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.
A Screen of Approved Drugs Identifies the Androgen Receptor Antagonist Flutamide and Its Pharmacologically Active Metabolite 2-Hydroxy-Flutamide as Heterotropic Activators of Cytochrome P450 3A In Vitro and In Vivo
