Structure–activity relationship of Aza-steroids as PI-PLC inhibitors

• Published in: Bioorganic & medicinal chemistry 2001-05, Vol.9 (5), p.1073-1083
• Main Authors: Xie, Wenge, Peng, Hairuo, Kim, Deog-Il, Kunkel, Mark, Powis, Garth, Zalkow, Leon H.
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Azacosterol - chemical synthesis; Azacosterol - pharmacology; Azasteroids - chemical synthesis; Azasteroids - pharmacology; Biological and medical sciences; Cholestanols - chemical synthesis; Cholestanols - pharmacology; Drug Screening Assays, Antitumor - methods; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; General aspects; Humans; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; Phosphatidylinositol Diacylglycerol-Lyase; Phosphoinositide Phospholipase C; Structure-Activity Relationship; Tumor Cells, Cultured - cytology; Tumor Cells, Cultured - drug effects; Type C Phospholipases - antagonists & inhibitors; Type C Phospholipases - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(00)00302-3

A number of aza-steroids were synthesized as potent phosphatidylinositol phospholipase C (PI-PLC) inhibitors. The epimeric mixtures 22,25-diazacholesterol ( 8a) and 3β-hydroxy-22,25-diazacholestane ( 8b) were among the most active of these inhibitors, with IC 50 values of 7.4 and 7.5 μM, respectively. The 20α epimer, 8a2 (IC 50=0.64 μM), whose stereochemistry at C-20 coincides with that of cholesterol, was found 50 times more potent than the 20β epimer, 8a1 (IC 50=32.2 μM). 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 μM), 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 μM) 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 μM). 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 μM for 54 tumors. The 20α epimer ( 8a2) of 22,25-diazacholesterol, the most potent of a number of azasteroids tested (IC 50 of 0.64 μM), was 50 times more potent than the epimeric 20β isomer ( 8a1) as a PIPLC inhibitor. The epimeric mixture ( 8a) of compounds 8a1 and 8a2 (1:1) exhibited selective growth inhibition effects in the NCI in vitro tumor cell screen with a GI 50 MG-MID values of 5.75 μM for 54 human tumors.