Comparative Analysis of Cytotoxic Activity of New Nitrosyl Iron-Sulfur Complexes in Human Tumor Cells In Vitro.

We studied cytotoxic activity of new tetranitrosyl NO-generating binuclear iron-sulfur [Fe-S] complexes containing different ligands in the molecule against tumor cells in vitro. Cytotoxic activity of the most active complex with cysteamine (CysAm) was compared with that of antitumor drug cisplatin. Caspase activation and morphological changes in cells were visualized by fluorescence microscopy. Fluorescence of active caspases 3 and 7 and changes in nuclear DNA in cells in the presence of CyAm were detected by using fluorochrome-labeled inhibitor of caspases (FLICA) and Hoechst and propidium iodide reagents. Similar cytotoxic activities of CyAm and cisplatin were demonstrated in various human tumor cell lines of different histogenesis. Therefore, a new class of NO-donating [Fe-S] complexes can provide the base of potential drugs for chemotherapy with a new mechanism of action.

[N6-dipeptide derivatives of the N12-ribosyl-indolo[2,3-a]carbazole].

N6-derivatives of N12-ribosyl-indolo[2,3-a]pirrolo[3,4-c]carbazole-5,7-dione are synthesized as potential antitumor agents, in which an atom of N6-pyrrole part of heterocycle is included into the dipeptide residual of the general formula >N6-(CH2)n-CO-Ala/ßAla-OMe (n = 2 or 3). These compounds are derived by reacting of 13-methyl-12-(2,3,4-three-O-acetyl-ß-D-ribopyranosyl)indolo[2,3-a]furano[3,4-c] carbazole-5,7-dione with dipeptides, having an unreplaced N-amino end-group, in DMF at 130°C, wherein the nitrogen atom of peptide amino group replaces oxygen O6 in furan ring of heterocycle and is embedded in imide nitrogen atom of pyrrole N6. The ability of the obtained compounds to inhibit growth of SKOV3 human ovarian carcinoma cells was studied, only derivative with radical >N6-(CH2)3-CO-L-Ala-OMe showed cytotoxic activity with an inhibitory concentration of IC50 = 8 µM.

[Synthesis and cytotoxicity of allobetulin derivatives].

The synthesis and screening of antitumor activity in vitro (cytotoxicity) of various oxygen, nitrogen, sulfur and platinum-containing derivatives of allobetulin, including different arrangements of the double bonds in the A and B rings, penta- and hexacyclic ring A, 21-acetyl-20,28-epoxy-18α,19ßH-ursane-isomeric cycle E, was carry out. (3R,5R)-19ß,28-Epoxy-4,5-seco-18α-olean-3(5)-ozonide and 2,3-indolo-21ß-acetyl-20ß,28-epoxy-18α, H-19ß-ursane showed significant cytotoxic activity against melanoma MeWo and Leukemia SR cells, appropriately. (3S,5S)-Diastereomer of the first compound showed no cytotoxicity.

In vitro effect of Knotolan, a new lignan from Abies sibirica, on the growth of hormone-dependent breast cancer cells.

Here we present antiestrogenic effects of Knotolan, a new dietary lignan from Abies sibirica raw material. Knotolan abolished growth-stimulating effects of 17ß-estradiol on hormone-dependent MCF-7 cells.

[Isolation of factor IX concentrate from cryosupernatant of donor's plasma]. / Vydelenie kontsentrata faktora IX iz kriosupernatanta donorskoi plazmy.

Soviet anion-exchangers were comparatively studied to specify an optimal carrier useful for isolation of factor ix of the blood coagulation system from donor's blood cryosupernatant. The main criteria of gel selection were the yield and purification degree of factor IX, as well as its specific activity and concentration in eluates. It has been shown that DEAE-agarose 6B-CL, possessing pronounced activity with respect to specific sorption of factor IX, meets these requirements to the greatest degree.

[The physicochemical and biological properties of the bovine hemoglobin polymer]. / Izuchenie fiziko-khimicheskikh i riada biologicheskikh svoistv polimera gemoglobina byka.

