SAR Studies around the SULT1A1-Activated Alkylator YC-1 as Cytotoxic Agents against Biliary Tract Cancer Cells

A quantitative high-throughput screen using biliary tract cancer cell lines had identified the small-molecule YC-1 as being selectively cytotoxic against the IDH1-mutant cell lines with high expression of SULT1A1. We discuss the structure-activity relationship study of YC-1 analogs and identify the key structural motifs that are essential for this cytotoxicity. We highlight the narrow SAR around the furfuryl alcohol that has been reported as a critical motif that is activated to a reactive electrophile by the sulfotransferase enzyme SULT1A1. Drug-like properties of key analogs are evaluated, including a close look at YC1 hepatic metabolism. We also show the SAR of a smaller subset of 2-choloro-4-amino benzyl alcohols from the NCI compound collection with a similar benzyl alcohol motif. We also demonstrate the ability of key analogs to act as substrates of SULT1A1 in a colorimetric biochemical assay.