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 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.