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Title: (−)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects
Author: Makowski, Kamil
Mir Bonnín, Joan Francesc
Mera Nanín, Paula
Ariza Piquer, Xavier
Asins Muñoz, Guillermina
Hegardt, Fausto
Herrero Rodríguez, Laura
García Gómez, Jordi
Serra i Cucurull, Dolors
Keywords: Àcids grassos
Inhibidors enzimàtics
Càncer d'ovari
Fatty acids
Enzyme inhibitors
Ovarian cancer
Issue Date: 12-Mar-2017
Publisher: Elsevier Masson SAS
Abstract: C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately. The results showed that both enantiomers inhibit FAS activity and have potent cytotoxic effects in several tumour cell lines, such as the ovarian cell cancer line OVCAR-3. The (−)-UB006 enantiomer's cytotoxic effect on OVCAR-3 was 40-fold higher than that of racemic C75, and 2- and 38-fold higher than that of the racemic mixture and its opposite enantiomer, respectively. This cytotoxic effect on the OVCAR-3 cell line involves mechanisms that reduce mitochondrial respiratory capacity and ATP production, DDIT4/REDD1 upregulation, mTOR activity inhibition, and caspase-3 activation, resulting in apoptosis. In addition, central and peripheral administration of (+)-UB006 or (−)-UB006 into rats and mice did not affect food intake or body weight. Altogether, our data support the discovery of a new potential anticancer compound (−)-UB006 that has no anorexigenic side effects.
Note: Versió postprint del document publicat a:
It is part of: European Journal of Medicinal Chemistry, 2017, vol. 131, p. 207-221
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ISSN: 0223-5234
Appears in Collections:Articles publicats en revistes (Química Inorgànica i Orgànica)

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