S. A. Fedoreev

HISTOCHROME: A NEW ORIGINAL DOMESTIC DRUG

Among biologically active substances of natural origin, the secondary metabolites of marine organisms are of special interest. Occurring in a medium significantly different from dry land, these organisms originated from more ancient times and passed through a longer path of evolution and adaptation. All this is reflected in the peculiarities of their biosynthesis and metabolism and the related structural variety of biologically active substances found in marine organisms that differ from those of animals and plants occurring on solid ground. In particular, sea hedgehogs (Echinoidea), entering in considerable amounts into marine biocenoses and widely used by populations of the Asian Pacific Region, offer a unique and rich source of such special biologically active substances. These include spinochromes [1], representing quinoid pigments of crusts and spines, which were found [2, 3] to possess high antioxidant activity. Subsequent detailed investigations revealed an important property of spinochromes: a large variety of mechanisms of antioxidant action. These include the trapping of active oxygen radicals, interaction with lipoperoxide radicals, chelation of metals acting as peroxidation catalysts, synergism with phospholipids of plasma membranes, and regulation of the activity of enzymes determining the redox state in living cells [2, 4 – 7]. This unique combination distinguishes the quinoid pigments of hedgehogs from other well-known bioantioxidants and makes them a promising base for the creation of new drugs for the treatment of a variety of pathologies. Among spinochromes, the maximum activity was observed for echinochrome, or 2,3,5,6,8-pentahydroxy-7-ethylnaphtho-1,4-quinone. In contrast to the basic endogenous antioxidants (vitamin E and ubiquinone), echinochrome is capable of neutralizing iron cations – the main initiators of nonenzymatic oxidation of membrane lipids – accumulating in the regions of the ischemic damage of a tissue [8]. Echinochrome stabilizes erythrocyte membranes, reduces the blood cholesterol level, and produces antimicrobial action [9]. It is the natural lipophilic echinochrome that represents the active parent substance for the new water-soluble antioxidant drug Histochrome (registered trademark) created and developed at the Pacific-Ocean Institute of Bioorganic Chemistry (Vladivostok) [10, 11]. Histochrome (registered trademark) is an original domestic preparation, a broad investigation of which was initiated ten years ago. Here is the first attempt at summarizing the results of this work.

Chemical composition and pharmacological activity of anthraquinones from Rubia cordifolia cell culture

The results of qualitative and quantitative determination of anthraquinones in Indian madder (Rubia cordifolia L.) cell culture are presented. According to the 1H and 13C NMR, UV, IR, and mass-spectroscopic data, seven anthraquinones have been identified, in which munjistin and purpurin are predominant. The cell culture preparation exhibits antiinflammatory activity, which is manifested by an antiexudative effect and antiproliferative action during the rapid development of a model edema. Adecrease in the antioxidant state without significant suppression of enzymatic activity is demonstrated.

Minor polyphenols from Maackia amurensis wood

The rare α,4,2′,4′-tetrahydroxydihydrochalcone, flavanones liquiritigenin and naringenin, isoflavones calycosin and 5-methoxydaidzein, and reduced stilbene dihydroresveratrol were isolated for the first time from Maackia amurensis wood. The structures of the pure compounds were established using 2D NMR COSY, NOE, HMBC, and HSQC experiments.

Maksar: A preparation based on Amur maackia

In recent years, specialists of the Pacific-Ocean Instituteof Bioorganic Chemistry (Vladivostok) have performed anextensive search for natural antioxidants among medicinalplants of Far-Eastern flora. Several promising species havebeen found, which contain effective antioxidants belongingto the class of polyphenols. The most interesting medicinalplant in this respect is Amur maackia, whose extract exhibitspronounced antioxidant properties at low toxicity. This com-bination of properties gave grounds to study the correspond-ing preparation as a potential hepatoprotector against toxicdamage of the liver. The complex of polyphenolic com-pounds extracted from Amur maackia was used as a base forthe original domestic hepatoprotector maksar (named afterO. B. Maksimov and A. S. Saratikov, heads of the R&Dgroup). The new drug has proven to exceed, in specific activ-ity, well-known hepatoprotectors such as legalon and silibor[1 – 4].Amur maackia (

About native components of extracts fromMaackia amurensis wood

A new dimeric stilbene, the name for which is suggested as maackin A, is isolated from the wood ofMaackia amurensis. The structure of maackin A is determined by NMR, UV, and IR spectral methods. Thecis-isomers that are observed during fractionation of the extracts are not native components of the wood but are formed from thetrans-dimers under certain separation conditions.

