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LFER.
The above examples are only illustrative and
reflective of the type of datasets that are incorporated
log 1/C )-0.97((0.15)Ã+ + 5.14((0.12)
in these database. Many more such comparisons are
possible, and as the database expands, it will become
n ) 7, r2 ) 0.983, s ) 0.124, q2 ) 0.967
much more fruitful to search via MERLIN for novel
comparisons. Again using similarity searching on
outlier: 2-OH (19)
C6H5CHdCH2, we find a number of reactions of
QSAR 18 has a Ã+ term of borderline value, while styrenes and styrene derivatives with radicals from
its activity is mainly a function of size as delineated mechanistic organic chemistry.
by CMR. The range in log 1/C for eq 18 is 3.6-5.3, Reaction of X-C6H4CHdCH2 with 4-Cl-C6H4S" 106i
while the range in eq 19 is 4.4-6.4. Not only are in cyclohexane
congeners of QSAR eq 19 more potent, the correlation
of QSAR eq 19 is much sharper. A SMILES search
log k )-0.58((0.15)Ã+ + 7.73((0.06)
with benzamide yields a number of studies on hy-
drolysis, three of which have very similar F+ terms,
n ) 7, r2 ) 0.949, s ) 0.055, q2 ) 0.924 (22)
of which the following is an example.
Hydrolysis105 of X-C6H4CONH2 in 40% aqueous
Reaction of X-C6H4CHdCH2 with C6H5S" 106i in
ethanol at 65 °C
cyclohexane
log k )-0.28((0.08)Ã+ - 5.10((0.03)
log k )-0.33((0.08)Ã+ + 7.45((0.03)
n ) 4, r2 ) 0.996, s ) 0.014, q2 ) 0.902 (20)
n ) 6, r2 ) 0.970, s ) 0.026, q2 ) 0.842
Through resonance implied by eq 20 would suggest
outlier: 4-Br (23)
the following resonance form to be important in the
case of compounds from QSAR eq 19.
Reaction of X-C6H4CHdCH2 with (CH3)3COO" 107
in benzene
log krel )-0.31((0.22)Ã+ + 0.04((0.09)
n ) 5, r2 ) 0.862, s ) 0.063, q2 ) 0.645 (24)
Chem-Bioinformatics Chemical Reviews, 2002, Vol. 102, No. 3 801
Reaction of X-C6H4CHdCH2 with Cl3C" 108 in Toxicity to HeLa cells compared to colchicine of113
benzene
log krel )-0.49((0.13)Ã+ + 0.05((0.04)
n ) 8, r2 )0.937, s ) 0.044, q2 ) 0.882
log 1/C )-1.51((0.32)Ã+ -
outliers: 4-CN, 4-NO2 (25)
0.62((0.26)B54 + 4.36((0.69)
Reaction of X-C6H4C(CH2CH3)dCH2 with :CCl2109
n ) 12, r2 ) 0.931, s ) 0.321, q2 ) 0.880
log krel )-0.37((0.13)Ã+ - 0.03((0.05) outliers: 4-NH2, 4-Br, 6-CF3, 4-NHC4H9 (30)
n ) 5, r2 ) 0.964, s ) 0.032, q2 ) 0.786 (26)
It is clear that Ã+ is the parameter of choice,
suggesting a radical mechanism in these pharmaco-
"
Reaction of X-C6H4CHdCHC6H5 with SCH2COOH logical actions. Hence, it would be an exercise in
heat110 futility to try to develop a drug in which an aromatic
CHdCH2 is conjugated to an electron-rich moiety. As
in the butadiene cases, all of these examples are
log krel )-0.40((0.18)Ã+ - 0.01((0.07)
correlated with Ã+ having negative F values. Another
drug with liver toxicity recently withdrawn from the
market is baycol.
n ) 5, r2 ) 0.944, s ) 0.041, q2 ) 0.828
outlier: 3,4-di-OMe (27)
There are fewer examples from biological systems
for comparison.
Elevation of serum alanine transaminase in mice
Here we find a styrene-like moiety that may well
due to hepatic toxicity by X-C6H4CHdCH2111
be the cause of toxicity.
Another functional group that has received atten-
log 1/C )-0.46((0.26)Ã+ + 3.22((0.18)
tion from chemists and biologists is the sulfonamido
entity. Equation 31 shows the substituent effect on
ionization of X-C6H4SO2NH2.114
n ) 6, r2 ) 0.862, s ) 0.118, q2 ) 0.738
pKa )-0.87((0.07)Ã + 10.0((0.04)
outlier: H (28)
n ) 13, r2 ) 0.985, s ) 0.058, q2 ) 0.977 (31)
-Adrenoceptor blocking activity of complex styrenes
in right atria of guinea pigs112
Thus, the F value for ionization would be 0.87.
