Shallow- and Deep-Water <i>Ophiura</i> Species Produce a Panel of Chlorin Compounds with Potent Photodynamic Anticancer Activities
Antonina Klimenko,
Robin Huber,
Laurence Marcourt,
Dmitry Tabakaev,
Alexey Koval,
Salim Sh. Dautov,
Tatyana N. Dautova,
Jean-Luc Wolfender,
Rob Thew,
Yuri Khotimchenko,
Emerson Ferreira Queiroz,
Vladimir L. Katanaev
Affiliations
Antonina Klimenko
Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva, Switzerland
Robin Huber
School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva, Switzerland
Laurence Marcourt
School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva, Switzerland
Dmitry Tabakaev
Department of Applied Physics, Faculty of Sciences, University of Geneva, Rue de l’Ecole-De-Médecine 20, CH-1205 Geneva, Switzerland
Alexey Koval
Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva, Switzerland
Salim Sh. Dautov
A.V. Zhirmunsky National Scientific Center of Marine Biology, Far East Branch of Russian Academy of Sciences, Palchevsky St. 17, 690041 Vladivostok, Russia
Tatyana N. Dautova
A.V. Zhirmunsky National Scientific Center of Marine Biology, Far East Branch of Russian Academy of Sciences, Palchevsky St. 17, 690041 Vladivostok, Russia
Jean-Luc Wolfender
School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva, Switzerland
Rob Thew
Department of Applied Physics, Faculty of Sciences, University of Geneva, Rue de l’Ecole-De-Médecine 20, CH-1205 Geneva, Switzerland
Yuri Khotimchenko
Institute of Life Sciences and Biomedicine, Far Eastern Federal University, 690090 Vladivostok, Russia
Emerson Ferreira Queiroz
School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva, Switzerland
Vladimir L. Katanaev
Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Rue Michel-Servet 1, CH-1206 Geneva, Switzerland
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.
