Synthesis and antimicrobial activity of copper(II) and manganese(II) α,ω-dicarboxylate complexes

Copper(II) ,-dicarboxylate complexes of general formulae, [Cu(O₂C(CH₂)_nCO₂)]·xH₂O, [Cu(O₂C(CH₂)_nCO₂) (phen)₂]·xH₂O and [Cu(O₂C(CH₂)_nCO₂)(bipy)_y]·xH₂O (n=1–8; y=1, 2; phen = 1,10-phenanthroline; bipy = 2,2-bipyridine) were synthesised. These copper complexes, some related manganese(II) complexes and the metal-free ligands were screened in vitro for their ability to inhibit the growth of Candida albicans. Metal-free 1,10-phenanthroline and all of the copper(II) and manganese(II) phenanthroline complexes were potent growth inhibitors, with only one bipyridine complex, [Cu(O₂C(CH₂)CO₂)(bipy)₂]·2H₂O, having moderate activity. The remaining substances were effectively inactive. Complexes which were active against C. albicans also proved effective against C. glabrata, C. tropicalis and C. kreusi with the manganese complexes retaining superior activity. For the phenanthroline complexes the active drug species is thought to be the dication [M(phen)₂(H₂O)_n]²⁺ (M = Cu, Mn). Escherichia coli and Staphylococcus aureus were resistant to all of the metal complexes and also to metal-free 1,10-phenanthroline. Only the copper phenanthroline complexes showed intermediate activity against Pseudomonas aeruginosa.     

Synthesis, characterization and cytotoxic activity of palladium (II) dithiocarbamate complexes with α,ω-diamines

The polymeric [PdCl(dithiocarbamate)]_n complexes, in which the ligand ion is dimethyldithiocarbamate (DMDT), pyrrolidine dithiocarbamate (PyDT, (CH₂)₄NCS₂⁻) and sarcosine ethyl ester dithiocarbamate (ESDT, EtO₂CCH₂N(CH₃)CS₂⁻), have been reacted with chelating diamines, like ethylenediamine (en) or 1,3-diaminopropane (dap) and long chain diamines, like 1,4-diaminobutane (dab) or 1,7-diaminoheptane (dah). The reaction products depend on either diamine chain length or molar ratio. By operating at PdCl(dithiocarbamate)/diamine molar ratio 1:1 chelating diamines yielded the ionic [Pd(dithiocarbamate)(diamine)]Cl species (diamine = en or dap), whereas with long chain diamines species of the type [Pd(dithiocarbamate)(diamine)]_nCl_n (diamine = dab or dah) were obtained, in which each Pd(dithiocarbamate)⁺ unit binds to the NH₂ group of two different molecules, in a network of bridging diamines. At molar ratio 1:0.5, the long chain diamines yielded the binuclear [Pd₂Cl₂(dithiocarbamate)₂(diamine)] complexes (diamine = dab or dah), whereas exchange reactions take place generally in the presence of en or dap. The reaction trend is described on the basis of IR and proton NMR spectra. The new dithiocarbamate complexes were preliminarily tested for their cytotoxicity on human cancer cells.     

Chiroptical properties of diastereomeric five-coordinate Pt(II)–olefin complexes. Molecular structure of [PtCl2{(S,S)-(E)-CNCHCHCN}(R,R)-{C6H5CH(CH3)N(CH3)CH2}2]·C6H6

The chiroptical properties of five-coordinate diastereomeric complexes of general formula [PtCl₂(R,R)-{C₆H₅CH(CH₃)N(CH₃)CH₂}₂{olefin}], with olefin ligands having electron-withdrawing substituents, have been investigated. The sign of CD bands in the 28 000–30 000 cm⁻¹ region appears to be correlated to the absolute configuration of the prochiral coordinated alkene. Single-crystal X-ray diffraction structure determination has been performed on the single diastereomer [PtCl₂(E-but-2-enedinitrile)(R,R)-{C₆H₅CH(CH₃)N(CH₃)CH₂}₂]· C₆H₆. The compound crystallizes in the monoclinic space group C2 with a = 17.842(2), b = 8.466(1), c = 10.464(1) Å, β = 109.34(1)°, Z = 2. The number of observed reflections was 1943 and the final R and R_w values were 0.020 and 0.028 respectively. Trigonal-bipyramidal geometry is observed around the Pt atom, with the two Cl atoms in axial positions. The unsaturated ligand lies in the equatorial plane disclosing S,S absolute configuration.     

