B. S. Fedorov

Polyfunctional action of biologically active compounds in antitumor chemotherapy of cyclophosphamide

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·HNO3), 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·HNO3 to the animals was studied by ESR spectroscopy. The mechanism of the action of DHA·HNO3 enhancing the chemotherapeutic effect of cyclophosphan was proposed.

Synthesis and the crystal structures of N-(2-nitroxyethyl)isonicotinamide and its complexes with PdCl2 and PtCl2 as potential antitumor medicines

Previously unknown N-(2-nitroxyethyl)isonicotinamide was synthesized by the reaction of isonicotinoyl chloride with 2-nitroxyethylamine and was used as a ligand in the reactions with PdCl2 and PtCl2 to prepare new complexes, viz., trans-bis[(2-nitroxyethyl)isonicotinamide-N]dichloropalladium(ii) and cis-bis[(2-nitroxyethyl)isonicotinamide-N]dichloroplatinum(ii), respectively. The structures of the ligand and the resulting complexes were established by X-ray diffraction analysis.

Effect of Cyclic Hydroxamic Acids Derived from Glycine and D,L-Alanine on Activity of Ca2+, Mg2+-ATPase Hydrolases of Sarcoplasmic Reticulum and Cyclic Guanosine Monophosphate Phosphodiesterase

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.

Novel transformations of nitraminodiol diacetates

A novel scission reaction of nitraminodiol diacetates of the formula AcO[CH2N(NO2)xCH2OAc (x = 1–4) in concentrated sulfuric acid to form formaldehyde, nitramide, and 2-nitro-2-azapropane-1,3-diol disulfate was found.A novel scission reaction of nitraminodiol diacetates of the formula AcO[CH2N(NO2)xCH2OAc (x = 1–4) in concentrated sulfuric acid to form formaldehyde, nitramide, and 2-nitro-2-azapropane-1,3-diol disulfate was found.

New antimetastatic preparations based on chlorodinitromethyl-1,3,5-triazines

An approach to the synthesis of water-soluble chlorodinitromethyl-1,3,5-triazines was developed. For this purpose, a diamine bound to the 1,3,5-triazine cycle and capable to form hydrochloride salts on chlorination is introduced in a molecule.

Synthesis and structure of the PdII complex with 3,3-dinitropropylamine

The reaction of 3,3-dinitropropylamine with PdCl2 gave the previously unknown complex, bis(3,3-dinitropropylaminato-N,C3)palladium(II). The structure of the complex was established by X-ray diffraction analysis.

New reaction of the sodium salt of 2-nitroethanol. X-ray analysis of the sodium salt of 2-oxo-3-hydroxypropionic acid oxime, 2-bromo-2-nitropropane-1,3-diol, and the model 2,2-dinitropropane-1,3-diol

A novel reaction of the sodium salt of 2-nitroethanol in aqueous ammonia resulted in the sodium salt of 2-oxo-3-hydroxypropionic acid oxime (1) has been found. Bromination of1 affords 2-bromo-2-nitropropane-1,3-diol (2) with a previously unknown molecular conformation. The formation mechanisms of compounds1 and2 were suggested. X-ray analysis of products1,2 and that of the model compound, 2,2-dinitropropane-1,3-diol, was performed.

1,1,4,4-Tetranitrobutane-2,3-diol and its derivatives. 3. Synthesis of 1,4-dichloro- and 1,4-dibromo-1,1,4,4-tetranitrobutane-2,3-diol dinitrates and their crystalline structure

Abstract1,4-Dichloro- (1) and 1,4-dibromo-1,1,4,4-tetranitrobutane-2,3-diol dinitrates (2) were synthesized by nitration of the corresponding diols with a mixture of trifluoroacetic anhydride and nitric acid. The x-ray diffraction investigations of 1 and 2 that have been carried out showed the influence of the intramolecular interactions of the nitro and nitrate groups on the packing of the molecules in the crystal.

Hydroxamic acids: synthesis and adjuvant activity in combinatorial anticancer therapy

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.

Cyclic hydroxamic acids derived from α-amino acids 2. Regioselective synthesis, crystal structure, and antitumor activity of spiropiperidine- imidazolidine hydroxamic acids based on glycine and dl-alanine

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.