Evaluation of Thiol-Mediated Uptake in VHL-Based PROTACs

Modification of biologically active molecules with 1,2-dithiolane derivatives constitutes a promising strategy to increase the cellular uptake of compounds by leveraging thiol-mediated uptake pathways. In this study, we evaluate the effect of introducing 1,2-dithiolane handles to von Hippel-Lindau (VHL)-based proteolysis targeting chimeras (PROTACs) on their cytotoxic properties. Starting from a previous molecular design, two sets of derivatives with 1,2-dithiolane handles and control compounds comprising the corresponding carbon-equivalents were synthesized and studied for their anticancer properties. Increased or equipotent cytotoxicity towards cancer cells (HeLa) was observed for several derivatives compared to the parent compound. Especially for lipoic acid derivatives, and the corresponding all-carbon derivatives, a significant increase in cytotoxicity compared to the unfunctionalized compound was observed. These results suggest effects other than or in addition to thiol-mediated uptake for acylated PROTAC derivatives. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/692502v1_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@b2943aorg.highwire.dtl.DTLVardef@21777aorg.highwire.dtl.DTLVardef@12afe24org.highwire.dtl.DTLVardef@1931e4b_HPS_FORMAT_FIGEXP M_FIG C_FIG