T. E. Sashenkova

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.

The effect of ascorbic acid on the efficiency of cytotoxic therapy with cytostatic drugs in combination with NaNO3 and hydroxamic acids

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.

Ways to enhance chemosensitizing of tumor cells with NO donors in tumor therapy with cytostatics and hydroxamic acids

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.

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.

Synthesis, structure, and biological activity of the cis-[4-amino-2,2,6,6-tetramethylpiperidine-N,N′]dichloropalladium(ii) complex

A previously unknown palladium complex was synthesized by the reaction of 4-amino-2,2,6,6-tetramethylpiperidine with PdCl2. The X-ray diffraction study showed that the complex formed by 4-amino-2,2,6,6-tetramethylpiperidine with PdCl2 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.

Sulfur-containing phenolic antioxidants increasing antitumor efficiency of cyclophosphamide and its combination with nitric oxide donor

Due to the multifactorial nature of cancer diseases, investigations of combinations of the known cytostatics with substances that are chemosensitizers and act on various molecular target in the organism gain increasing significance. Polyfunctional compounds, whose molecules contain several reaction centers, serve as resources improving the efficiency of the chemosensitizing effect of various substances for chemotherapy by cytostatic agents. Classical representatives of such polyfunctional substances are sulfur-containing derivatives of alkylated phenols, the high oxidation activity of which is determined by a combination of the antiradical activity of the phenol fragments with the antiperoxide activity of the sulfur-containing groups. It is shown that the sulfur-containing phenolic antioxidant sodium S-[3-(3-tert-butyl-4-hydroxyphenyl) propyl] thiosulfate (TC-13) has no antitumor activity but enhances chemotherapeutic activity of cytostatic cyclophosphamide taken in a subtherapeutic dose, increasing the index of average life span of mice with leukemia P388 from 196 to 283%. In addition, a combination of TC-13 with the nitric oxide donor (NaNO2) increases the antitumor activity of cytostatic cyclophosphamide by 110% for the same experimental model of mice at 50% survived animals.