Isolation and Identification of Impurities in the Parent Substance of Echinochrome and in the Drug Histochrome

Mishchenko, Natalia P.; Федореев, С. А.; Глазунов, В. П.; Денисенко, В. А.; Krasovskaya, N. P.; Glebko, L. I.; Maslov, L. G.; Dmitrenok, Pavel S.; Bagirova, V. L.

doi:10.1023/b:phac.0000027646.78310.37

Cited by 11 publications

(15 citation statements)

References 4 publications

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“…In the HPLC-DAD-MS method, we have developed HPLC conditions to successfully separate more than 20 quinonoid pigments of sea urchins during one short analysis. For its development, we used standard samples of spinochromes, the structures of which were previously established by us using NMR spectroscopy and high-resolution mass spectrometry [ 10 , 19 , 20 , 21 , 22 , 23 ]. The use of a diode array detector (DAD) makes it possible to obtain absorption spectra of spinochromes in the wavelength range from 200 to 700 nm, with characteristic absorption maxima for each compound.…”

Section: Resultsmentioning

confidence: 99%

“…For over 15 years, the drug substance Echinochrome has been produced from the sea urchin Scaphechinus mirabilis ; therefore, outcoming control of the content and composition of pigments in natural raw materials and analysis of accompanying impurities (their rate is not more than 2%) is performed in the finished product. Our experience shows that, at one of the stages of the technological process (vacuum sublimation stage), at least 10 degradation products of echinochrome A are formed, the structures of which were identified as derivatives of juglone (3,5,6,7-tetrahydroxy-2-ethyl-1,4-naphthoquinone; 2,5,6,7-tetrahydroxy-3-ethyl-1,4-naphthoquinone) and naphthazarin (2,5,8-trihydroxy-3-ethyl-1,4-naphthoquinone; 2,5,6,8-tetrahydroxy-3-ethyl-1,4-naphthoquinone (ethylmompain); 2,5,7,8-tetrahydroxy-3-ethyl-1,4-naphthoquinone (ethylisomompain); 2,3,5,8-tetrahydroxy-1,4-naphthoquinone (spinazarin); 6-ethyl-2,3,5,8-tetrahydroxy-1,4-naphthoquinone (ethylspinazarin) [ 19 , 43 ]. Similarly, 3-acetyl-2,7-dihydroxy-6-methylnaphthazarin was isolated from the test and spines of M. nudus after vacuum sublimation [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

“…Elyakov Pacific Institute of Bioorganic Chemistry (Vladivostok, Russia). Mompain was isolated as an impurity of the drug substance echinochrome A [ 19 ]. Mirabiquinone [ 20 ] and echinamines A and B [ 21 ] were isolated previously from Scaphechinus mirabilis .…”

Section: Methodsmentioning

confidence: 99%

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Spinochrome Identification and Quantification in Pacific Sea Urchin Shells, Coelomic Fluid and Eggs Using HPLC-DAD-MS

Васильева

Mishchenko

Tran³

et al. 2021

Marine Drugs

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The high-performance liquid chromatography method coupled with diode array and mass spectrometric detector (HPLC-DAD-MS) method for quinonoid pigment identification and quantification in sea urchin samples was developed and validated. The composition and quantitative ratio of the quinonoid pigments of the shells of 16 species of sea urchins, collected in the temperate (Sea of Japan) and tropical (South-China Sea) climatic zones of the Pacific Ocean over several years, were studied. The compositions of the quinonoid pigments of sea urchins Maretia planulata, Scaphechinus griseus, Laganum decagonale and Phyllacanthus imperialis were studied for the first time. A study of the composition of the quinonoid pigments of the coelomic fluid of ten species of sea urchins was conducted. The composition of quinonoid pigments of Echinarachnius parma jelly-like egg membrane, of Scaphechinus mirabilis developing embryos and pluteus, was reported for the first time. In the case of Scaphechinus mirabilis, we have shown that the compositions of pigment granules of the shell epidermis, coelomic fluid, egg membrane, developing embryos and pluteus are different, which should enable a fuller understanding of the functions of pigments at different stages of life.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Spinochrome Identification and Quantification in Pacific Sea Urchin Shells, Coelomic Fluid and Eggs Using HPLC-DAD-MS

Васильева

Mishchenko

Tran³

et al. 2021

Marine Drugs

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“… HPLC profiles of Histochrome (Ech A) oxidation products. Unmarked peaks are natural impurities of the Ech A substance [ 24 ]. …”

