title: Novel Very Long-Chain α-Methoxylated Δ5,9 Fatty Acids from the Sponge Asteropus niger Are Effective Inhibitors of Topoisomerases IB.
abstract: The novel fatty acids (2R,5Z,9Z)-2-methoxy-25-methyl-5,9-hexacosadienoic acid (1a) and (2R,5Z,9Z)-2-methoxy-24-methyl-5,9-hexacosadienoic acid (1b) were isolated in 80 % purity from the Caribbean sponge Asteropus niger by chloroform/methanol extraction followed by solvent partitioning and silica gel column chromatography. The compounds were characterized by utilizing a combination of gas chromatography-mass spectrometry, nuclear magnetic resonance, and circular dichroism. Acids 1a and 1b were not detected in the phospholipids (PtdCho and PtdIns) of the sponge, but rather as free FA and possibly in glycosylceramides. The mixtures of 1a and 1b displayed cytotoxicity towards THP-1 and HepG2 cells with EC50's between 41 and 35 μg/mL. Apoptosis was not the preferred mode of cell death induced by 1a-1b in the THP-1 cells. This implies other types of cytotoxicity mechanisms, such as membrane disruption and/or the inhibition (EC50 = 1.8 μg/mL) of the human topoisomerase IB enzyme (hTopIB), with a mechanism of inhibition different from the one displayed by camptothecin (CPT). In a separate experiment, the mixture of 1a and 1b also displayed cytotoxicity towards ex vivo mouse splenocytes infected with Leishmania infantum amastigotes (IC(50) = 0.17 mg/mL) and free living promastigotes (IC(50) = 0.34 mg/mL). It was also found that the FA were inhibitory of the Leishmania topoisomerase IB (LTopIB) with an EC(50) = 5.1 μg/mL. Taken together, 1a and 1b represent a new class of FA with potential as TopIB inhibitors that preferentially inhibit hTopIB over LTopIB.
authors.affiliation: Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR, 00931-3346, USA. nestor.carballeira1@upr.edu.
authors.forename: Néstor M
authors.initials: NM
authors.lastname: Carballeira
authors.affiliation: Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR, 00931-3346, USA.
authors.forename: Nashbly
authors.initials: N
authors.lastname: Montano
authors.affiliation: Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR, 00931-3346, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Amador
authors.affiliation: Department of Chemistry, University of Puerto Rico, Rio Piedras Campus, PO Box 23346, San Juan, PR, 00931-3346, USA.
authors.forename: Abimael D
authors.initials: AD
authors.lastname: Rodríguez
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, ND, 58202-9037, USA.
authors.forename: Mikhail Y
authors.initials: MY
authors.lastname: Golovko
authors.affiliation: Department of Basic Sciences, University of North Dakota, Grand Forks, ND, 58202-9037, USA.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Golovko
authors.affiliation: Department of Biomedical Sciences, University of León, Campus de Vegazana s/n, 24071, León, Spain.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Reguera
authors.affiliation: Department of Biomedical Sciences, University of León, Campus de Vegazana s/n, 24071, León, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Álvarez-Velilla
authors.affiliation: Department of Biomedical Sciences, University of León, Campus de Vegazana s/n, 24071, León, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Balaña-Fouce
mesh_terms: D000818:Animals; D026942:DNA Topoisomerases / Q000096:biosynthesis* / Q000737:chemistry; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000494:pharmacology; D008401:Gas Chromatography-Mass Spectrometry; D006028:Glycosphingolipids / Q000737:chemistry*; D056945:Hep G2 Cells; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects / Q000472:pathogenicity; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011161:Porifera / Q000737:chemistry*; D059003:Topoisomerase Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D005231:Fatty Acids, Unsaturated; D006028:Glycosphingolipids; D059003:Topoisomerase Inhibitors; D026942:DNA Topoisomerases
keywords: Asteropus niger; Cancer; Leishmania infantum; Leishmaniasis; Methoxylated fatty acids; Sponges; Topoisomerase IB