TY - JOUR
T1 - Structure - Activity relationship of Aza-steroids as PI-PLC inhibitors
AU - Xie, Wenge
AU - Peng, Hairuo
AU - Kim, Deog Il
AU - Kunkel, Mark
AU - Powis, Garth
AU - Zalkow, Leon H.
N1 - Funding Information:
We gratefully acknowledge support of this research by the NCI/NIH (Grant 5U19 CA52995). We are grateful to Dr. Leslie T. Gelbaum for his assistance in obtaining high resolution NMR spectra, and Mr. David E. Bostwick and Ms. Sarah J. Shealy for their assistance in obtaining high resolution mass spectra.
PY - 2001/5
Y1 - 2001/5
N2 - 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 IC50 values of 7.4 and 7.5 μM, respectively. The 20α epimer, 8a2 (IC50 = 0.64 μM), whose stereochemistry at C-20 coincides with that of cholesterol, was found 50 times more potent than the 20β epimer, 8a1 (IC50 = 32.2 μM). In diaza-estrone derivatives, the 3-methoxy group on the aromatic A-ring of 23 exhibited moderate PI-PLC inhibitory activity (IC50 = 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, IC50 = 7.4 μM) exhibited more potent PI-PLC inhibitory activity than their counterparts with 3-methoxyl group on the non-aromatic A-ring (26, IC50 = 17.4 μM). We have illustrated in our previous publication that 3-hydroxyl-6-aza steroids are potent PI-PLC inhibitors. 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 GI50 value (MG-MID) of 5.75 μM for 54 tumors.
AB - 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 IC50 values of 7.4 and 7.5 μM, respectively. The 20α epimer, 8a2 (IC50 = 0.64 μM), whose stereochemistry at C-20 coincides with that of cholesterol, was found 50 times more potent than the 20β epimer, 8a1 (IC50 = 32.2 μM). In diaza-estrone derivatives, the 3-methoxy group on the aromatic A-ring of 23 exhibited moderate PI-PLC inhibitory activity (IC50 = 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, IC50 = 7.4 μM) exhibited more potent PI-PLC inhibitory activity than their counterparts with 3-methoxyl group on the non-aromatic A-ring (26, IC50 = 17.4 μM). We have illustrated in our previous publication that 3-hydroxyl-6-aza steroids are potent PI-PLC inhibitors. 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 GI50 value (MG-MID) of 5.75 μM for 54 tumors.
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U2 - 10.1016/S0968-0896(00)00302-3
DO - 10.1016/S0968-0896(00)00302-3
M3 - Article
C2 - 11377165
AN - SCOPUS:0034999411
SN - 0968-0896
VL - 9
SP - 1073
EP - 1083
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 5
ER -