(-)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects.
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.
Department of Chemistry, YachayTech University, Hacienda San Jose SN, San Miguel de Urcuqui 100119, Ecuador.
Kamil
K
Makowski
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.
Joan Francesc
JF
Mir
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.
Paula
P
Mera
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.
Xavier
X
Ariza
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.
Guillermina
G
Asins
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.
Fausto G
FG
Hegardt
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.
Laura
L
Herrero
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.
Jordi
J
García
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.
Dolors
D
Serra
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley
C000618473:(4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005663:Furans; D064429:Fatty Acid Synthases
C75 derivatives; CPT1 carnitine palmitoyltransferase 1; FAS fatty acid synthase; Ovarian cell cancer