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The reaction of DL-valine hydroxamic acid with triacetonamine proceeds as the N,N'-regioselective condensation to form (±)-1-hydroxy-3-isopropyl-7,7,9,9-tetramethyl-1,4,8-triazaspiro[4,5]decan-2-one. A study of the antimetastatic and antitumor activities of the resulting hydroxamic acid in vivo by the combined therapy with a cytostatic of the alkylation type on a model of experimental transplanted mouse melanoma B16 showed that the compound is capable of increasing the sensitivity of the tumor to the known antitumor drug cyclophosphamide applied at a subtherapeutic dose. The chemosensitizing activity of hydroxamic acid combined with cyclophosphamide led to an almost twofold increase in the antitumor effect of the cytostatic and a marked decrease in the number of metastases, which showed up as an increase in the metastasis inhibition index (MII) to 74%.

The effect of 10 racemic spirocyclic hydroxamic acids (CHA 1–10, derivatives of 1-hydroxy-1,4,8-triazaspiro[4,5]decan-2-one), containing pharmacophore imidazolidinone and piperidine fragments with different substituents, on the activity of enzyme histone deacetylase (HDAC) was studied. It was shown that CHA (1–10) inhibit HDAC activity in cultured breast cancer cells. It was shown that CHA (1–10) as a part of polychemotherapy with cisplatin and cyclophosphane have a pronounced chemosensitizing antitumor activity in vivo. The results obtained on tumor models in vivo showed that CHA can be considered as potential medicinal components of tumor polychemotherapy.

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.

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.

The effects of cyclic hydroxamic acids (CHAs) derived from glycine and D,L-alanine on the enzymatic activity of Ca2+,Mg2+-ATPase from sarcoplasmic reticulum (Ca2+,Mg2+-ATPase SR) and cyclic guanosine monophosphate phosphodiesterase (PDEcGMP) were investigated. CHAs I (C5H10N2O2), II (C6H12N2O2), III (C8H15N3O2), IV (C9H17N3O2), V (C11H21N3O2), and VI (C12H23N3O2) were modulators of Ca2+,Mg2+-ATPase SR enzyme activity. Compounds I-VI decoupled to various extents the hydrolytic and transport functions of Ca2+,Mg2+-ATPase SR, disrupting the ratio of intra- and extracellular Ca2+ ions. This affected the adhesion of metastatic cells to capillary endothelium. Compounds IV and VI had the highest metastasis inhibition indices (MII%) for B-16 melanoma of 33 and 81%, respectively. This correlated with a decreased Ca2+ transmembrane transfer coefficient into SR vesicles of 0.75 for IV and 0.5 for VI compared with a [Ca2+]/[ATP] ratio in the control of 1.4. CHAs I-VI did not affect the functioning of PDEcGMP. The results enabled potential antimetastatic drugs in the CHA series to be predicted.

Regioselective cyclocondensation of glycine hydroxamic and dl-alanine hydroxamic acids with 1-methylpiperidin-4-one gave 1-hydroxy-8-methyl-1,4,8-triazaspiro[4.5]decan-2-one (5) and (±)-1-hydroxy-3,8-dimethyl-1,4,8-triazaspiro[4.5]decan-2-one (6), respectively. The X-ray diffraction data showed that acid 6 formed racemic crystals with two independent molecules, whose structure was studied and compared with the analog obtained earlier. The in vivo tests on the leukemia P388 and L1210 models showed that the low-toxic spirocyclic hydroxamic acids 5 and 6 were the adjuvants of clinic cytostatics cisplatin and cyclophosphamide. Chemotherapy of the leukemias P388 and L1210 was more efficient with the combination of acid 6 with cisplatin and cyclophosphamide, respectively.

The reactions of glycine hydroxamic and DL-alanine hydroxamic acids with triacetonamine are chemoselective and afford 1-hydroxy-7,7,9,9-tetramethyl-1,4,8-triazaspiro[4.5]decan-2-one (3) and (±)-1-hydroxy-3,7,7,9,9-pentamethyl-1,4,8-triazaspiro[4.5]decan-2-one (4), respectively. The X-ray diffraction study showed that compound 3 crystallizes as a solvate with MeCN (1: 1). As shown by ESR measurements, spiro hydroxamic acids 3 and 4 are NO donors in in vitro biological systems. The NO-donor activity of compounds 3 and 4 was found to be substantially higher in the presence of DMSO. Homologue 4 is a stronger NO donor than 3. Compound 4 also exhibits high antimetastatic activity (81%) on the B16-melanoma model.