Section: Figurementioning

confidence: 99%

Isolation and Structure Determination of Echinochrome A Oxidative Degradation Products

et al. 2020

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Echinochrome A (Ech A, 1) is one of the main pigments of several sea urchin species and is registered in the Russian pharmacopeia as an active drug substance (Histochrome®), used in the fields of cardiology and ophthalmology. In this study, Ech A degradation products formed during oxidation by O2 in air-equilibrated aqueous solutions were identified, isolated, and structurally characterized. An HPLC method coupled with diode-array detection (DAD) and mass spectrometry (MS) was developed and validated to monitor the Ech A degradation process and identify the appearing compounds. Five primary oxidation products were detected and their structures were proposed on the basis of high-resolution electrospray ionization mass spectrometry (HR-ESI-MS) as 7-ethyl-2,2,3,3,5,7,8-heptahydroxy-2,3-dihydro-1,4-naphthoquinone (2), 6-ethyl-5,7,8-trihydroxy-1,2,3,4-tetrahydronaphthalene-1,2,3,4-tetraone (3), 2,3-epoxy-7-ethyl-2,3-dihydro-2,3,5,6,8-pentahydroxy-1,4-naphthoquinone (4), 2,3,4,5,7-pentahydroxy-6-ethylinden-1-one (5), and 2,2,4,5,7-pentahydroxy-6-ethylindane-1,3-dione (6). Three novel oxidation products were isolated, and NMR and HR-ESI-MS methods were used to establish their structures as 4-ethyl-3,5,6-trihydroxy-2-oxalobenzoic acid (7), 4-ethyl-2-formyl-3,5,6-trihydroxybenzoic acid (8), and 4-ethyl-2,3,5-trihydroxybenzoic acid (9). The known compound 3-ethyl-2,5-dihydroxy-1,4-benzoquinone (10) was isolated along with products 7–9. Compound 7 turned out to be unstable; its anhydro derivative 11 was obtained in two crystal forms, the structure of which was elucidated using X-ray crystallography as 7-ethyl-5,6-dihydroxy-2,3-dioxo-2,3-dihydrobenzofuran-4-carboxylic acid and named echinolactone. The chemical mechanism of Ech A oxidative degradation is proposed. The in silico toxicity of Ech A and its degradation products 2 and 7–10 were predicted using the ProTox-II webserver. The predicted median lethal dose (LD50) value for product 2 was 221 mg/kg, and, for products 7–10, it appeared to be much lower (≥2000 mg/kg). For Ech A, the predicted toxicity and mutagenicity differed from our experimental data.

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“…The last compound is the dimethylether of ethylmompain (2,7-dihydroxy-3-ethylnaphthazarin). Ethylmompain (13) itself, which was first isolated from spines of the sea urchin Echinus diadema [7], was observed among the impurities of natural BAS echinochrome [8]. 7: R 1 = Cl, R 2 = R 3 = OMe; 8: R 1 = R 3 = OMe, R 2 = Cl; 9: R 1 = OH, R 2 = R 3 = Cl; 10: R 1 = R 3 = Cl, R 2 = OH 11: R 1 = R 2 = OMe; 12: R = OMe; 13: R = OH; 14: R 1 = R 2 = Cl, R 3 = OH; 15: R 1 = R 2 = Cl 16: R 1 = OMe; R 2 = OH; 17: R 1 = R 2 = OMe, R 3 = OH; 18: R 1 = R 3 = OH, R 2 = OMe; 19: R 1 = OMe, R 2 = R 3 = OH Naphthazarins 9-11 are new compounds, the structures of which were established using IR and NMR spectroscopy and mass spectrometry.…”

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confidence: 99%

Cytotoxic activity of intermediates and side products of echinochrome synthesis

et al. 2008

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Isolation and Identification of Impurities in the Parent Substance of Echinochrome and in the Drug Histochrome

Cited by 11 publications

References 4 publications

Spinochrome Identification and Quantification in Pacific Sea Urchin Shells, Coelomic Fluid and Eggs Using HPLC-DAD-MS

Spinochrome Identification and Quantification in Pacific Sea Urchin Shells, Coelomic Fluid and Eggs Using HPLC-DAD-MS

Isolation and Structure Determination of Echinochrome A Oxidative Degradation Products

Cytotoxic activity of intermediates and side products of echinochrome synthesis

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