The resultant antimicrobial peptide nanoparticles retain biocidal activity, protect the peptide from proteolytic degradation, and facilitate a continuous release of the antibiotic over time. Taken together, these properties demonstrate the therapeutic potential of self-synthesizing biomaterials that retain the biocidal properties of antimicrobial peptides.     

Efficient enhancement of DNA cleavage activity by introducing guanidinium groups into diiron(III) complex

Inspired by the structures of natural nucleases, guanidinium groups were introduced into binuclear iron(III) systems. Compared with the corresponding analogue without guanidinium groups, the new diiron(III) system led to considerable rate enhancement on DNA cleavage. The cooperativity between metal ions and guanidine groups was evidenced by the fact that no significant cleavage was observed after incubating pBR322 plasmid DNA with non-metalated ligands or free Fe3+ ion. DNA binding experiments indicated that introduction of positively charged guanidinium groups can obtain more than one order of magnitude enhancement in the affinity of complex with DNA.     

Diphosphines as bridging ligands in polymeric and dimeric thione-S-ligated Ag(I) nitrate complexes

Reactions of silver(I) nitrate with equimolar amounts of the diphos ligands 1,4-bis(diphenylphosphino)butane (dppb) or 1,2-bis(diphenylphosphino)ethane (dppe) and some heterocyclic thiones (L) in acetonitrile/methanol solvent afforded mixed-ligand complexes, the nature of which was found to be strongly influenced by the backbone length of the diphosphine ligand. The longer chained diphos ligand formed a series of dinuclear complexes of the type [Ag(dppb)(L)]₂(NO₃)₂ with both the diphosphine and thione ligands acting as bridging ligands between the two four-coordinate pseudo-tetrahedrally coordinated metal centers. In the unique case of L=4-methyl-5-trifluoromethyl-4H-1,2,4-triazoline-3(2H)-thione (mftztH), the reaction proceeded under exclusion of the thione ligand from the coordination sphere and coordination of the nitrate anions instead, leading to the diphosphine-doubly bridged dimeric compound [Ag(dppb)(NO₃)]₂. On the other hand, the complexes produced when using the short bite 1,2-bis(diphenylphosphino)ethane (dppe) turned out to be diphosphine-bridged cationic polymers of the type [Ag(dppe)(L)₂]_n(NO₃)_n. The structures of one representative for each of the two aforementioned series of complex compounds, namely [Ag(dppb)(py2SH)]₂(NO₃)₂ · 2H₂O and [Ag(dppe)(pymtH)₂]_n(NO₃)_n, have been established by single-crystal X-ray diffraction.     

Poly(ethylene glycol) multiblock copolymer as a carrier of anti-cancer drug doxorubicin

The synthesis of a novel water-soluble polymer drug carrier system based on biodegradable poly(ethylene glycol) block copolymer is described in this paper. The copolymer consisting of PEG blocks of molecular weight 2000 linked by means of an oligopeptide with amino end groups was prepared by interfacial polycondensation of the diamine and PEG bis(succinimidyl carbonate). The structure of the oligopeptide diamine consisting of glutamic acid and lysine residues was designed as a substrate for cathepsin B, a lysosomal enzyme, which was assumed to be one of the enzymes responsible for the degradation of the polymer carrier in vivo. Each of the oligopeptide blocks incorporated in the carrier contained three carboxylic groups of which some were used for attachment of an anti-cancer drug, doxorubicin (Dox), via a tetrapeptide spacer Gly-Phe-Leu-Gly. This tetrapeptide spacer is susceptible to enzymatic hydrolysis. In vitro release of Dox and the degradation of the polymer chain by cathepsin B as well as preliminary evaluation of in vivo anti-cancer activity of the conjugate are also demonstrated.     