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.

The reactions of glycine hydroxamic acid with aliphatic ketones and acetophenone are commonly used for the regioselective synthesis of cyclic hydroxamic acids 6a–e; spiro hydroxamic acid 6a was structurally characterised by X-ray diffraction analysis.

Condensation of glycine and dl-alanine hydroxamic acids with 1-methyl-4-piperidone regioselectively gave the corresponding titled spiro piperidine hydroxyimidazolidinones capable of enhancing sensitivity of P388 and L1210 leukemias in mice models to the known anticancer drugs cisplatin and cyclophosphamide.

The cyclocondensation of racemic valine, leucine and β-phenylalanine hydroxamic acids with acetone regioselectively affords corresponding cyclic hydroxamic acids; the crystal structure of the 5-isobutyl derivative was determined by X-ray diffraction analysis and compared with that of its 5-methyl homologue.

Enantiomeric dilactones ((1R,4R)-(+)-1 and (1S,4S)-(-)-1) of αα′-dihydroxy-αα′-di-tert-butylglutaric acid have been prepared. The Cotton effect sign of the n→π*-transition of the lactone chromophore in enantiomers1 is determined by the contribution of the uncompensated bonds of the δ-dilactone ring, but not by that of the γ-monolactone ring of1. The correlation of the Cotton effect sign of the n→π*-transition with the chirality of the cage structure and the absolute configuration for the series of 1,4-dialkyldilactones of type1 has been suggested. The contribution of the pseudo-a-oriented amide group to, the Cotton effect sign of the lactone n→π*-transition (the effect of the third chiral sphere) in diastereomeric lactonamides2a,b predominates over that of the nonplanar bonds of the heterocycle (over the effect of the second chiral sphere).

By optimization of the geometry of 2, 5-dioxabicyclo[2. 2.1]heptane-3.6-dione (1) with an ab initio (RHF/6-31 G') calculation, we have found that a single synchro(+, +)-twist form (A) corresponds to the (1 R,4R)-enantiomer (the dihedral angles of the lactone bridges areϕ 0 = 2.6°). According to MM2(91) and MM3(92) calculations, (1R,4R)-1 exists as the s-ynchro(+, +)-A-twist (ϕ 0 = 3.9°) and the synchro(-, -)-B-twist (ϕ = -3.8°) forms, respectively. Investigating the torsional energy surface of the dilactone 1 (MM2(91)), we found only the (1R,4R,P)-diastereomeric form (A), which is stabilized compared with the (1R,4P,M) form (B) (probably as a result of the more preferred dipole-dipole interaction of the carbonyl groups). According to the calculated puckering coordinates, the five-membered and six-membered moieties of the bicycle 1 are flattened compared with norbornane.

The reaction of glycine hydroxamic acid with benzaldehyde regioselectively affords the title racemic cyclic hydroxamic acid, which crystallises as enantiomorphic crystals (space group P212121) from a methanol solution.

The condensation reaction of glycine and alanine hydroxamic acids with piperidone (II) regioselectively affords the title spiro compounds (III), which are capable of enhancing sensitivity of P388 and L1210 leukemias in mice models to the known anticancer drugs cisplatin and cyclophosphamide.

The condensation of glycine hydroxamic acid with acetone regioselectively leads to the formation of the title achiral cyclic hydroxamic acid, which crystallises from an acetone solution as chiral crystals (space groupP2 1 2 1 2 1 ) of (P,1R,3S) and (M,1S,3R) enantiomers.

Cyclic hydroxamic acids (III) are regioselectively obtained in a self-catalytic cyclocondensation reactions of racemic valine, leucine, and β-phenylalanine hydroxamic acids with acetone under mild reaction conditions.

