Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Antioxidants (Basel)
2023 Feb 05;122:. doi: 10.3390/antiox12020386.
Show Gene links
Show Anatomy links
Shallow- and Deep-Water Ophiura Species Produce a Panel of Chlorin Compounds with Potent Photodynamic Anticancer Activities.
Klimenko A
,
Huber R
,
Marcourt L
,
Tabakaev D
,
Koval A
,
Dautov SS
,
Dautova TN
,
Wolfender JL
,
Thew R
,
Khotimchenko Y
,
Queiroz EF
,
Katanaev VL
.
???displayArticle.abstract???
A Pacific brittle star Ophiura sarsii has previously been shown to produce a chlorin (3S,4S)-14-Ethyl-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (ETPA) (1) with potent phototoxic activities, making it applicable to photodynamic therapy. Using extensive LC-MS metabolite profiling, molecular network analysis, and targeted isolation with de novo NMR structure elucidation, we herein identify five additional chlorin compounds from O. sarsii and its deep-sea relative O. ooplax: 10S-Hydroxypheophorbide a (2), Pheophorbide a (3), Pyropheophorbide a (4), (3S,4S,21R)-14-Ethyl-9-(hydroxymethyl)-21-(methoxycarbonyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (5), and (3S,4S,21R)-14-Ethyl-21-hydroxy-9-(hydroxymethyl)-4,8,13,18-tetramethyl-20-oxo-3-phorbinepropanoic acid (6). Chlorins 5 and 6 have not been previously reported in natural sources. Interestingly, low amounts of chlorins 1-4 and 6 could also be identified in a distant species, the basket star Gorgonocephalus cf. eucnemis, demonstrating that chlorins are produced by a wide spectrum of marine invertebrates of the class Ophiuroidea. Following the purification of these major Ophiura chlorin metabolites, we discovered the significant singlet oxygen quantum yield upon their photoinduction and the resulting phototoxicity against triple-negative breast cancer BT-20 cells. These studies identify an arsenal of brittle star chlorins as natural photosensitizers with potential photodynamic therapy applications.
Figure 1. (A,B) Brittle stars Ophiura sarsii (A) and Ophiura ooplax (B). Scale bars: 1 cm. (C) Basket star Gorgonocephalus cf. eucnemis. (D) Map depicting the sample collection locations: Russky Island in the Japan sea for O. sarsii, Guyot Koko in the Pacific Ocean for O. ooplax, and G. cf. eucnemis.
Figure 2. Feature-based Molecular Network of the EtOAc and MeOH (butanolic fraction) extracts of Ophiura sarsii. Nodes colored in blue belong to the “tryptophan alkaloid” predicted natural product superclass (NPClassifier). The previously isolated ETPA is displayed as a diamond. (A) The cluster containing chlorin ETPA and several related compounds. (B) Other major clusters of the Feature-Based Molecular Network. (C) Structure of the previously isolated ETPA. (D) UHPLC-MS profile of the MeOH extract (butanolic fraction) of O. sarsii with the 10 most intense ions of the chlorin cluster indicated with letters. (E) UHPLC-UV profile at 360 nm of the same extract. The same network mapped with the predicted natural product pathways is displayed in Supplementary Figure S33.
Figure 3. (A,B) UHPLC-PDA-ELSD analysis of the raw MeOH extract of Ophiura sarsii and its butanolic fraction. (C) Optimized HPLC-PDA-ELSD analysis of the MeOH extract (butanolic fraction) of O. sarsii. (D) semi-preparative HPLC-UV analysis after gradient transfer using a dry load injection. See Supplementary Figure S34 for the chromatograms of the EtOAc extract.
Figure 4. Structures and the yields of the chlorin compounds isolated from O. sarsii.
Figure 5. Physical properties of chlorin compounds from O. sarsii. (A) UV-Vis absorbance spectra of the chlorins. (B) Scheme of the device for measurement of the singlet oxygen generation. IFB—bandpass interference filter; L1—laser beam focusing lens; Sample—cell with chlorin solution; CH—cuvette holder; L2—singlet oxygen phosphorescence collecting lens; L3—phosphorescence focusing lens; SPAD—single-photon avalanche diode. (C) Quantification of the relative singlet oxygen quantum yield.
Figure 6. Phototoxicity of chlorins from O. sarsii against triple-negative breast cancer BT-20 cells. (A) Dark cytotoxicity of the compounds. (B) Emission spectrum of the LED lamp used in the phototoxicity experiment. (C) Phototoxicity of the compounds. (D) Phototoxic Index (PI) of the compounds. Commercial Pheophorbide a was used as a control in the experiments. The data are representatives of four independent experiments.
