T. G. Nikolaeva

Synthesis and cytotoxic activity of 3-triarylmethylindoles. III. 3-[Diphenyl(pyridyl)methyl]indoles

Aseries of isomeric heterosubstituted 3-triarylmethylindoles were synthesized and their properties were evaluated. The activity of the synthesized compounds was found to depend on the mass of the side-chain substituent and on the position of the nitrogen atom in the heteroaromatic ring.

Cytotoxicity of Photoheme-Containing Ferrimagnetic Fluid in Alternating Magnetic Field

Ferrimagnetic fluids suitable for magnetothermosensitization (MTS) of tumor cells in ac magnetic field were obtained by mixing photoheme (PH) and dextran ferrite (DF) sols. The mechanisms of the PH + DF-induced MTS most likely involves free-radical processes.

Increase in Photohem Cytotoxicity in a High-Frequency Magnetic Field

The decrease in survivability of cells containing photosensitive substances depends on the degree of excitation [1 – 12]. By the same token, the survival of cells containing magnetically sensitive agents and or substances excited by heating in the dark is determined by the degree of magnetic-field-induced excitation [5, 6] and or the thermal excitation [6, 7]. Hematoporphyrin (HP), its derivatives such as photohem (PH) [1 – 4], and other compounds which, being irradiated by light with a wavelength of 600 – 1000 nm, exhibit electron excitation with the formation of superoxide anions capable of producing singlet oxygen and thus increasing cytotoxicity belong to the class of photosensitizers. Previously, we have developed the PH analog photohem [1 – 4] and used this derivative in the process of photohem-induced magnetothermosensitization (MTS) of cells in the dark. Photohem is capable, by analogy with HP (Fig. 1) [9], of forming superoxide radical anions generating singlet oxygen, an agent destroying tumor cells. In the course of the MTS process, as well as during photosensitization, intercalated photohem particles may increase their ability to generate free radicals. As is known, histidine is capable of trapping singlet oxygen [5, 9]. The increase in the HP-induced damage during tumor cell hyperthermia was inhibited by -carotene (another well-known agent trapping singlet oxygen) or superoxide radical anion (O2 ), but not by mannitol (this agent traps only hydroxyl radicals). Hematoporphyrin and its derivatives also increase the radiosensitizing action of 2-deoxy-D-glucose on tumor cells, probably by reducing the energy spent for the reversible inhibition of DNA repair and increasing cytogenetic damage and tumor cell loss [9 – 11]. An analysis of the literature devoted to photohem (Russia) and its analog photofrin (USA and Canada) showed that

Effect of 4,5-disubstituted 1,2,3-triazoles and their N(2)-ribosides on the incorporation of pyrimidine precursors into the nucleic acids of tumor cells

The nucleosides of five-membered nitrogen bases imidazole, 1,2,4-and 1,2,3-triazoles, and pyrazole can be considered as analogs of the Nl-nucleoside of 5-amino-4-carbamoylimidazole (AICAR), the phosphate of which is a key product of the biosynthesis of purine nucleotides do novo. This class of Compounds includes l-B-D-ribofuranosyl-3-carbamoyl-l,2,4-triazole (virazole, RB), nucleoside antibiotics: bredinin, pyrazomycin, as well as the synthetic C2-nucleoside of 4-carbamoylthiazole. The biological effect of the most important nucleosides of five-membered nitrogen heterocycles in most of the known cases is not associated with inhibition of the enzymes participating in AICAR metabolism; these nucleosides are phosphorylated in the cell under the action of adenosine kinase, and the nucleotides formed are inhibitors of inosine monophosphate dehydrogenase (EC 1.2oi.14), an enzyme that participates in the biosynthesis of guanylate and also acts on other processes of guanosine metabolism [3].

Investigation of the biological activity of indole nucleosides relationship between structure and biological activity

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Effect of iscador, a drug from mistletoe (Viscum album), on DNA synthesis in tumor cells and the functional activity of normal phagocytic cells

lscador, a drug based on the extract from mistletoe (Viscum album), is intended for the treatment of tumors and has been used for more than three decades in some European clinics [1 -5] . However, neither an optimum administration scheme nor a standard protocol are available for iscador because this preparation represents a multicomponent mixture and the nature of its principal acting component is not yet established. Experimental investigations performed in recent years have achieved some progress in elucidating the mechanism of iscador action. It was demonstrated that the drug produces a cytotoxic effect upon various tumor cell lines [6 8] and inhibits the growth of transplanted tumors in experimental animals [9, 10]. In addition, iscador possesses immunomodulating properties [11]. Iscador contains biologically active components belonging to two classes: proteins-lectins subdivided into three classes (ML I, ML II, and ML III) [12] and polypeptidesviscotoxins [ 13] capable of acting upon the cell membranes. We have studied six iscador preparations (obtained from Verein Krebsforschung, Switzerland) differing in the content of lectins and viscotoxins. The aim of this work was to establish which of the iscador components are responsible for (1) its cytotoxic action on tumor cell cultures of various genesis and (2) its influence on the functional activity of normal phagocytic cells. For this purpose, we have studied the effect of various doses of the iscador samples on DNA synthesis in human tumor cells and on the chemiluminescence of normal phagocytes (human blood neutrophils and peritoneal macrophages of mice).

