Chemosensitizing activity of histone deacetylases inhibitory cyclic hydroxamic acids for combination chemotherapy of lymphatic leukemia.

Chemosensitizing activity of histone deacetylases inhibitory cyclic hydroxamic acids for combination chemotherapy of lymphatic leukemia.

Curr Cancer Drug Targets. 2017 Jun 23;:

Authors: Mishchenko DV, Neganova ME, Klimanova EN, Sashenkova TE, Shevtsova EF, Vystorop IV, Tarasov VV, Ashraf GM, Yarla NS, Aliev G

Abstract
Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) prepared from Glycine (a), Alanine (b), Valine (c), Leucine (d), and Phenylalanine (e) hydroxamic acids and α-biperidones-4 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 chelators, 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. 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.

PMID: 28669342 [PubMed - as supplied by publisher]

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