title: Structure-activity relationship of aza-steroids as PI-PLC inhibitors.
abstract: A number of aza-steroids were synthesized as potent phosphatidylinositol phospholipase C (PI-PLC) inhibitors. The epimeric mixtures 22,25-diazacholesterol (8a) and 3beta-hydroxy-22,25-diazacholestane (8b) were among the most active of these inhibitors, with IC(50) values of 7.4 and 7.5 microM, respectively. The 20alpha epimer, 8a2 (IC(50)=0.64 microM), whose stereochemistry at C-20 coincides with that of cholesterol, was found 50 times more potent than the 20beta epimer, 8a1 (IC(50)=32.2 microM). In diaza-estrone derivatives, the 3-methoxy group on the aromatic A-ring of 23 exhibited moderate PI-PLC inhibitory activity (IC(50)=19.7 microM), while compound with a free hydroxyl group (21) was inactive. However, in diaza-pregnane derivatives, epimers with a 3-hydroxyl group (8a, IC(50)=7.4 microM) exhibited more potent PI-PLC inhibitory activity than their counterparts with 3-methoxyl group on the non-aromatic A-ring (26, IC(50)=17.4 microM). We have illustrated in our previous publication that 3-hydroxyl-6-aza steroids are potent PI-PLC inhibitors.(3) However, simultaneous presence of the 6-aza and 22,25-diaza moieties in one molecule as in 13, led to loss of activity. Epimeric mixture 8a showed selective growth inhibition effects in the NCI in vitro tumor cell screen with a mean GI(50) value (MG-MID) of 5.75 microM for 54 tumors.
authors.affiliation: School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: W
authors.initials: W
authors.lastname: Xie
authors.forename: H
authors.initials: H
authors.lastname: Peng
authors.forename: D I
authors.initials: DI
authors.lastname: Kim
authors.forename: M
authors.initials: M
authors.lastname: Kunkel
authors.forename: G
authors.initials: G
authors.lastname: Powis
authors.forename: L H
authors.initials: LH
authors.lastname: Zalkow
mesh_terms: D001373:Azacosterol / Q000138:chemical synthesis* / Q000494:pharmacology*; D001378:Azasteroids / Q000138:chemical synthesis* / Q000494:pharmacology*; D002777:Cholestanols / Q000138:chemical synthesis* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054801:Phosphoinositide Phospholipase C; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors* / Q000187:drug effects
chemical_list: D001378:Azasteroids; D002777:Cholestanols; D004791:Enzyme Inhibitors; C018263:22,25-diazacholestanol; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D001373:Azacosterol