New UB006 Derivatives With Higher Solubility and Cytotoxic Activity in Ovarian Cancer Cells.

Abstract

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.