Synthesis,reactivity and biological activity of N(4)-boronated derivatives of 2′-deoxycytidine

By seeking new stable boron-containing nucleoside derivatives, potential BNCT boron delivery agents, a novel synthetic approach was tested, aimed at a boron attachment via a single bond to an aliphatic carbon of sp³ hybridization. The latter allowed successful modification of deoxycytidine in the reaction with 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane of the deoxynucleoside amino group. For new compounds, detailed NMR, LDI HRMS (Laser Desorption/Ionization High-Resolution Mass Spectrometry) analyses along with in vivo phosphorylation studies, toxicity assays and DFT modelling are presented.     

The Inhibition of Adenosine Kinase by α,ω-Di (Adenosin - N 6- YL) Alkanes1

Abstract

Members of a series of α,ω-di(adenosin- N ⁶-yl)alkanes, comprising two adenosine residues linked with alkyl bridges from 1 to 14 methylene units in length, were found to be inhibitors of rat liver and BHK cell adenosine kinase. The inhibition was competitive with respect to adenosine and non-competitive with respect to ATP. The corresponding α,ω-di(cytidin-N ⁴-yl) alkanes were not inhibitors and N ⁶-alkyladenosines inhibited only weakly.     

Iridium(I) dimers with bridging N,N′-di-p-tolylformamidine. X-ray molecular structure of Ir2(μ-p-CH3C6H4NCHN-p-C6H4CH3)(μ-NH-p-C6H4CH3)(C8H14)2

The reaction of [IrCl(COD)]₂ with K[CH(N-p- C₆H₄CH₃)₂] (K⁺form⁻) has been carried out in both neat toluene and in the presence of Bu^tOH. In the first case [Ir(form)(COD)]₂ (1) was obtained in good yields. The other reaction follows a somewhat different course with partial alcoholysis of the formamidine ligand and formation of Ir₂(μ-form)(μ-NH-p-C₆H₄CH₃)(COD)₂ (2). Crystal data for compound 2: space group P2₁/c, a = 9.389(2), b = 21.083(4), c = 16.810(2) Å, β = 91.54(1)° V=3326(2) ų, Z = 4, R = 0.0343 for 3707 data with F_o² > 3σ(F_o²).     

Effect of N,N′-bis (alkyldimethyl)-α,ω-alkanediammonium dibromides on bacteria of the genusclostridium

Antibacterial effect of 17 ammonium compounds of the type of N,N′-bis(alkyldimethyl)-α,ω-alkanediammonium dibromides was tested on anaerobically sporulating bacteria of the genusClostridium. A sizable antibacterial activity was displayed by five N,N′-bis(alkyldimethyl)-1,6-hexanediammonium dibromides and by four N,N′-bis(decyldimethyl)-α,ω-alkanediammonium dibromides. These compounds exhibited activity higher than, or comparable with, that of the reference standards Ajatin and Septonex. The maximum antibacterial activity was found in compounds whose alkyl chain contained 9–12 carbon atoms. Compounds with a lower number of carbon atoms in the chain (less than 8) exhibited a low activity.     

PPL catalyzed monoesterification of α,ω-dicarboxylic acids

Summary A regioselective strategy for PPL catalysed monoesterification of aliphatic ,-dicarboxylic acids with n-butanol have been developed. In addition to high regioselectivity, the method also ensures chemoselective esterification of a saturated acid moiety in presence of a conjugated acid function.     

