C1'-Branched acyclic nucleoside phosphonates mimicking adenosine monophosphate: Potent inhibitors of Trypanosoma brucei adenine phosphoribosyltransferase.

Some pathogens, including parasites of the genus Trypanosoma causing Human and Animal African Trypanosomiases, cannot synthesize purines de novo and they entirely rely on the purine salvage pathway (PSP) for their nucleotide generation. Thus, their PSP enzymes are considered as promising drug targets, sparsely explored so far. Recently, a significant role of acyclic nucleoside phosphonates (ANPs) as inhibitors of key enzymes of PSP, namely of 6-oxopurine phosphoribosyltransferases (PRTs), has been discovered. Herein, we designed and synthesized two series of new ANPs branched at the C1' position as mimics of adenosine monophosphate. The novel ANPs efficaciously inhibited Trypanosoma brucei adenine PRT (TbrAPRT1) activity in vitro and it was shown that the configuration on the C1' chiral centre strongly influenced their activity: the (R)-enantiomers proved to be more potent compared to the (S)-enantiomers. Two ANPs, with Ki values of 0.39 µM and 0.57 µM, represent the most potent TbrAPRT1 inhibitors reported to date and they are an important tool to further study purine metabolism in various parasites.

Nucleotide analogues containing a pyrrolidine, piperidine or piperazine ring: Synthesis and evaluation of inhibition of plasmodial and human 6-oxopurine phosphoribosyltransferases and in vitro antimalarial activity.

Parasites of the Plasmodium genus are unable to produce purine nucleotides de novo and depend completely on the salvage pathway. This fact makes plasmodial hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] a valuable target for development of antimalarial agents. A series of nucleotide analogues was designed, synthesized and evaluated as potential inhibitors of Plasmodium falciparum HGXPRT, P. vivax HGPRT and human HGPRT. These novel nucleoside phosphonates have a pyrrolidine, piperidine or piperazine ring incorporated into the linker connecting the purine base to a phosphonate group(s) and exhibited a broad range of Ki values between 0.15 and 72 µM. The corresponding phosphoramidate prodrugs, able to cross cell membranes, have been synthesized and evaluated in a P. falciparum infected human erythrocyte assay. Of the eight prodrugs evaluated seven exhibited in vitro antimalarial activity with IC50 values within the range of 2.5-12.1 µM. The bis-phosphoramidate prodrug 13a with a mean (SD) IC50 of 2.5 ± 0.7 µM against the chloroquine-resistant P. falciparum W2 strain exhibited low cytotoxicity in the human hepatocellular liver carcinoma (HepG2) and normal human dermal fibroblasts (NHDF) cell lines at a concentration of 100 µM suggesting good selectivity for further structure-activity relationship investigations.

Efficient Synthesis of α-Branched Purine-Based Acyclic Nucleosides: Scopes and Limitations of the Method.

An efficient route to acylated acyclic nucleosides containing a branched hemiaminal ether moiety is reported via three-component alkylation of N-heterocycle (purine nucleobase) with acetal (cyclic or acyclic, variously branched) and anhydride (preferentially acetic anhydride). The procedure employs cheap and easily available acetals, acetic anhydride, and trimethylsilyl trifluoromethanesulfonate (TMSOTf). The multi-component reaction is carried out in acetonitrile at room temperature for 15 min and provides moderate to high yields (up to 88%) of diverse acyclonucleosides branched at the aliphatic side chain. The procedure exhibits a broad substrate scope of N-heterocycles and acetals, and, in the case of purine derivatives, also excellent regioselectivity, giving almost exclusively N-9 isomers.

Fusarium Mycotoxins in Two Hulless Oat and Barley Cultivars Used for Food Purposes.

Hulless oats and hulless barley are highly valued for their excellent nutritional attributes and are increasingly being promoted in human nutrition. However, special attention should be paid to the risk of their contamination by Fusarium mycotoxins, as the rate of mycotoxin reduction during processing could be much lower than that for hulled cereals. In the present study, mycotoxin contamination of two cultivars, each of hulless oats and barley suitable for food purposes were studied in a 3-year field trial established in two contrasting environments. The contents of the mycotoxins regulated by law (deoxynivalenol and zearalenone) were low, and the present legal limits for their maximum content in unprocessed cereals were far from being exceeded. The mycotoxins most frequently occurring in hulless barley were enniatins (enniatin B, enniatin B1 and enniatin A1), beauvericin and nivalenol; hulless oats most frequently contained the HT-2 and T-2 toxins, beauvericin and enniatin B. The contents of enniatins and nivalenol were higher in barley than in oats. Close, positive relationships between the contents of the individual enniatins and between enniatins, beauvericin and nivalenol were observed, which implies that co-exposure could enhance the toxic potential of these mycotoxins through synergistic effects. The results highlight the need to pay more attention to the occurrence of enniatins, beauvericine and nivalenol in hulless oats and barley used for food purposes.

Synthesis of α-Branched Acyclic Nucleoside Phosphonates as Potential Inhibitors of Bacterial Adenylate Cyclases.

Inhibition of Bordetella pertussis adenylate cyclase toxin (ACT) and Bacillus anthracis edema factor (EF), key virulence factors with adenylate cyclase activity, represents a potential method for treating or preventing toxemia related to whooping cough and anthrax, respectively. Novel α-branched acyclic nucleoside phosphonates (ANPs) having a hemiaminal ether moiety were synthesized as potential inhibitors of bacterial adenylate cyclases. ANPs prepared as bisamidates were not cytotoxic, but did not exhibit any profound activity (IC50 >10 µm) toward ACT in J774A.1 macrophages. The apparent lack of activity of the bisamidates is speculated to be due to the inefficient formation of the biologically active species (ANPpp) in the cells. Conversely, two 5-haloanthraniloyl-substituted ANPs in the form of diphosphates were shown to be potent ACT and EF inhibitors with IC50 values ranging from 55 to 362 nm.

Syngas production from pyrolysis of nine composts obtained from nonhybrid and hybrid perennial grasses.

A pyrolysis of compost for the production of syngas with an explicit H2/CO = 2 or H2/CO = 3 was investigated in this study. The composts were obtained from nonhybrid (perennial) grasses (NHG) and hybrid (perennial) grasses (HG). Discrepancies in H2 evolution profiles were found between NHG and HG composts. In addition, positive correlations for NHG composts were obtained between (i) H2 yield and lignin content, (ii) H2 yield and potassium content, and (iii) CO yield and cellulose content. All composts resulted in H2/CO = 2 and five of the nine composts resulted in H2/CO = 3. Exceptionally large higher heating values (HHVs) of pyrolysis gas, very close to HHVs of feedstock, were obtained for composts made from mountain brome (MB, 16.23 MJ/kg), hybrid Becva (FB, 16.45 MJ/kg), and tall fescue (TF, 17.43 MJ/kg). The MB and FB composts resulted in the highest syngas formation with H2/CO = 2, whereas TF compost resulted in the highest syngas formation with H2/CO = 3.