Grant-in-Aid for Scientific Research (C)
|Allocation Type||Single-year Grants|
Drug development chemistry
|Research Institution||Kobe Pharmaceutical University|
YAMAGAMI Chisako Kobe Pharmaceutical University, Faculty of Pharmacy, Associate Professor, 薬学部, 助教授 (20140410)
MOTOHASHI Noriko Kobe Pharmaceutical University, Faculty of Pharmacy, Associate Professor, 薬学部, 助教授 (60068343)
AKAMATSU Miki Kyoto University, Graduate School of Agriculture, Associate Professor, 大学院・農学研究科, 助教授 (70183134)
|Project Period (FY)
2003 – 2004
Completed(Fiscal Year 2004)
|Budget Amount *help
¥3,600,000 (Direct Cost : ¥3,600,000)
Fiscal Year 2004 : ¥1,000,000 (Direct Cost : ¥1,000,000)
Fiscal Year 2003 : ¥2,600,000 (Direct Cost : ¥2,600,000)
|Keywords||structure-activity relationship / hydrophobicity parameter / electronic parameter / steric parameter / hydrogen-bonding parameter / prediction system|
In order to predict log P_<oct>(P_<oct>t:1-octanol/water partition coefficient) values, it is important to estimate correctly the contribution of H-bonding effect involved in log P_<oct>. For H-acceptors, the prediction is well done by using a new H-acceptor scale, S_<HAt>, which we recently proposed. In this research, we attempted to predict reliable log P_<oct> values for compounds with H-donating substituent(s) by using phenols as model compounds.
1.Accumulation of data for log P and their prediction.
The log P_<CL> (P_<CL> : chloroform/water partition coefficient) and log P_E (P_E : butyl ether/water partition coefficient) values for monosubstsituted phenols with nonamphiprotic substituent X were measured and the relationship with log P_<oct> was analyzed quantitatively in terms of S_<HAt> for the X-substituent, providing excellent correlations (σ^0 : electronic substituent constant).
log P_<CL>=1.050 log P_<oct>- 1.172σ^0+0.754 S_<HA>-1.968
log P_E=1.188 log P_<oct>- 0.280σ^0-0.298 S_
The differences in the corresponding coefficients describe well the differences in H-bonding behavior of the amphiprotic OH group with chloroform(H-donor) and butyl ether(H-accepter), demonstrating that the S_<HA> parameter is applicable to predict log P_<oct> values for H-donors(amphiprotics).
2.Prediction of electronic and steric parameters and application to QSAR analyses for phenols.
Antioxidant activities(IC_<50>) for benzalacetones were measured and their QSAR analyses were performed in terms of physicochemical parameters, demonstrating that activities are predicted nicely by the following general formula.
In this equation, σ+ represents the through resonance electronic parameter and Es represents the steric parameter applied to the substituent(s) ortho to the phenolic OH group.
Although the physicochemical meaning of this equation is straightforward, the σ+ and Es parameters are derived from appropriate experimental values and are not always accessible. Therefore, we tried to predict these parameters by calculations and found the following correlation as an alternative equation.
-log IC_<50>=e E_<HOMO>+ fΣ F_<H,O>+[CoMFA steric field]+const.
In this equation, σ+ is described by E_<HOMO>(the HOMO energy) and F_<H,O>(frontier electron density on OH), and Es is replaced with the steric field term by CoMFA analysis. This means that the activity is predictive only by calculations. Less