Chemistry Reference
In-Depth Information
n
= 40,
r
= 0.920,
s
= 0.223,
F
4,35
= 47.9 < 0.001
Equation (24) gives a good cross-validated
r
2
CV
value (
q
2
) of 0.837. A most significant aspect of this study is that
every data point was included in the formulation of equation (24). Such an outcome is rarely found and merits
special consideration. We find this to be quite unusual since one usually finds some outliers in QSAR papers which
must be omitted to obtain a high correlation.
From equation (24) the following aspects may be highlighted: (1) the coefficient of MR
8
is a squared negative term,
and hence the presence of the methyl group at position 8 is detrimental in relation to the antiproliferative activity;
accordingly, it is advisable that a hydrogen atom be in this position because this atom has a smaller value for MR;
(2) there is no electronic contribution of the group located at position 7 of the quinolinium ring. This is most
remarkable in the case of the 7-NH
2
group, which is located at the same relative position (although in the other
aromatic ring) as the 4-substituent in relation to the N
+
atom, and its presence should have further facilitated the
delocalization of the positive charge of the endocyclic N atom.
A plausible explanation is that the 7-methyl group exerts a steric hindrance making it impossible for that 7-NH
2
group to adopt a coplanar disposition in relation to the aromatic ring. This is necessary for the electronic
delocalization to take place. Therefore, 7-substituent contributes only to the global lipophilicity of the molecules; (3)
finally, lipophilicity contributes in two aspects to the antiproliferative activity: (a) on one hand, a global contribution
(clog
P
) and on the other, a contribution at a specific site on the molecules (
linker
). Both descriptors are orthogonal
and therefore the participation of both is justified in the QSAR equation.
The relative contribution of
linker
in equation (1) is higher than that of log
P
and, it can be hypothesized that
favourable hydrophobic interactions between the enzyme and the linker would modulate the coupling inhibitor-
ChoK. Although according to equation (1) the increase in the global lipophilicity and in the lipophilicity of the
linker would augment the antiproliferative activity, the solubility was the reason for limiting the spacers to the 3,3'-,
4,4'-biphenyl and 4,4' bibenzyl moieties.
When the experimental
p
(IC
50
)
HT-29
values are correlated with the theoretical ones calculated by equation (24),
equation (25) is obtained corresponding to the straight line represented in Fig.
5
:
p
(IC
50
)
HT-29 experimental
= -0.35 + 1.05 (± 0.08)
p
(IC
50
)
HT-29 theoretical
(25)
n
= 40,
r
= 0.916,
s
= 0.220,
F
1,38
= 199, < 0.001
p
IC
50
(exp)= 1.05
p
IC
50
(theo) - 0.35
R
2
= 0 .84 0
7.00
6.50
6.00
5.50
5.00
4.50
4.00
4.00
4.50
5.00
5.50
6.00
6.50
7.00
Predicted HT-29
p
IC
50
Figure 7: Gra
ph between experimental and predicted antiproliferative activities for the test set.
