| Abstract
| - In this comprehensive study on the caspase-mediated apoptosis-inducing effect of 51 substitutedphenols in a murine leukemia cell line (L1210), we determined the concentrations needed toinduce caspase activity by 50% (I50) and utilized these data to develop the following quantitativestructure−activity relationship (QSAR) model: log 1/I50 = 1.06 B52 + 0.33 B53 − 0.18π2,4 − 0.92.B53 and B52 represent steric terms, while π2,4 represents the hydrophobic character of thesubstituents on the ring. The strong dependence of caspase-mediated apoptosis on mostly stericparameters suggests that the process is a receptor-mediated interaction with caspases ormitochondrial proteins being the likely targets. Conversely, cytotoxicity studies of 65 electron-releasing phenols in the L1210 cell line led to the development of the following equation: log 1/ID50 = −1.39σ+ − 0.28 B52,6 + 0.16 log P − 0.58I2 − 1.04I1 + 3.90. The low coefficient with log Pmay pertain to cellular transport that may be enhanced by a modest increase in overallhydrophobicity, while the presence of σ+ is consistent with the suggestion that radicalstabilization is of prime importance in the case of electron-releasing substituents. On the otherhand, the QSAR for the interactions of 27 electron-attracting phenols in L1210 cells, log 1/ID50= 0.56 log P − 0.30 B52 + 2.79, suggests that hydrophobicity, as represented by log P is ofcritical importance. Similar cytotoxicity patterns are observed in other mammalian cell linessuch as HL-60, MCF-7, CCRF-CEM, and CEM/VLB. The significant differences between thecytotoxicity and apoptosis QSAR for electron-releasing phenols suggest that cytotoxicity involvesminimal apoptosis in most of these substituted monophenols.
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