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Mar Drugs
2020 Dec 29;191:. doi: 10.3390/md19010011.
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A Cytotoxic Porphyrin from North Pacific Brittle Star Ophiura sarsii.
Klimenko A
,
Huber R
,
Marcourt L
,
Chardonnens E
,
Koval A
,
Khotimchenko YS
,
Ferreira Queiroz E
,
Wolfender JL
,
Katanaev VL
.
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Triple-negative breast cancer (TNBC) represents the deadliest form of gynecological tumors currently lacking targeted therapies. The ethanol extract of the North Pacific brittle star Ophiura sarsii presented promising anti-TNBC activities. After elimination of the inert material, the active extract was submitted to a bioguided isolation approach using high-resolution semipreparative HPLC-UV, resulting in one-step isolation of an unusual porphyrin derivative possessing strong cytotoxic activity. HRMS and 2D NMR resulted in the structure elucidation of the compound as (3S,4S)-14-Ethyl-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid. Never identified before in Ophiuroidea, porphyrins have found broad applications as photosensitizers in the anticancer photodynamic therapy. The simple isolation of a cytotoxic porphyrin from an abundant brittle star species we describe here may pave the way for novel natural-based developments of targeted anti-cancer therapies.
19-515-55013 Russian Foundation for Basic Research, 13.1902.21.0012 Ministry of Science and Higher Education of Russia, 316030_164095 Swiss National Science Foundation
Figure 1. Extracts of Ophiura sarsii reveal anti-Wnt and cytotoxic activities. (A,B) Chromatograms of ethanol extracts of O. sarsii after additional solid-phase extraction (SPE) with elution with water (A) and methanol (B). Polar compounds, most probably inorganic salts, are abundant in the water fraction (A), while the methanol fraction (B) appears enriched in secondary metabolites of interest. (C,D) Acute cytotoxicity (CMV-Renilla) and anti-Wnt (TopFlash) biological assays reveal that the methanol fraction (D) is indeed enriched in both activities. (E) Scheme of the liquid–liquid extraction of the methanol fraction, which produced the butanol phase where the biological activities concentrated.
Figure 2. Isolation of the cytotoxic activity from O. sarsii. (A) Gradient transfer from the analytical HPLC-PDA (up) to the semipreparative HPLC-UV (down) of the butanol phase, resulted in the isolation of fraction 14. (B) NMR tubes of the different fractions, showing the strong dark-blue coloration of fraction 14. (C) Fraction 14 mediated the cytotoxic activity of O. sarsii in the acute cytotoxicity (CMV-Renilla) assay.
Figure 3. A porphyrin compound, (3S,4S)-14-Ethyl-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid, mediates cytotoxicity of O. sarsii. (A) UV spectrum of the fraction 14 reveals absorbance peaks typical for porphyrins. (B) NMR identified the compound in fraction 14 as (3S,4S)-14-Ethyl-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (1); ROESY correlations of compound 1 are shown as blue arrows. (C) Cell proliferation (MTT) assay shows a broad cytotoxicity of compound 1 against breast cancer lines. IC50 data are shown to the right of the graph as mean ± SEM values, n = 4.
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