2. Academic Validation
  3. (-)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects

(-)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects

  • Eur J Med Chem. 2017 May 5:131:207-221. doi: 10.1016/j.ejmech.2017.03.012.
Kamil Makowski 1,  Joan Francesc Mir 2,  Paula Mera 3,  Xavier Ariza 4,  Guillermina Asins 2,  Fausto G Hegardt 2,  Laura Herrero 5,  Jordi García 6,  Dolors Serra 7
Affiliations

Affiliations

  • 1 Department of Chemistry, YachayTech University, Hacienda San Jose SN, San Miguel de Urcuqui 100119, Ecuador.
  • 2 Department of Biochemistry and Physiology, Facultat de Farmàcia i Ciències de l'A limentació and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain.
  • 3 Department of Biochemistry and Physiology, Facultat de Farmàcia i Ciències de l'A limentació and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain; Columbia University Medical Center, 701 West 168th Street, New York, USA.
  • 4 Department of Inorganic and Organic Chemistry, Section of Organic Chemistry, Facultat de Química, Universitat de Barcelona, E-08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain.
  • 5 Department of Biochemistry and Physiology, Facultat de Farmàcia i Ciències de l'A limentació and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain.
  • 6 Department of Inorganic and Organic Chemistry, Section of Organic Chemistry, Facultat de Química, Universitat de Barcelona, E-08028 Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain. Electronic address: jordigarciagomez@ub.edu.
  • 7 Department of Biochemistry and Physiology, Facultat de Farmàcia i Ciències de l'A limentació and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, E-08028 Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain. Electronic address: dserra@ub.edu.
PMID: 28324785 DOI: 10.1016/j.ejmech.2017.03.012
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.

Keywords

C75 derivatives; CPT1 carnitine palmitoyltransferase 1; FAS fatty acid synthase; Ovarian cell cancer.

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