Chemistry Reference
In-Depth Information
activities, the synthesis of a new set of compounds is proposed based on changing the pyridinium for quinolinium
moieties of the biscationic acyclic compounds.
The aim of this section specifically focuses on studying the effect to be expected on the biological activities by a
variation in the linker that connects the two quinolinium cations. These quinolinium moieties have electron-releasing
groups at their position 4, with other different groups at positions 3, 7 and 8 of the heterocycle (Fig.
4
) [25].
R
4
R
4
R
3
R
3
R
3
= H, Me
R
4
= cyclic tertiary and
acyclic amino groups
R
7
= H, Cl, NH
2
R
8
= H, Me
n = 0, 2
R
7
N
N
R
7
3
3'
R
8
R
8
4
(CH
2
)
n
4'
2Br
Figure 6:
Bisquinolinium compounds.
There was a trial to correlate the human ChoK inhibitory activity for the whole set of compounds with the electronic
and lipophilic parameters, but all the attempts turned out to be fruitless. In general it can be deduced that the activity
against the HT-29 cell line is greater than the corresponding activity against ChoK, with which the symmetrical
bisquaternized salts could act on another point of the pathway triggered by
ras
activation [25].
The octanol-water partition coefficient, used in its logarithmic form (log
P
), is the most widely accepted measure of
lipophilicity. Reproducibility and accuracy of experimental log
P
determinations are not exact for extremely
lipophilic and/or hydrophilic compounds such as the bisquinolinium structures (Fig.
4
). Fragmental methods make it
possible to create data banks and to perform log
P
calculations by computer.
The clog
P
values of the bissalts were calculated by using the Ghose-Crippen modified atomic contribution system
[26] (ATOMIC5 option) of the PALLAS 2.0 program [21].
spacer
is the substituent constant for the linker calculated
by using the Ghose-Crippen modified atomic contribution system [26] (ATOMIC5 option) of the PALLAS 2.0
program [21].
One of the most important chemico-physical properties used in QSAR studies is the molar refractivity (MR). The
significance of MR in QSAR equations of some ligand-enzyme interactions has being interpreted with the help of
3D structures. These investigations showed that substituents modelled by MR bind in polar areas, while substituents
modelled by a bind in a hydrophobic space [27, 28]. Correspondingly, a positive sign of MR in a QSAR equation
can be explained by binding the substituents to a polar surface, while a negative sign or a nonlinear relationship
indicates a limited area or steric hindrance at this binding site [28].
The Hammett-type
R
values for the amino, dimethylamino and anilino groups were taken from the Hansch and
Leo tables [13], whilst we have previously published [23] such values for the pyrrolidino, perhydroazepino, and
N
-methylanilino groups. The same methodology [23] was used to estimate the unknown
R
value for the 4-
chloro-
N
-methylanilino group by using the
13
C chemical shifts of the previously reported compounds 1,1'-
biphenyl-3,3'-diylmethylene)bis[4-(4-chloro-
N
-methylanilino)- pyridinium] dibromide and 1,1'-biphenyl-4,4'-
diylmethylene)bis[4-(4-chloro-
N
-methylanilino)pyridinium] dibromide [29].
When the effect of the volume (MR
8
)
§
, global lipophilicity (clog
P
), the substituent constant of the linker, and the
electronic parameters (
R
4
)
§
of the R
4
substituent were taken into account for the antiproliferative activity, equation
(23) was obtained:
p
(IC
50
)
HT-29
= - 2.66 - 0.03 (± 0.00) MR
8
2
+ 0.10 (± 0.02) clog
P
+ 1.05 (± 0.31)
linker
- 3.73 (± 0.71)
R
(24)
§
The subscript refers to the position of the substituent
