3β-Hydroxy-6-aza-cholestane and related analogues as phosphatidylinositol specific phospholipase C (PI-PLC) inhibitors with antitumor activity Original Research Article

6-Aza steroid analogues were synthesized as PI-PLC inhibitors. The most active compound, 3β-hydroxy-6-aza-cholestane () showed potent PI-PLC inhibition (IC50=1.8 μM), similar to that of the commercially available steroid analogue U73122 (IC50=1–2.1 μM). Compound exhibited significant growth inhibition effects (IC50=1.3 μM in each case) against MCF-7 and HT-29 cancer cells in in vitro cell culture. Compound also inhibited the in vitro adhesion and transmigration of HT-1080 fibrosarcoma cells at 2.5 and 5.0 μM, respectively. In vivo, compound , at 1 mg/kg/day, reduced the volume of MCF-7 tumors in xenograft models, without weight loss in mice. Structure–activity relationships of this series of compounds revealed that a hydrophobic cholesteryl side chain, 3β-hydroxy group and a C-6 nitrogen containing a hydrogen atom at position-6 are crucial for activity. N-Maleic amidoacid derivative 11 also exhibited weak inhibition (IC50=16.2 μM).