Synthetic sphingolipids with 1,2-pyridazine appendages improve anti-proliferative activity in human cancer cell lines

A synthetic sphingolipid related to a ring-constrained hydroxymethyl pyrrolidine analog of FTY720 that was known to starve cancer cells to death was chemically modified to include a series of alkoxy-tethered 3,6-substituted 1,2-pyridazines. These derivatives exhibited excellent antiproliferative activity against eight human cancer cell lines from four different cancer types. A 2.5- to 9-fold reduction in IC in these cell lines was observed relative to the lead compound, which lacked the appended heterocycle.