title: 3Beta-hydroxy-6-aza-cholestane and related analogues as phosphatidylinositol specific phospholipase C (PI-PLC) inhibitors with antitumor activity.
abstract: 6-Aza steroid analogues were synthesized as PI-PLC inhibitors. The most active compound, 3beta-hydroxy-6-aza-cholestane (1) showed potent PI-PLC inhibition (IC50 = 1.8 microM), similar to that of the commercially available steroid analogue U73122 (IC50 = 1-2.1 microM). Compound 1 exhibited significant growth inhibition effects (IC50 = 1.3 microM 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 microM, respectively. In vivo, compound 1, 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, 3beta-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 microM).
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta 30332, USA.
authors.forename: W
authors.initials: W
authors.lastname: Xie
authors.forename: H
authors.initials: H
authors.lastname: Peng
authors.forename: L H
authors.initials: LH
authors.lastname: Zalkow
authors.forename: Y H
authors.initials: YH
authors.lastname: Li
authors.forename: C
authors.initials: C
authors.lastname: Zhu
authors.forename: G
authors.initials: G
authors.lastname: Powis
authors.forename: M
authors.initials: M
authors.lastname: Kunkel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001372:Aza Compounds / Q000737:chemistry / Q000494:pharmacology*; D002777:Cholestanols / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054801:Phosphoinositide Phospholipase C; D013057:Spectrum Analysis; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*
chemical_list: C411083:3beta-hydroxy-6-aza-cholestane; D000970:Antineoplastic Agents; D001372:Aza Compounds; D002777:Cholestanols; D004791:Enzyme Inhibitors; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase