Igor V. Vystorop

2,5-Dioxybicyclo[2.2.2]octane-3,6-diones. A conformational study by ab initio molecular orbital methods and molecular mechanics calculations

Ab initio molecular orbital calculations at the RHF, MP2 and hybrid density functional theoretical levels with the 6-31G∗ basis set have been used to obtain the optimized structures of 2,5-dioxabicyclo[2.2.2]octane-3,6-dione (1) and its 1,4-dimethyl derivative (2) which reproduce the available experimental (X-ray analysis) data for 2 reasonably well. Molecular mechanics calculations with mm2(91) and mm3(92) force fields of equilibrium structures for 1, 2 are also given. According to all calculations the [2.2.2] frame structure of (1R,4R)-dilactones 1 and 2 corresponds to a single synchro( +, +, + )-twist-form (A) which is in agreement with the experimental crystal structure for 2. Investigation of the torsional energy surface of 1 by the mm2(91) method does not suggest the existence of any other structure than the synchro( +, +, + )-twist-A-conformer. The factors that determine the relative stabilization of the single form of dilactones 1, 2 are considered. Experimental coupling constants (3JHH) of dilactones 1, 2 are also consistent with a single conformer in solution.

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.

The Effectiveness of Cyclic Hydroxamic Acid CHA-5 against Drug-Resistant P388 Leukemia Strains

We studied the effectiveness of cyclic hydroxamic acid CHA-5 against drug-resistant and multidrug-resistant murine P388 leukemia strains. More than 60% mice receiving transplantation of rubomycin-resistant leukemia P388 strain survived after CHA-5 monotherapy; combined therapy with CHA-5 and cisplatin was also highly effective. Vincristine-resistant tumor was highly sensitive to combined treatment with CHA-5 and cyclophosphamide. It should be emphasized that standard antitumor agents were used in very low doses in combination therapy and CHA-5 significantly potentiated their effect.

Biological Activity of Spirocyclic Hydroxamic Acids

Iron-chelating activity of synthesized spirocyclic hydroxamic acids, their toxicity, and effects on mitochondrial function were studied using primary culture of cerebral cortical neurons from newborn rats. All tested compounds effectively chelated Fe(II) ions. Activity of spirocyclic hydroxamic acids more strictly depended on the structure their piperidine, but not imidazolidine fragment. All compounds were non-toxic for normal neuronal culture.

Autoassembly of cage structures. 4. Stereochemistry of 2,5-di-tert-butyl-γ-butyrolactone-4-carboxy-s-(α)-phenylethylamide

The diastereoisomeric lactonamides (2a, b), obtained from the dilactone (1) and S-phenylethylamine, have been separated. X-ray crystallography shows that the high-melting isomer (2a) has theR-configuration at the chiral centers C2 and C4, the enantiomeric conformation of the γ-lactone ring being of theS-type in thetwist form, intermediate between envelope2E and semi-chair32T. It is shown by molecular mechanics that the minimum steric energy of2a corresponds to a conformation of the heterocycle close to the envelope form3E. Examination of van der Waals interactions shows that the calculated structure for2a is preferred. The reasons for the nonidentity of the forms of the γ-lactone ring of2a in the crystal and the free state are discussed. The crystal structure of2a is composed of two geometrically similar independent molecules associated along the axis by weak hydrogen bonds of two types, the energies of which have been estimated from the vXH values, which are related by the expression vXH=f(RX...O), where X=N, O.