Thioether-bridged arylalkyl-linked N-phenylpyrazole derivatives: Design,synthesis, insecticidal activities,structure-activity relationship and molecular-modeling studies

Owing to thioether diverse physicochemical properties by non-covalent interactions with bio-macromolecules, thioether derivatives containing heterocyclic moiety are known for their interesting insecticidal bioactivities and attracting considerable attention as neuroactive insecticides. Here we synthesis a series of novel thioether bridged N-phenylpyrazole derivatives incorporating various (hetero)aromatic substituents into 4-position of the pyrazole ring. Structure-activity relationship (SAR) studies resulted in compounds 6d and 7d with the most potent insecticidal activity among the series containing various substituted benzene substituents (LC₅₀?=?13.70–25.47?μg/g). Further optimization to increase the lipophilicity and charge density of aromatic substituents of compounds 6d and 7d resulted in compounds 12d, 14d and 16d with sulfur-containing heterocycle substituents possessing good insecticidal activity against Musca domestica L. among the series (LC₅₀?=?0.67–1.30?μg/g). The thioether bridge N-phenylpyrazole derivatives, which exhibit different length of the spacer arm introduced between N-phenylpyrazole moiety and the (hetero)aromatic substituents, were also prepared and evaluated. By contrast, the insecticidal activities of compounds containing the short thioether bridge, 1,2-bis((hetero)aromatic thio) ethane, are higher than that containing the long thioether bridge, 1,3-bis((hetero)aromatic thio) propane. The results of molecular docking and pharmacophore analyses indicated A299, T303, and L306 of a subunit were essential to form non-covalent interactions contacts with the ligands. Specially, the sulfur-containing heterocycle substituent derivatives 12d and 14d as the sterically favored areas could form the important hydrophobic interactions with the deeper residue P295.     

Lead optimization of methionine aminopeptidase-2 (MetAP2) inhibitors containing sulfonamides of 5,6-disubstituted anthranilic acids

A series of aryl sulfonamides of 5,6-disubstituted anthranilic acids were identified as potent inhibitors of methionine aminopeptidase-2 (MetAP2). Small alkyl groups and 3-furyl were tolerated at the 5-position of anthranilic acid, while -OCH(3), CH(3), and Cl were found optimal for the 6-position. Placement of 2-aminoethoxy group at the 6-position enabled interaction with the second Mn(2+) but did not result in enhancement in potency. Introduction of a tertiary amino moiety at the ortho-position of the sulfonyl phenyl ring gave reduced protein binding and improved cellular activity, but led to lower oral bioavailability.     

The relationship of some copper (II) complexes of facultative tetrathioethers to the coordination environment in the "blue" copper proteins

The facultative potentially tetradentate thioether ligands 1,2-bis(methylthioethylthio)ethane (2,2,2), 1,3-bis(2-methylthioethylthio)propane (2,3,2) and 1,2-bis(3-methylthiopropylthio)ethane (3,2,3) react with copper(II) salts to form Cu2(2,2,2)Cl4, Cu3(ligand)X6 (ligand = 2,3,2 and 3,2,3 X = Cl; ligand = 2,2,2 2,3,2 and 3,2,3 X = Br), and Cu(ligand)(ClO4)2. The stoichiometry and structures of these complexes are discussed in terms of the steric demands of the ligand and the nature of the halide. The [Cu(2,3,2)(ClO4)] ClO4 and [Cu(3,2,3)(ClO4) [ClO4 complexes have electronic spectra which exhibit the intense 600 nm band characteristic of the "blue" copper proteins. In fact, the spectrum of [Cu(2,3,2)(ClO4)]ClO4 is very similar to that of pseudomonas aeroginosa azurin.     

Inhibition of nitrogen fixation by nitrite inAnabaena variabilis

Addition of nitrite to rapidly growing, nitrogen-fixing filaments ofAnabaena variabilis caused an immediate drop in nitrogenase activity. This was followed by a transient induction of nitrite reductase, recovery of nitrogen fixation and cyanobacterial growth. The experiments with isolated heterocysts and a partially purified nitrogenase preparation from heterocysts showed that nitrite primarily exerted its inhibitory effect by inactivating nitrogenase irreversibly, rather than interfering with photosynthetic energy conservation.Abbreviations ATCC American type culture collection - Chl chlorophyll - FCCP carbonyl cyanide p-trifluoromethoxy phenylhydrazone - Tes 2-{[2 hydroxy-1,1-bis(hydroxymethyl)ethyl] amino} ethane sulfonic acid