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New UB006 Derivatives With Higher Solubility and Cytotoxic Activity in Ovarian Cancer Cells
Marc Reina1,2,3, Xavier Ariza2,3,4, Dolors Serra1,3,4
1Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Universitat de Barcelona, E-08028 Barcelona, Spain.
Background/Objectives:
The compound (±)-UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one) is a promising anti-cancer molecule. The enantiomer (-)-UB006 displays a potent cytotoxic effect in several tumor cell lines, particularly the ovarian cancer OVCAR-3 cell line, with a 40-fold increase in potency compared with the fatty acid synthase (FAS) inhibitor C75. Furthermore, in vivo, (-)-UB006 reduced the tumor burden in neuroblastoma xenografts. This effect was attributed to FAS inhibition and upregulation of apoptotic markers. However, CoA adducts of UB006 presented low solubility.
Methods:
We synthesized several (±)-UB006 derivatives by elongating the carbon chain of the primary alcohol and/or by adding hydroxyl groups with the aim of finding more potent and soluble anti-cancer compounds.
Results:
Our results showed a decrease in cytotoxicity when the carbon chain was elongated by more than two carbons. However, ethyl or propyl polyhydroxylated four-branched compounds showed an increased or maintained potency and solubility. The most promising compound was (±)-UB035 (IC50: 2.1 ± 0.2 µM), with a 2.5-fold increase in cytotoxicity in the OVCAR-3 cell line and a >4-fold increase in solubility (>2 mM) compared with (±)-UB006.
