Two new compounds from the class of bis(3-halopropionyl)amides were synthesized by the reaction of 3-halopropionyl chloride with N,N′-dimethylethylenediamine. These structural analogs of prodimin, a water insoluble anticancer drug, are soluble in water, which significantly expands methods for their administration into a body. The compounds obtained and prodimin (as a reference substance) were studied on P388 murine leukemia and some of its drug-resistant strains. The data obtained suggest a high efficacy of one synthesized compound against drug-resistant tumors.

A series of amino acid derivatives of oxalic acid were obtained. In combination therapy with conventional cytostatics used in lower doses, the new compounds substantially increase the efficacy of the drugs in the treatment of experimental P388 murine leukemia and some its drug-resistant 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.

The influence of an organic NO donor belonging to non-steroidal anti-inflammatory drugs (NSAIDs) — NO-indomethacin (NO-Ind) on the antitumor effect of cyclophosphamide (CP) and its compositions with asparagyl hydroxamic acid (AHA) were studied, along with the influence on the activity of cytochrome P-450. Compared to a previously studied NSAID — diclofenac hydroxamic acid nitrate — NO-Ind exhibited lower enhancement of CP activity even when hydroxamic acid was added to the drug composition. EPR spectroscopy was used to evaluate the changes in activity of P-450 under the action of modified NSAIDs. The studies demonstrated partial inhibition of cytochrome P-450, the inhibition time is being greater for the first NSAID than for NO-Ind. The duration of P-450 inhibition under the action of different NO donors influences activity of CP.

Monoand disubstituted N-hydroxyamides of dicarboxylic acids were prepared by reaction of dicarboxylic acids or acid anhydrides with hydroxylamine. The use of these compounds in combinatorial cytostatic therapy of implanted tumors with cisplatin or cyclophosphamide totally inhibits metastasis formation in B16 melanoma and Lewis lung carcinoma, and resulted in 100% survival of leukemic animals.

The present investigation is based on the paradoxical dichotomy of the biological action of nitric oxide (NO). Depending on its concentration in the organism, it can have therapeutic or pathogenic effect. It was shown that during the treatment with cisplatin (cPt) or cyclophospamide (CP), adjunct therapy with ascorbic acid (AA) known to increase the NO content in the organism extended the average lifespan (ALS) by 20—30% as compared to cytostatic monotherapy. Combination of cytostatics with sodium nitrate extended ALS by 20—38% depending on the concentration of the nitrate. The efficiency of cytotoxic therapy in combination with two chemo sensitizers (NaNO3 and hydroxamic acid) also depends on the concentration of injected NaNO3. Addition of AA to these combinations extended ALS by 16%, or inhibited it by 40%. Variation of the dose of injected NaNO3 that is a NO donor in combination with endogenous NO stimulated with AA controls the action of cytostatics and combinations thereof.

Combinations of the known cytostatic cyclophosphamide (cyclophosphan) with hydroxamic acids (asparagylhydroxamic and salicylhydroxamic), nitric oxide donor (sodium nitrate), and an original hybrid non-steroidal anti-inflammatory compound, viz. , diclofenachydroxamic acid nitrate salt (DHA·HNO 3 ), were studied. The use of cyclophosphan in combination with these substances increases the efficiency of chemotherapy and elongates the life of animals with leukemia P-388. The dynamics of changes in the signal from cytochrome P-450 in the liver samples after the administration of DHA·HNO 3 to the animals was studied by ESR spectroscopy. The mechanism of the action of DHA·HNO 3 enhancing the chemotherapeutic effect of cyclophosphan was proposed.

A previously unknown palladium complex was synthesized by the reaction of 4-amino-2,2,6,6-tetramethylpiperidine with PdCl 2 . The X-ray diffraction study showed that the complex formed by 4-amino-2,2,6,6-tetramethylpiperidine with PdCl 2 is a chelate, in which the bidentate ligand adopts a boat conformation with the nitrogen atoms occupying cis positions at the palladium atom. The resulting cis -[4-amino-2,2,6,6-tetramethylpiperidine- N,N ′]dichloro-palladium( ii ) complex exhibits strong antimetastatic activity against experimental B16 melanoma at moderate toxicity.

It has been showed that the introduction of nitrocompounds (as nitic oxide donors) in to the compositions of cyclophosphamide and hydroxamic acids for curing animals having leukemia P-388 increased duration of life by 290%. Thereby 40% of animals have recovered. The therapeutic dose cyclophosphamide have been reduced by 6 times.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

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 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.

The effect of cyclic hydroxamic acids (CHAs) derived from glycine and D,L-alanine on the enzymatic activity of Ca 2+ ,Mg 2+ -ATPase of sarcoplasmic reticulum (SR Ca 2+ ,Mg 2+ -ATPase) and phosphodiesterase of cyclic guanosine monophosphate (cGMP PDE) has been investigated. CHAs I (C 5 H 10 N 2 O 2 ), II (C 6 H 1 2N 2 O 2 ), III (C 8 H 15 N 3 O 2 ), IV (C 9 H 17 N 3 O 2 ), V (C 11 H 21 N 3 O 2 ), and VI (C 12 H 23 N 3 O 2 ) are modulators of the SR Ca 2+ ,Mg 2+ -ATPase enzyme activity. Compounds I – VI separate the hydrolytic and transport functions of Ca 2+ ,Mg 2+ -ATPase to various degrees, thus violating the ratio of extra- and intracellular Ca 2+ ions that affects the adhesion of metastatic cells to a capillary endothelial tissue. Compounds IV and VI show maximum values of the index of metastases inhibition (IMI, %) for melanoma B-16 (amounting to 33 and 81%, respectively), which correlates with decreasing coefficient of transmembrane transfer of Ca 2+ ions to SR vesicles (equal to 0.95 for IV and 0.5 for VI) as compared to the [Ca 2+ ]/[ATP] ratio of 1.4 in the control. At the same time, CHAs I – VI do not affect the cGMP PDE function. The obtained experimental data allow potential antimetastatic drugs in the CHA family to be predicted.

In experimental animals with tumors it was studied antitumor activity of spirocyclic hydroxamic acids which could be classified as targeted agents as their target was enzyme histonedeacetylase, which was involved in the neoplastic process. The results showed that the hydroxamic acids were chemosensitizers for anticancer agents increasing their efficacy and enabling the researchers to reduce significantly the therapeutic dose. Also it was showed that hydroxamic acid, containing nitrogen mustard, was effective in the action on tumors with phenotype and genotype of multidrug resistance.