Mechanisms of cytotoxic action of a series of directionally synthesized heterocyclic hydroxamic acids

Cyclic hydroxamic acids based on quinazoline-4(3H)-one and dihydroquinazoline-4(1H)-one have been synthesized. The antioxidant and iron-chelating properties of these compounds, their effect on the activity of the histone deacetylase enzyme, and their cytotoxic effect on cells of various tumor lines have been investigated. We have identified two compounds-hits, which exhibit the multipharmacological type of the antineoplastic activity. Their cytotoxic effect on cells of human lung carcinoma A549 and breast adenocarcinoma MCF-7 is obviously associated with their ability to modulate the level of reactive oxygen species and to chelate Fe(II) ions, as well as to inhibit the metalloenzymes, histone deacetylases, involved in the epigenetic regulation of tumor genesis. Thus, the synthesized hydroxamic acids may be considered as a promising basis for creating potential oncolytics.

Facile Access to Fe(III)-Complexing Cyclic Hydroxamic Acids in a Three-Component Format

Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic constructs for targeted delivery. An earlier described three-component variant of the Castagnoli—Cushman reaction of homophthalic acid (via in situ cyclodehydration to the respective anhydride) was extended to involve hydroxylamine in lieu of the amine component of the reaction. Using hydroxylamine acetate and O-benzylhydroxylamine was key to the success of this transformation due to greater solubility of the reagents in refluxing toluene (compared to hydrochloride salt). The developed protocol was found suitable for multigram-scale syntheses of N-hydroxy- and N-(benzyloxy)tetrahydroisoquinolonic acids. The cyclic hydroxamic acids synthesized in the newly developed format have been tested and shown to be efficient ligands for Fe3+, which makes them suitable candidates for the above-mentioned applications.

Establishing biotic stress tolerance of maize (Zea mays L.) by measuring hydroxamic acid contents

Cyclic hydroxamic acids are the most considerable secondary metabolites in grasses and their main task is to protect these species from pathogens and pests. The cyclic hydroxamic acid content and common smut susceptibility were examined in our experiments. 27 maize hybrids were used for experimental plants in a climate room, where the plants were grown on a nutrient solution. An infiltration method was used for the inoculation of the plants. The total quantity of cyclic hydroxamic acids was determined and the ratio of infected plants and the ratio of inhibition was determined, too. Based on our results, on the basis of all hybrids’ data, the total hydroxamic acid content of the infected plants was higher than in the control. On the level of individual hybrids, only 9 of them had higher cyclic hydroxamic acid content in the case of infection. Increase in cyclic hydroxamic content induced by the fungus in this case is a tool for the fungus to suppress other pathogens and pests. Amongst the hybrids’ cyclic hydroxamic acid contents, significant differences were detected in the control and in the infected treatment, too. The so-called “sweetcorn” hybrids showed high level of cyclic hydroxamic acid content. According to the differences amongst hybrids, homogenous groups were created which groups differed in the case of control and infected treatment, because of the difference in increase of cyclic hydroxamic acid content. The examined hybrids showed different levels of infection and different rate of growth inhibition for the effect of inoculation. According to the infection caused damage hybrids were ranked. Infection caused notable damage for hybrids Prelude, Desszert 73, DKC5276 and DK440.

Chemosensitizing Activity of Histone Deacetylases Inhibitory Cyclic Hydroxamic Acids for Combination Chemotherapy of Lymphatic Leukemia

Background: Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. Objective: The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. Method: Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. Results: Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. Conclusion: It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.