The following biological examples can be compared
with the effect of substituents on the acidity of the
sulfonamide function. One can then determine if the
ionization of sulfonamides impacts their biological
activity.
Inhibition of lyase, carbonic anhydrase by X-C6H4-
pA2 )-0.98((0.22)ÃX+ + 0.53((0.32)B1X,5 -
SO2NH2115
1.36((0.31)B1R + 7.41((0.43)
log 1/C ) 0.90((0.23)Ã +
n ) 21, r2 ) 0.894, s ) 0.184, q2 ) 0.839
0.23((0.17)Clog P + 5.36((0.15)
outliers: R ) CMe3, X) H; R ) CHMe2, X)
n ) 16, r2 ) 0.930, s ) 0.176, q2 ) 0.884
3,5-di-Cl; R ) CMe3, X) 3,5-di-Cl; R )
CMe3, X) 3-Me, 5-Cl; R ) CMe3, X) 3-Me (29) outlier: 2-Me, 2-Cl, 2-NO2 (32)
802 Chemical Reviews, 2002, Vol. 102, No. 3 Hansch et al.
Naturiuretic action in rats of X-C6H4SO2NH2116 of the two steric effects would seem to make sense
in that the removal of hydrogen in each example is
log 1/C ) 0.77((0.22)Ã - critical. The electronic effects in the two sets are quite
different, reflecting a homolytic bond dissociation
0.16((0.16)Clog P + 0.30((0.13)
"
reaction in QSAR eq 35 (removal of H) and a
heterolytic reaction in QSAR eq 36 (removal of a
n ) 14, r2 ) 0.849, s ) 0.151, q2 ) 0.734
proton) where one normally finds Ã- to be the
parameter of choice for phenols. Steric effects in
outliers: 3-NO2, 4-Cl; 4-NO2, 3-CF3 (33)
QSAR eqs 35 and 36 are independent of electronic
effects.
Despite the extra term in eq 33 and the fact that
the action is occurring in rats, the agreement with Running a similarity search on the double database
eq 31 in terms of F is good. The following is another with Ã- turns up many interesting QSAR for com-
example in whole animals. parison. Searching with 15 S- finds 1362 QSAR with
ED50 against electroshock seizures in mice by Ã- terms. Next, using 16 in Table 1 16 .7
X-C6H4SO2N(Y)2117 isolates 329 QSAR with F between 0.7 and 2. Now
using the sort procedure all QSAR are listed in order
log 1/C ) 0.91((0.25)ÃX + of increasing slopes on Ã-. One of the first equations
that appears is QSAR eq 36 above for the enzymatic
0.47((0.16)Clog P - 0.58log(  10Clog P + 1) +
sulfation of phenols. Another example of enzymatic
3.03((0.12)
sulfation is that of X-C6H4CHdNOH.120
Sulfation by arylsulfotransferase
n ) 16, r2 ) 0.913, s ) 0.100, q2 ) 0.836,
)-1.31
log Vmax/Km ) 0.75((0.25)Ã- +
outliers: X ) 4-Br, Y ) OCH3, H; X) 4-Br, Y )
0.56((0.40)Clog P + 6.21((0.86)
CH3, CH3 (34)
n ) 5, r2 ) 0.990, s ) 0.072, q2 ) 0.897 (37)
Despite the complexity of QSAR eq 34, the F value
is in good agreement with eqs 31-33.
This makes sense in that the removal of hydrogen
We have been interested in studying the use of the
in each example is critical. The electronic effects in
sterimol parameter B1 for the correlation of steric
the two sets are equivalent. This resembles phenols
effects emanating from the ortho position. From the
H-bonding in 1,2-dichloroethane with pyridine121
combined datasets we can make the following search.
15 B1 1220 hits
log k ) 0.73((0.13)Ã- - 0.67((0.13)B12 +
12 phenol 33 hits
1.95((0.20)
This finds 33 QSAR based on phenols. Inspecting the
results of a mechanistic organic chemical reaction for
n ) 17, r2 ) 0.941, s ) 0.099, q2 ) 0.896
comparison with a biological QSAR can be done by
viewing the results with machine sorting on the [ Pobierz całość w formacie PDF ]