Biocatalytic,one-pot diterminal oxidation and esterification of n-alkanes for production of α,ω-diol and α,ω-dicarboxylic acid esters

Direct and selective terminal oxidation of medium-chain n-alkanes is a major challenge in chemistry. Efforts to achieve this have so far resulted in low specificity and overoxidized products. Biocatalytic oxidation of medium-chain n-alkanes – with for example the alkane monooxygenase AlkB from P. putida GPo1- on the other hand is highly selective. However, it also results in overoxidation. Moreover, diterminal oxidation of medium-chain n-alkanes is inefficient. Hence, α,ω-bifunctional monomers are mostly produced from olefins using energy intensive, multi-step processes.By combining biocatalytic oxidation with esterification we drastically increased diterminal oxidation upto 92 mol% and reduced overoxidation to 3% for n-hexane. This methodology allowed us to convert medium-chain n-alkanes into α,ω-diacetoxyalkanes and esterified α,ω-dicarboxylic acids. We achieved this in a one-pot reaction with resting-cell suspensions of genetically engineered Escherichia coli.The combination of terminal oxidation and esterification constitutes a versatile toolbox to produce α,ω-bifunctional monomers from n-alkanes.     

Measurement of 2J(H,C)- and 3J(H,C)-coupling constants by α/β selective HC(C)H-TOCSY

A new heteronuclear NMR pulse sequence for the measurement of ⁿJ(C,H) coupling constants, the /selective HC(C)H-TOCSY, is described. It is shown that the S³E element (Meissner et al., 1997a,b) can be used to obtain spin state selective coherence transfer in molecules, in which adjacent CH moieties are labeled with ¹³C. Application of the / selective HC(C)H-TOCSY to a 10nt RNA tetraloop 5-CGCUUUUGCG-3, in which the four uridine residues are ¹³C labeled in the sugar moiety, allowed measurement of two bond and three bond J(C,H) coupling constants, which provide additional restraints to characterize the sugar ring conformation of RNA in cases of conformational averaging.     

Inhibition of activity of the ethylene-forming enzyme by α(p-chlorophenoxy)isobutyric acid

(p-Chlorophenoxy)isobutyric acid (PCIB) inhibited indole-3-acetic acid (IAA)-induced ethylene production in etiolated mung bean hypocotyl sections. The endogenous level of 1-aminocyclopropane-1-carboxylic acid (ACC) was not significantly affected by PCIB, indicating that PCIB exerted its effect primarily by inhibiting the activity of the ethylene-forming enzyme (EFE). This conclusion was supported by the observations that PCIB inhibited the conversion of exogenously applied ACC to ethylene. The inhibitory effect of PCIB was already evident with 0.05 mM PCIB, and it increased with time after application of the inhibitor. PCIB also significantly inhibited ethylene production in apple fruit tissues, but it only slightly reduced the level of endogenous ACC. Similar to mung bean, EFE activity in apple tissue was significantly inhibited by PCIB. The possibility that PCIB also inhibits auxin-induced ACC synthase activity is discussed.     

Effect of stereospecific hydroxylation of N6-(Δ 2-Isopentenyl)adenosine on cytokinin activity

The cytokinin activities of cis and trans ribosylzeatin isomers and that of N⁶-(²-isopentenyl)adenosine were compared in four bioassays. The trans isomer was found to be more active than the cis isomer in stimulation of cucumber cotyledon expansion (100x), retention of chlorophyll in detached leaf pieces (7x), induction and stimulation of chlorophyll synthesis in cucumber cotyledons (20x) and of betacyanin synthesis in Amaranthus caudatus seedlings grown in the dark (60x). The N⁶-(²-isopentenyl)adenosine adenosine was less active than the trans ribosylzeatin in all four bioassays and more active than the cis ribosylzeatin in induction and stimulation of betacyanin and chlorophyll synthesis. These results show that the hydroxylation of the trans methyl group in the N⁶ side chain of N⁶-(²-isopentenyl)adenosine increases the biological activity and that this activity is either decreased or not significantly changed when the cis methyl group is hydroxylated.Abbreviations i⁶Ado N⁶-(²-isopentenyl)adenosine or 6-(3-methyl-2-butenylamino)-9--D-ribofuranosylpurine - t-to⁶Ado trans-ribosylzeatin or 6-(4-hydroxy-3-methyl-trans-2-butenylamino)-9--D-ribofuranosylpurine - c-io⁶Ado cis-ribosylzeatin or 6-(4-hydroxy-3-methyl-cis-2-butenylamino)-9--D-ribofuranosylpurine - HPLC high pressure liquid chromatography     

