Project description:New quaternary ammonium derivatives (quats) based on apple pectin (PA) were synthesized by the chemical modification of native polysaccharides with various quaternization mixtures containing epichlorohydrin (ECH) and a tertiary amine. Pectin derivatives (QPAs) were studied by elemental analysis, conductometric titration, Fourier-transform infrared spectroscopy (FTIR), and 13C nuclear magnetic resonance (13C NMR). Viscosity measurements enabled the evaluation of the viscosity average molar mass (Mv) for the unmodified polysaccharide, as well as its intrinsic viscosity ([η]) value. Dynamic light scattering (DLS) analysis revealed that the PA and its quats formed aggregates in an aqueous solution with either a unimodal (PA) or bimodal (QPAs) distribution. Scanning transmission electron microscopy analysis (STEM) of the PA and its derivatives demonstrated the presence of individual polymeric chains and aggregates in aqueous solution, with the smallest sizes being specific to amphiphilic polymers. Thermal stability, as well as wide-angle X-ray diffraction (WAXD) studies, generally indicated a lower thermal stability and crystallinity of the QPAs compared with those of the PA. Antipathogenic activity demonstrated that the PA and its derivatives exhibited effectiveness against S. aureus ATCC 25923 bacterium and C. albicans ATCC 10231 pathogenic yeast.
Project description:The synthesis and biological evaluation of a novel series of dimeric camphor derivatives are described. The resulting compounds were studied for their antiviral activity, cyto- and genotoxicity. Compounds 3a and 3d in which the quaternary nitrogen atoms are separated by the C5H10 and ?9H18 aliphatic chain, exhibited the highest efficiency as an agent inhibiting the reproduction of the influenza virus A(H1N1)pdm09. The cytotoxicity data of compounds 3 and 4 revealed their moderate activity against malignant cell lines; compound 3f had the highest activity for the CEM-13 cells. These results show close agreement with the data of independent studies on toxicity of these compounds, in particular that the toxicity of compounds strongly depends on spacer length.
Project description:This paper presents a study on a series of quaternary ammonium salt (QAS) derivatives of glucopyranosides with an elongated hydrophobic hydrocarbon chain. The new N-[6-(β-D-glucopyranosyloxy)hexyl]ammonium bromides and their O-acetyl derivatives were analyzed via (1)H and (13)C NMR spectroscopy. The mutagenic activity of the newly synthesized QAS was investigated using two different techniques: The Vibrio harveyi luminescence assay and the Ames test. The obtained results support previous findings contesting QAS safety and indicate that QAS, specifically pyridinium derivatives, might be mutagenic.
Project description:A series of novel quaternary ammonium 4-deoxypyridoxine derivatives was synthesized. Two compounds demonstrated excellent activity against a panel of Gram-positive methicillin-resistant S. aureus strains with MICs in the range of 0.5-2 μg/mL, exceeding the activity of miramistin. At the same time, both compounds were inactive against the Gram-negative E. coli and P. aeruginosa strains. Cytotoxicity studies on human skin fibroblasts and embryonic kidney cells demonstrated that the active compounds possessed similar toxicity with benzalkonium chloride but were slightly more toxic than miramistin. SOS-chromotest in S. typhimurium showed the lack of DNA-damage activity of both compounds; meanwhile, one compound showed some mutagenic potential in the Ames test. The obtained results make the described chemotype a promising starting point for the development of new antibacterial therapies.
Project description:Antibody drug conjugates (ADCs) have emerged as a highly promising class of cancer therapeutics, comprising antibodies, effector molecules, and linkers. Among them, DS-8201a with DXd as the effector molecule, has shown remarkable anti-tumor efficacy against solid tumors, sparking a surge of interest in ADCs with camptothecin derivatives as ADC effector molecules. In this study, we introduced and successfully constructed quaternary ammonium ADCs utilizing camptothecin derivatives WL-14 and CPTS-1 for the first time. All four ADCs displayed excellent stability under physiological conditions and in plasma, facilitating their prolonged circulation in vivo. Moreover, the four ADCs, employing Val-Cit or Val-Ala dipeptide linkers effectively achieved complete release of the effector molecules via cathepsin B. Although, the in vitro antitumor activity of these ADCs was comparatively limited, the development of quaternary ammonium ADCs based on novel camptothecin derivatives as effector molecules is still a viable and promising strategy. Significantly, our study provides valuable insights into the crucial role of linker optimization in ADCs design.
Project description:A series of novel vancomycin analogues with quaternary ammonium moieties have been designed and synthesized for fighting with clinically isolated drug-resistant bacteria. Partial target molecules exhibited potent activity against the tested strains. Among all of the compounds, a triazole quaternary ammonium vancomycin (QAV) derivative QAV-a1 exerted the best antibacterial activities. QAV-a1 was found to be 4- to 32-fold more efficacious than vancomycin against MRSA. Meanwhile, QAV-a1 showed a good pharmacokinetic profile with a half-life of 5.19 ± 0.10 h, which is longer than that of vancomycin (4.3 ± 1.9 h). These results provided guidance for the further exploitation of vancomycin derivatives against drug-resistant bacteria.
Project description:Chemical modification of chitosan is increasingly studied for its potential of providing new applications of chitosan. Here, a group of novel chitosan quaternary ammonium derivatives containing pyridine or amino-pyridine were designed and successfully synthesized through chemical modification of chitosan. Pyridine and amino-pyridine were used as functional groups to improve the antifungal activity of chitosan derivatives. The chitosan derivatives' antioxidant activity against hydroxyl-radical and 1,1-Diphenyl-2-picrylhydrazyl (DPPH)-radical was tested in vitro. The results showed that chitosan derivatives had better water solubility and stronger antioxidant activity compared with chitosan in all assays. Especially, compounds 3C and 3E (with 3-amino pyridine and 2,3-diamino pyridine as substitute respectively) exhibited stronger hydroxyl-radical and DPPH-radical scavenging ability than other synthesized compounds. These data demonstrated that the synergistic effect of the amino group and pyridine would improve the antioxidant activity of chitosan derivatives, and the position of the amino group on pyridine could influence the antioxidant property of chitosan derivatives.
Project description:There is a lack of comprehensive toxicity studies of QACs associated with pulmonary toxicity. Therefore, we aimed to elucidate the potential pulmonary toxic effects of QACs based on toxicogenomic approach. We conducted transcriptome analysis using RNA sequencing to identify alterations in gene expression associated with QACs exposure.