A study was made of bovine hemoglobin polymer obtained by a new method: intraerythrocytic polymerization of hemoglobin followed by isolation of hemoglobin polymer. The polymer obtained had weighted mean and numerical average molecular mass of 388 kD and 134 kD, respectively, P 32 mm Hg, arteriovenous difference 5.1 vol%, Hill's coefficient 2.14, oxygen output rate constant 55 sec, and it retained its activity during long-term storage. Its solution in a concentration of 9-10 g/dl has a viscosity of 2.34, and an oncotic pressure of 240 mm water. Bovine hemoglobin polymer is nontoxic and capable of long-term circulation in the blood. Its safety and clinical effectiveness should be studied in an extended biological experiment.

[Study of functional properties of chemically-modified hemoglobin during circulation in the blood channel]. / Izuchenie funktsional'nykh kharakteristik khimicheski modifitsirovannogo gemoglobina v protsesse tsirkuliatsii v krovenochnom rusle.

Functional activity of the solutions of chemically modified hemoglobins (Hb) with different structure had been investigated during the replacement of acute fatal blood loss in dogs. It was found the correlation between polymerization degree of Hb derivatives and alterations of its oxygen-carrying characteristics in the process of circulation. It was shown that decline of functional activity at the prolonged terms of circulation was more expressed for macromolecular Hb derivatives with heterogeneous structure. Therefore chemically modified Hb free from high molecular weight fractions may be considered as a potential oxygen-carrying fluids, because they are capable of more effective support of the oxygen transport level in the organism.

[The structuro-functional heterogeneity of an artificial oxygen carrier based on hemoglobin]. / Strukturno-funktsional'naia geterogennost' iskusstvennogo perenoschika kisloroda na osnove gemoglobina.

Pyridoxylated polymerized hemoglobin (PP-Hb) was fractionated by the method of high pressure liquid chromatography, Molecular weight distribution, oxygen carrying capacity and antigenic characteristics of separated fractions have been investigated. It was demonstrated that a fraction may be separated from the crude PP-Hb, which is greatly homogeneous if structural and functional characteristics are concerned, and also optimal according to the parameters investigated. So, by a corresponding fractionation method it is possible to overcome the main limitation for use of PP-Hb as an artificial oxygen carrier--its heterogeneity.

[Biochemical properties of intramolecularly cross-linked hemoglobin]. / Biokhimicheskie svoistva vnutrimolekuliarno sshitogo gemoglobina.

The chemical modification of hemoglobin was conducted with the help of bifunctional crosslinking agent--glutaraldehyde. By SDS-polyacrylamide gel electrophoresis and gel-filtration it was shown that the final product contained 70% of modified protein which consisted of non-dissociating hemoglobin dimers and tetramers. It was also shown that the chemical modification didn't produce significant changes in the oxygen-transporting properties of the starting hemoglobin, but had influence on the character of the interaction with the allosteric regulator of reversible oxygenation (pyridoxal-5'-phosphate). The half-disappearance period in animals of the intramolecularly crosslinked hemoglobin was two times longer in comparison with the native protein.

[Oxygen-dissociation properties and the regulation of the oxygen affinity of a hemoglobin polymer in the bull]. / Kislorodno-dissotsiatsionnye svoistva i reguliatsiia srodstva k kislorodu polimera gemoglobina byka.

Oxygen-dissociation properties and some aspects of allosteric regulation of bovine hemoglobin (Hb) and its polymerized form (HbP) have been examined. It has been shown that bovine HbP as well as bovine Hb does not require the presence of organic phosphates for normal functioning and has gas transport characteristics which are similar to those of the whole human blood. Pyridoxal-5'-phosphate (PP) works as an allosteric regulator of bovine HbP only in the absence of Cl- ions and vice versa. However, in covalent binding of PP to HbP both the effectors (PP and Cl- ions) can work simultaneously and independently. Thus, by varying the Hb/PP ratio it is possible to prepare HbP solutions with preset P50 values within the range 30-55 mm Hg. The results can be used in simulation of gas transport characteristics of artificial oxygen carriers.