Synthesis and Structural Study of Tetravalent (Zr4+, Hf4+, Ce4+, Th4+, U4+) Metal Complexes with Cyclic Hydroxamic Acids

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.

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ChemInform Abstract: CYCLIC HYDROXAMIC ACIDS IN THE INDOLE SERIES

Chemischer Informationsdienst ◽

10.1002/chin.198529190 ◽

1985 ◽

Vol 16 (29) ◽

Author(s):

N. A. KOGAN ◽

V. E. IVANOV

Keyword(s):

Hydroxamic Acids ◽

Cyclic Hydroxamic Acids ◽

Indole Series

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Nitrones and Oxaziridines. XXXVI. Synthesis of Cyclic Thiohydroxamic Acids

Australian Journal of Chemistry ◽

10.1071/ch9880037 ◽

1988 ◽

Vol 41 (1) ◽

pp. 37 ◽

Cited By ~ 2

Author(s):

DS Black ◽

KL Ooi

Keyword(s):

Hydroxamic Acids ◽

Demethylating Agent ◽

Ethyl Xanthate ◽

Cyclic Hydroxamic Acids ◽

Trimethylsilyl Iodide ◽

Potassium Ethyl Xanthate

2-Cyano-1-pyrroline 1-oxides (1) could not be converted directly into the related cyclic thiohydroxamic acids (8). Potassium ethyl xanthate transformed nitrones (1) into the imidates (2). The cyclic hydroxamic acids (4) can be converted into the thiohydroxamic acids (8) via the methoxypyrrolidinones (5) and the methoxypyrrolidine thiones (6), making use of sodium p- tolylmercaptide as the demethylating agent. Reaction of methoxy thiones (6) with trimethylsilyl iodide led to the formation of the 2-methylthio-1-pyrroline 1-oxides (7).

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Syntheses of Cyclic Hydroxamic Acids and Lactams with 2,3-dioxo-1,4-benzoxazine skeleton

Journal für praktische Chemie ◽

10.1002/prac.19933350409 ◽

1993 ◽

Vol 335 (4) ◽

pp. 359-362 ◽

Cited By ~ 7

Author(s):

H. Hartenstein ◽

D. Sicker

Keyword(s):

Hydroxamic Acids ◽

Cyclic Hydroxamic Acids

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Synthetic studies related to mycobactins. III. Approaches to the synthesis of the cobactin ring system

Australian Journal of Chemistry ◽

10.1071/ch9722429 ◽

1972 ◽

Vol 25 (11) ◽

pp. 2429 ◽

Cited By ~ 7

Author(s):

DSC Black ◽

RFC Brown ◽

AM Wade

Keyword(s):

Primary Amine ◽

Ring Expansion ◽

Hydroxamic Acids ◽

Ring System ◽

Ethyl Benzoate ◽

Yield Reduction ◽

Similar Reaction ◽

Oxidation Reactions ◽

Cyclic Hydroxamic Acids ◽

Synthetic Studies

The synthesis of several seven-membered cyclic hydroxamic acids has been carried out in low yield. Reduction of diethyl 2-hydroxyiminoheptane-l,7-dioate afforded ethyl 1-hydroxy-7-oxohexahydroazepine-2-carboxylate, together with related acyclic products. The cobactin precursor 3-bromo-1-hydroxyhexahydro-azepin-2-one was obtained by the ring expansion of 2-bromocyclohexanone with benzenesulphonohydroxamic acid and also by the peracid oxidation of 6-bromo-7-ethoxy-3,4,5,6-tetrahydro-2H-azepine. The methyl and cinnamyl imidates of hexanolactam were oxidized by peracid to 1-hydroxyhexahydroazepin-2-one, in addition to the related imino- and nitroso-hexanoic esters. In a similar reaction, 1-hydroxypiperidin-2-one was obtained from 2-methoxy-3,4,5,6-tetrahydropyridine. During the course of these oxidation reactions, the intermediate oxaziridines 7-methoxy-8-oxa-1-azabicyclo[5,1,0]octane and 6-bromo-7-ethoxy-8-oxa-1-azabicyclo[5,1,0]octane were isolated and identified. The peraoid oxidation of ethyl N-cyclohexylbenzimidate yielded cyclohexylhydroxylamine and ethyl benzoate in reasonable yields. This reaction suggests a useful method for the conversion of a primary amine into the related hydroxylamine.

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

Molecules ◽

10.3390/molecules24050864 ◽

2019 ◽

Vol 24 (5) ◽

pp. 864 ◽

Cited By ~ 2

Author(s):

Evgeny Chupakhin ◽

Olga Bakulina ◽

Dmitry Dar’in ◽

Mikhail Krasavin

Keyword(s):

Iron Overload ◽

Targeted Delivery ◽

Hydroxamic Acids ◽

Hydrochloride Salt ◽

Soluble Iron ◽

Cyclic Hydroxamic Acids

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.

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