Figure 7. Log10 of the MS peak area (from UHPLC-HRMS/MS analysis) of the 6 isolated chlorins in the EtOAc and MeOH extracts of Ophiura sarsii, Ophiura ooplax, and Gorgonocephalus cf. eucnemis.
Agius,
Photodynamic action of bonellin, an integumentary chlorin of Bonellia viridis, Rolando (Echiura, Bonelliidae).
1979, Pubmed
Agius,
Photodynamic action of bonellin, an integumentary chlorin of Bonellia viridis, Rolando (Echiura, Bonelliidae).
1979,
Pubmed
Aroso,
Photodynamic disinfection and its role in controlling infectious diseases.
2021,
Pubmed
Atanasov,
Natural products in drug discovery: advances and opportunities.
2021,
Pubmed
Bandaranayake,
The nature and role of pigments of marine invertebrates.
2006,
Pubmed
Chansakaow,
Isolation of pyropheophorbide a from the leaves of Atalantia monophylla (ROXB.) CORR. (Rutaceae) as a possible antiviral active principle against herpes simplex virus type 2.
1996,
Pubmed
Chen,
The seafood Musculus senhousei shows anti-influenza A virus activity by targeting virion envelope lipids.
2020,
Pubmed
Cheng,
Cytotoxic pheophorbide-related compounds from Clerodendrum calamitosum and C. cyrtophyllum.
2001,
Pubmed
Dührkop,
SIRIUS 4: a rapid tool for turning tandem mass spectra into metabolite structure information.
2019,
Pubmed
Eichwurzel,
Photophysical studies of the pheophorbide a dimer.
2000,
Pubmed
Gomes,
Marine Invertebrate Metabolites with Anticancer Activities: Solutions to the "Supply Problem".
2016,
Pubmed
Guillarme,
Method transfer for fast liquid chromatography in pharmaceutical analysis: application to short columns packed with small particle. Part II: gradient experiments.
2008,
Pubmed
Hamblin,
Photodynamic Therapy for Cancer: What's Past is Prologue.
2020,
Pubmed
Jacobi,
A new synthesis of chlorins.
2001,
Pubmed
Katanaev,
The Anticancer Drug Discovery Potential of Marine Invertebrates from Russian Pacific.
2019,
Pubmed
Katanaev,
Mining Natural Compounds to Target WNT Signaling: Land and Sea Tales.
2021,
Pubmed
Kennedy,
Porphyrins in invertebrates.
1975,
Pubmed
Khotimchenko,
Marine Natural Products from the Russian Pacific as Sources of Drugs for Neurodegenerative Diseases.
2022,
Pubmed
Kim,
NPClassifier: A Deep Neural Network-Based Structural Classification Tool for Natural Products.
2021,
Pubmed
Klimenko,
A Cytotoxic Porphyrin from North Pacific Brittle Star Ophiura sarsii.
2020,
Pubmed
,
Echinobase
Klimenko,
Chlorin Endogenous to the North Pacific Brittle Star Ophiura sarsii for Photodynamic Therapy Applications in Breast Cancer and Glioblastoma Models.
2022,
Pubmed
,
Echinobase
Klimenko,
Shallow- and Deep-Water Ophiura Species Produce a Panel of Chlorin Compounds with Potent Photodynamic Anticancer Activities.
2023,
Pubmed
Li,
Clinical development and potential of photothermal and photodynamic therapies for cancer.
2020,
Pubmed
Ohshima,
Pheophorbide a, a potent endothelin receptor antagonist for both ETA and ETB subtypes.
1994,
Pubmed
O'Neal,
Toward a general synthesis of chlorins.
2008,
Pubmed
Pandey,
Nature: a rich source for developing multifunctional agents. Tumor-imaging and photodynamic therapy.
2006,
Pubmed
Pluskal,
MZmine 2: modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data.
2010,
Pubmed
Queirós,
Photodynamic therapy in dermatology: Beyond current indications.
2020,
Pubmed
Queiroz,
Utility of dry load injection for an efficient natural products isolation at the semi-preparative chromatographic scale.
2019,
Pubmed
Rutz,
Taxonomically Informed Scoring Enhances Confidence in Natural Products Annotation.
2019,
Pubmed
Smoot,
Cytoscape 2.8: new features for data integration and network visualization.
2011,
Pubmed
Stöhr,
Global diversity of brittle stars (Echinodermata: Ophiuroidea).
2012,
Pubmed
,
Echinobase
Tan,
Management of glioblastoma: State of the art and future directions.
2020,
Pubmed
Wang,
Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking.
2016,
Pubmed
Zhu,
Comparison between porphin, chlorin and bacteriochlorin derivatives for photodynamic therapy: Synthesis, photophysical properties, and biological activity.
2018,
Pubmed
