3 beta-hydroxy-6-aza-cholestane and related analogues as phosphatidylinositol specific phospholipase C (PI-PLC) inhibitors with antitumor activity

6-Aza steroid analogues were synthesized as PI-PLC inhibitors. The most act ive compound, 3 beta-hydroxy-6-aza-cholestane (I) showed potent PI-PLC inhi bition (IC50 = 1.8 mu M), similar to that of the commercially available ste roid analogue U73122 (IC50=1-2.1 mu M). Compound 1 exhibited significant gr owth inhibition effects (IC50 = 1.3 mu M in each case) against MCF-7 and HT -29 cancer cells in in vitro cell culture, Compound 1 also inhibited the in vitro adhesion and transmigration of HT-1080 fibrosarcoma cells at 2.5 and 5.0 mu M, respectively. In vivo, compound 1: at 1 mg/kg/day, reduced the v olume of MCF-7 tumors in xenograft models, without weight loss in mice. Str ucture-activity relationships of this series of compounds revealed that a h ydrophobic cholesteryl side chain, 3 beta-hydroxy group and a C-6 nitrogen containing a hydrogen atom at position-6 are crucial for activity. N-Maleic amidoacid derivative it also exhibited weak inhibition (IC50 = 16.2 mu M). (C) 2000 Elsevier Science Ltd. All rights reserved.