New method for the synthesis of metal complexes based on PtIV and substituted nicotinamides and isonicotinamides and investigation of their antimetastatic activity

Complexes of platinum tetrachloride with substituted nicotinamides and isonicotinamides were synthesized by the reactions of the corresponding amides with hexachloroplatinic acid. All these complexes are low-toxic. The strong antimetastatic activity of these complexes against Lewis lung carcinoma and B16 melanoma experimental tumors was found in an enzyme system and was then shown in experiments on animals.     

Hydrophilic sulfur-containing antioxidant sodium 3-(3-tert-butyl-4-hydroxyphenyl)propylthiosulfate as a modulator of the activity of antitumor cytostatics and their combinations with a NO donor

Russian Chemical Bulletin - The interaction of a combination of a sulfur-containing phenolic antioxidant sodium 3-(3-tert-butyl-4-hydroxyphenyl)propylthiosulfate (TS-13) with a nitric oxide donor...     

Synthesis and antitumor properties of new platinum(IV) complexes with aminonitroxyl radicals

Acylation of cis,trans,cis-Pt^IV(RNH₂)(NH₃)(OH)₂Cl₂ with acetic anhydride afforded complexes cis,trans,cis-Pt^IV(RNH₂)(NH₃)(OAc)₂Cl₂, where R is 2,2,6,6-tetramethyl-1-oxylpiperidin-4-yl (1b) or 2,2,5,5-tetramethyl-1-oxylpyrrolidin-3-yl (2b). The complexes were characterized by elemental analysis, HPLC, and IR, UV, and ESR spectra. Complex 1b exhibits high antitumor activity comparable with that of Cisplatin against leukemia P388 used as the experimental tumor. Simultaneous administration of low doses of 1b and Cisplatin (1/20 of LD₅₀ each) results in synergism of the antitumor activity and 100% cure of animals. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 60–63, January, 2006.     

Synthesis, crystal structure, and antitumor activity of the cadmium dichloride complex with semicarbazide

The chelate cadmium dichloride complex with semicarbazide was synthesized. The use of this complex in the cytostatic combination therapy together with cyclophosphamide results in 67% survival of mice and a threefold increase in the average life span of survivors with P-388 leukemia.     

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.     

Hydroxamic acids: synthesis and adjuvant activity in combinatorial anticancer therapy

Russian Chemical Bulletin - Monoand disubstituted N-hydroxyamides of dicarboxylic acids were prepared by reaction of dicarboxylic acids or acid anhydrides with hydroxylamine. The use of these...     

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.     

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.     

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

Russian Chemical Bulletin - The influence of an organic NO donor belonging to non-steroidal anti-inflammatory drugs (NSAIDs) — NO-indomethacin (NO-Ind) on the antitumor effect of...