Synthesis and cytotoxic activity of 3-triarylmethylindoles. Part II. Chlorine-substitututed 3-triphenylmethylindoles

In the previous work we proposed a method for the tritylation of indoles with triarylcarbinols in the presence of zinc chloride and molecular sieves [1]. This very method was employed to obtain compounds Ia and II. However, in contrast to the reaction described in [1] where the process duration in boiling dioxane was about 2 h, the passage to chlorine-substituted lxiarylcarbinols led to a sharp drop in the reaction rate. For example, the synthesis of compound Ia required boiling the reaction mixture for over 10 h. For this reason, compounds I b I d were synthesized using a specially developed method of the indole tritylation with triphenylcarbinol in the melt in the presence of small amounts of ZnC12 [2]. Under these conditions, the reaction of indole with chlorine-substituted triarylcarbinols is completed within a few minutes, although the yield of 3-triarylmethylindoles somewhat de-

Synthesis of nucleoside dialdehydes and study of its cytotoxic and antitumor activity

Periodate oxidation of natural nucleosides results in nucleoside dialdehydes possessing cytotoxic properties in in vitro studies. A number of natural nucleoside dialdehydes exhibit antitumor activity [1, 2]. For example the dialdehyde obtained from inosine inhibits the development ofmurine leukemia [3, 4]. Clinical trials showed the therapeutic effects of this drug in acute leukemia, seminoma, and melanoma [5, 6]. The products of periodate oxidation of adenosine, cytidine, uridine [7], fluorouridine [8, 9], as well as of some O-glycosides exhibit antitumor activity in experiment [2]. The cytotoxic and antitumor properties of nucleoside dialdehydes are attributed to the reactive dialdehyde groups reacting with DNA and protein [10, 1 I]. Dialdehydes inhibit specifically thymidylate synthetase, ribonucleotide reductase, and DNA and RNA polymerases [6, 7, 12, 13]. However, a comparative study of dialdehydes obtained from nucleosides (metabolites and antimetabolites) aimed at estimating the aglycone contribution to the biological effect of nucleoside dialdehyde has not yet been performed. The aim of this work is to develop a convenient method of synthesis ofnucleoside dialdehydes avoiding the laborious purification from inorganic impurities and to perform a comparative study of their cytotoxic and antitumor activity in vitro and in vivo. We obtained the products ofperiodate oxidation of i) natural purine nucleosides (inosine, adenosine, guanosine, xanthosine), ii) pyrimidine nucleosides (cytidine, uridine, and l(!3-D-glucopyranosyl)thymine), iii) nucleoside antimetabolites (6-azauridine and 1-13-D-ribofuranosyl-3-aminocarbonyl-l,2,4-triazole (virazole)), and iv) methyl 1-13-Dgalactopyranoside and l-[3-D-glucopyranosyl-5-fluorouracil. We investigated the effect of the obtained dialdehydes on the incorporation of labeled thymidine into DNA of human ovarian carcinoma ceils and the antitumor activity of these corn-

Synthesis and cytotoxic activity of 3-triarylmethylindoles

The effect of a lipophilic substituent (a diphenylmethyl radical) in position 3 of simple indole derivatives is to increase the biological (antibacterial, antiviral, antifungal) activities of these compounds or to change the spectrum of their activities [11]. With the aim of identifying the effect of introducing substituents on the cytotoxic activity of indoles, we synthesized a series of derivatives in which the lipophilic group in position 3 of the indole molecule consisted of a triarylmethyl radical. Compounds I-VII were prepared by the reaction of indole with triarylmethylhalides or triarylcarbinol; these substances have a substituent in position 4 of one of the aromatic rings.

Preparation of amides and esters of the antibiotic bruneomycin and examination of their cytotoxic and antiretroviral activity

The antibiotic bruneomycin (I) (streptonigrin), and some of its amides and esters, in addition to possessing antitumor activity, are able to inhibit reverse viral transcriptase of retroviruses, in particular human immunodeficiency virus [7, 9, ii], and are of interest as potential drugs for the treatment of AIDS. For this reason, a search for new amides and esters of bruneomycin with improved cytotoxic and antiretrovirai activity is justified.