Triphenylphosphonium Analogs of Short Peptide Related to Bactenecin 7 and Oncocin 112 as Antimicrobial Agents.

Antimicrobial peptides (AMPs) have recently attracted attention as promising antibacterial agents capable of acting against resistant bacterial strains. In this work, an approach was applied, consisting of the conjugation of a peptide related to the sequences of bactenecin 7 (Bac7) and oncocin (Onc112) with the alkyl(triphenyl)phosphonium (alkyl-TPP) fragment in order to improve the properties of the AMP and introduce new ones, expand the spectrum of antimicrobial activity, and reduce the inhibitory effect on the eukaryotic translation process. Triphenylphosphonium (TPP) derivatives of a decapeptide RRIRPRPPYL were synthesized. It was comprehensively studied how the modification of the AMP affected the properties of the new compounds. It was shown that while the reduction in the Bac7 length to 10 a.a. residues dramatically decreased the affinity to bacterial ribosomes, the modification of the peptide with alkyl-TPP moieties led to an increase in the affinity. New analogs with structures that combined a decapeptide related to Bac7 and Onc112-Bac(1-10, R/Y)-and TPP attached to the C-terminal amino acid residue via alkylamide linkers, inhibited translation in vitro and were found to be more selective inhibitors of bacterial translation compared with eukaryotic translation than Onc112 and Bac7. The TPP analogs of the decapeptide related to Bac7 and Onc112 suppressed the growth of both Gram-negative bacteria, similar to Onc112 and Bac7, and Gram-positive ones, similar to alkyl-TPP derivatives, and also acted against some resistant laboratory strains. Bac(1-10, R/Y)-C2-TPP, containing a short alkylamide linker between the decapeptide and TPP, was transferred into the E. coli cells via the SbmA transporter protein. TPP derivatives of the decapeptide Bac(1-10, R/Y) containing either a decylamide or ethylamide linker caused B. subtilis membrane depolarization, similar to alkyl-TPP. The Bac(1-10, R/Y)-C2-TPP analog was proven to be non-toxic for mammalian cells using the MTT test.

A novel simple and sensitive approach for determination of 1,1-dimethylhydrazine in aqueous samples by high performance liquid chromatography with ultraviolet and tandem mass spectrometric detection after derivatization with unsubstituted aromatic aldehydes.

In this work, simple, rapid and highly sensitive method of hazardous chemical 1,1-dimethylhydrazine (unsymmetrical dimethylhydrazine, UDMH) determination based on pre-column derivatization with unsubstituted aromatic aldehydes and reversed-phase high performance liquid chromatography-ultraviolet-tandem mass spectrometry (RP HPLC-UV-MS/MS) has been developed. Along with benzaldehyde, commercially available aromatic aldehydes, namely: 2-naphthaldehyde, 2-pyridinecarboxaldehyde, and 2-quinolinecarboxaldehyde, were used as derivatizing reagents in the analysis of hydrazines for the first time. The reactions were studied in a wide pH range by varying reaction time and other conditions. A slightly alkaline pH 9 was shown to be optimal for the derivatization of UDMH by aromatic aldehydes. The quantitative yield of derivatization products under the established conditions was confirmed by HPLC analysis with amperometric detection. For all studied reagents, wide linear ranges of concentrations (0.01-1000 µg/L) in natural water samples were observed. The limits of detection for UDMH in natural water were in the 3.7-130 ng/L range. 2-Quinolinecarboxaldehyde was selected as the most appropriate reagent for HPLC-UV-MS/MS determination of UDMH. In case of using this reagent, the accuracy was in the range of 97-102%, and precision, expressed as RSD was less than 8%. The developed approach does not require laborious stages of pre-concentration and isolation of UDMH from natural water components.

New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma.

In this work, we have developed covalent and low molecular weight docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related to hepatocellular carcinoma cells. The resulting glycoconjugates have an excellent affinity to the asialoglycoprotein receptor (ASGPR) in the nanomolar range of concentrations and a high cytotoxicity level comparable to docetaxel. Likewise, we observed the 21-75-fold increase in water solubility in comparison with parent docetaxel and prodrug lability to intracellular conditions with half-life values from 25.5 to 42 h. We also found that the trivalent conjugate possessed selective toxicity against hepatoma cells vs control cell lines (20-35 times). The absence of such selectivity in the case of monovalent conjugates indicates the effect of ligand valency. Specific ASGPR-mediated cellular uptake of conjugates was proved in vitro using fluorescent-labeled analogues. In addition, we showed an enhanced generation of reactive oxygen species in the HepG2 cells, which could be inhibited by the natural ligand of ASGPR. Overall, the obtained results highlight the potential of ASGPR-directed cytostatic taxane drugs for selective therapy of hepatocellular carcinoma.