Hydrocyanation of 3-methylpentane-2,4-dione stereospecifically gave trans,trans-iminolactone 1, whose configuration was established by X-ray diffraction of the corresponding lactone 2; the rate of cyclization of the diastereoisomeric lactonic acids 3a,b and their esters 4a,b into dilactone 5 was controlled sterically by the methyl groups with cis,cis-isomers 3b, 4b predominating; alcoholysis of 5 regiospecifically afforded ester 4b.

The condensation of glycine hydroxamic acid with acetone regioselectively leads to the formation of the title achiral cyclic hydroxamic acid, which crystallises from an acetone solution as chiral crystals (space groupP2 1 2 1 2 1 ) of (P,1R,3S) and (M,1S,3R) enantiomers.

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 envelope 2 E and semi-chair 3 2 T. 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.

Stereoselective synthesis of d,l-α,α′-dioxy-α,α′-di-tert-butylglutaric acid hydroxyiminolactonitrile (3) was conducted by the reaction of dipivaloylmethane with HCN in ether. The corresponding hydroxylacetonitrile (4) and amide (5), acid (6), and its ester (7), from which dilactone (8) was synthesized with preparative yields, were obtained from3. Benzyl amide (9) was obtained by the reaction of8 with BnNH2. The iminolactone structure3 of dipivaloylmethane bis-cyanohyrin, thecis-pseudo-a orientation of the functional substituents in3–7 and9, and the structure of the dilactone8 were confirmed by the1H,13C NMR,IR and mass spectra.

The title dilactone has been resolved into its enantiomers (+)- (S,S)-1 and (–)-(R,R)- 1, whose absolute configurations were found by X-ray diffraction analysis of intermediate lactonic amide 2a; the magnitude of the n–π* Cotton effect increased with an increase in folding or a diminution in twist of the boat conformation of a dilactone ring.

Hydrocyanation of 3-methylpentane-2,4-dione stereospecifically gave trans,trans-iminolactone 1, whose configuration was established by X-ray diffraction of the corresponding lactone 2; the rate of cyclization of the diastereoisomeric lactonic acids 3a,b and their esters 4a,b into dilactone 5 was controlled sterically by the methyl groups with cis,cis-isomers 3b, 4b predominating; alcoholysis of 5 regiospecifically afforded ester 4b.

The correlation of the Cotton effect sign of the n → π* transition with the cage structure chirality and the absolute configuration of 1,4-dialkyl-2,5-dioxabicyclo[2.2.1]heptane-3,6-diones has been established.

The title dilactone exists in a crystalline state (110 K) as enantiomeric synchro-(+,+)-(R,R)- and synchro-(–,–)-(S,S)-twist forms (τ0 = |1.8°|) with the retention of C2 symmetry, linked by infinite zig-zag heterochiral chains (space group C2/c) by mutual H-bonds of the CH2–H‥O=C type.

A study of the 1 H NMR spectra of a series of 8-hydroxyquinolines has been carried out using the 2D-COSYLR method and inter-ring proton spin-spin coupling constants 4 J , 5 J , 6 J and 7 J have been detected; it has been established that the π- mechanism for transmission of spin–spin coupling predominates and in the case of the planar zig-zag arrangement this results in unexpected annulment of 6 J 2,7 and 6 J 3,6 .

1. The automatic assembly of dilactones from α,α′-dihydroxyglutaric acids and their derivatives is controlled not only by configuration (from the d, l and not the meso form) but also by conformation and is not realized in the presence of α,α′-substituents having predominantly pseudoequatorial orientation in the corresponding monolactone. Thus, γ-crotonolactone is formed instead of the expected dilactone during the thermolysis of d,l-α,α′-dihydroxyglutaric acid. 2. The diastereomers of α,α′-dibromoglutaric acid and the d,l-forms (in contrast to the meso form) of α,α′-dihydroxyglutaric acid and their esters are conformationally uniform in the case where there is no intramolecular hydrogen bond. 3. The meso forms of the conformationally uniform α,α′-disubstituted glutaric acids differ from the d,l-forms in the nonequivalence of the JCH spin-spin coupling constants with the protons of the CH2 group. 4. Pseudoaxial preference was detected for the CO2H and CO2Me groups in trans-2-hydroxy-4-carboxy-γ-butyrolactone and its methyl ester respectively.

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.