Synthesis and β-glucuronidase inhibitory activity of 2-arylquinazolin-4(3H)-ones

2-Arylquinazolin-4(3H)-ones 1–25 were synthesized by reacting anthranilamide with various benzaldehydes using CuCl₂·2H₂O as a catalyst in ethanol under reflux. Synthetic 2-arylquinazolin-4(3H)-ones 1–25 were evaluated for their β-glucuronidase inhibitory potential. A trend of inhibition IC₅₀ against the enzyme in the range of 0.6–198.2 μM, was observed and compared with the standard d-saccharic acid 1,4-lactone (IC₅₀ = 45.75 ± 2.16 μM). Compounds 13, 19, 4, 12, 14, 22, 23, 25, 15, 8, 17, 11, 21, 1, 3, 18, 9, 2, and 24 with the IC₅₀ values within the range of 0.6–44.0 μM, indicated that the compounds have superior activity than the standard. The compounds showed no cytotoxic effects against PC-3 cells. A structure–activity relationship is established.     

Synthesis,structure elucidation,and chemiluminescent activity of new 9-substituted 10-(ω-(succinimidyloxycarbonyl)alkyl)acridinium esters

Several new acridinium esters 2 – 9 having their central acridinium ring bearing a 9-(2,5-dimethylphenoxycarbonyl), 9-(2,6-bis(trifluoromethyl)phenoxycarbonyl) or 9-(2,6-dinitrophenoxycarbonyl) group, and a 10-methyl, 10-(3-(succinimidyloxycarbonyl)propyl), 10-(5-(succinimidyloxycarbonyl)pentyl), or 10-(10-(succinimidyloxycarbonyl)decyl) group, have been synthesized and their chemiluminescent properties have been tested. The 2,5-dimethylphenyl acridinium esters emit light slowly (glow) when treated with alkaline hydrogen peroxide, while the 2,6-dinitrophenyl and 2,6-bis(trifluoromethyl)phenyl esters emit light rapidly (flash). The substituent at the 10 position affects the hydrolytic stabilities of the compounds.     

Synthesis,antileishmanial activity and docking study of N′-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazides

A series of N′-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide derivatives is synthesized and evaluated for antileishmanial activity against Leishmania donovani promastigotes. Compounds 9a and 9i were shown significant antileishmanial when compared with standard sodium stilbogluconate. Antimicrobial study revealed that compound 9b has potent as well as broad spectrum antibacterial activity when compared with ampicillin and compound 9e showed promising antifungal activity when compared with miconazole. Also, none of the synthesized compounds showed cytotoxicity up to tested concentration. Further, docking study against pteridine reductase 1 enzyme of L. donovani showed good binding interactions. ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.     

Reduction of N(ω)-hydroxy-L-arginine by the mitochondrial amidoxime reducing component (mARC)

NOSs (nitric oxide synthases) catalyse the oxidation of L-arginine to L-citrulline and nitric oxide via the intermediate NOHA (N(ω)-hydroxy-L-arginine). This intermediate is rapidly converted further, but to a small extent can also be liberated from the active site of NOSs and act as a transportable precursor of nitric oxide or potent physiological inhibitor of arginases. Thus its formation is of enormous importance for the nitric-oxide-generating system. It has also been shown that NOHA is reduced by microsomes and mitochondria to L-arginine. In the present study, we show for the first time that both human isoforms of the newly identified mARC (mitochondrial amidoxime reducing component) enhance the rate of reduction of NOHA, in the presence of NADH cytochrome b? reductase and cytochrome b?, by more than 500-fold. Consequently, these results provide the first hints that mARC might be involved in mitochondrial NOHA reduction and could be of physiological significance in affecting endogenous nitric oxide levels. Possibly, this reduction represents another regulative mechanism in the complex regulation of nitric oxide biosynthesis, considering a mitochondrial NOS has been identified. Moreover, this reduction is not restricted to NOHA since the analogous arginase inhibitor NHAM (N(ω)-hydroxy-N(δ)-methyl-L-arginine) is also reduced by this system.