Antioxidant activity of polyphenols from the far-east plant Taxus cuspidata

Phenolic components of the wood and roots of far-east yew (Taxus cuspidata) have been isolated and investigated. Four lignans [(+)-taxiresinol, (+)-isotaxiresinol, (+)-isolariciresinol, (−)-secoisolariciresinol] and two catechins [(+)-catechin, (−)-epicatechin] were identified using spectroscopic techniques. HPLC data showed that wood, bark, roots, stems, and needles of the plant contain different amounts of lignans and catechins. The antioxidant and radical-scavenging activities of the polyphenols were evaluated on two in vitro model systems.

Quinoid pigments of far eastern representatives of the family Boraginaceae

From nine species of plants of the family Boraginaceae we have isolated and identified 11 compounds, nine of which have proved to be previously known naphthoquinones — derivatives of shikonin. The structure of the previously unknown δ-lactone of 5-(5′,8′-dihydroxy-1′,4′-naphthoquinon-2′-yl)-t-hydroxy-2-methylpent -2-enoic acid has been established. The qualitative and quantitative compositions of the pigments of the species studied and of groups of plants of the Boraginaceae family have been determined.

Effects of Histochrome on P53 Expression in Mouse Red Bone Marrow Cells in a Model of Chronic Stress

The clinical efficacy of the formulation Histochrome cannot be explained solely on the basis of its antioxidant properties. With the aim of identifying possible additional mechanisms of action of the medicinal substance (echinochrome A) in Histochrome, its effects on p53 expression were studied in bone marrow cells in SHK mice in a model of chronic stress. Echinochrome Aat a dose of 1 mg/kg (single daily i.p. doses for seven days prior of stress) normalized the level of p53 gene expression. The antioxidant formulation Histochrome had antistress properties in this experimental model in mice.

Deglycosylation of isoflavonoid glycosides from Maackia amurensis cell culture by β−D-glucosidase from Littorina sitkana hepatopancrease

Maakia amurensis (strain A-18) cell culture synthesizes a significant quantity of isoflavonoids, a large part of which consists of isoflavone glucosides and malonylglucosides. β−D-Hydrolase enzyme complexes from the marine mollusk Littorina sitkana and the marine mycelial fungus P. canescens were used to obtain isoflavones from their conjugated forms. The specificity of β−D-glucanases from L. sitkana for various glycosides was studied. The deglycosylation efficiency depended on the aglycon structure. The deglycosylated fraction of isoflavonoids obtained from M. amurensis cell culture exhibited antitumor activity.

AN ERITRICHIUM SERICEUM LEHM. (BORAGINACEAE) CELL CULTURE - A SOURCE OF POLYPHENOL COMPOUNDS WITH PHARMACOLOGICAL ACTIVITY

Polyphenol compounds consisting of caffeic acid oligomers were detected in cell cultures from Eritrichium sericeum Lehm.: (−)-rabdosiin, (+)-rosmarinic acid, and eritrichin; the quantitative contents of individual polyphenols were determined. The total content of polyphenol compounds in biotechnological raw material was 6.9% of dry tissue weight, which was 26.5 times greater than the content in the roots of the native plant. Studies of the pharmacological activity of the experimental Eritrichium sericeum Lehm. preparation, containing a complex of polyphenol compounds, demonstrated increases in renal excretory function and suppression of the exudative stage of inflammation as a result of prolonged use of the cell culture phytocomplex at a dose of 100 mg/kg.