B. Kupcewicz et al. / Bioorg. Med. Chem. Lett. xxx (2014) xxx–xxx
3
Table 2
Table 3
Cytotoxic activity of chalcones (1–11) against HL-60, NALM-6 and WM115 cancer cell
Definition of quantum mechanics derived molecular descriptors
lines
Symbol, name Definition
a
IC50
(lM)
l
g
r
x
(Chemical potential)
(Chemical hardness)
(Chemical softness)
(Electrophilicity)
l
g
r
x
= (ELUMO + EHOMO)/2
= (ELUMO ꢀ EHOMO)/2
Compound
HL-60
NALM-6
WM-115
= 1 ꢀ
g
1
2
3
4
5
6
7
8
55.4 1.3
18.0 2.5
6.3 0.6
5.3 0.6
7.1 0.3
8.3 0.5
7.7 1.0
7.3 0.4
5.8 0.6
48.7 3.9
39.3 3.5
19.1 4.7
51.1 1.7
0.8 0.1
23.9 2.5
37.5 3.0
18.0 5.1
5.5 0.5
40.6 5.1
9.3 0.4
6.1 0.4
6.8 0.8
6.9 0.7
50.2 2.5
31.7 2.2
8.2 0.5
57.6 8.6
0.7 0.3
43.1 2.7
40.8 3.7
42.0 9.6
61.3 6.5
69.1 3.5
48.9 3.0
7.6 0.5
50.0 3.4
27.6 2.7
60.5 7.1
56.4 4.4
53.2 2.8
71.2 3.2
18.2 4.3
=
l
2/2
g
For more comprehensive analysis of how variation in a molecu-
lar structure of chalcones might influence values of electronic
descriptors, the chalcone structure has been fragmented to its
basic components; two rings A and B, and the linkage. The com-
puted orbital energies of chalcones 1–11 are compared (Fig. 4) with
other model compounds that represent simple structural varia-
tions around the CC double bond. Also corresponding data of eval-
uated hardness, softness and electrophilicity are presented in
Figure 5. The highest value of ELUMO that correlates with the largest
HOMO–LUMO energy gap and the lowest value of electrophilicity
is found for ethene that is the simplest model of all considered
structures. Polarization of the C@C environment by substitutions
9
10
11
Chromanone
Flavanone
Cisplatin
a
IC50-concentration of a test compound required to reduce the fraction of sur-
viving cells to 50% of that observed in the control, non-treated cells. Mean values of
IC50 (in M) standard deviation from 3 experiments each performed in quintuple
l
are presented.
that mimic chalcone skeletal blocks around the
p bond shows
steady decrease of ELUMO and increase of EHOMO. Consequently,
increase of electrophilicity and softness, and decrease of hardness.
Therefore, a specific position and a character of substituents
100
80
60
40
20
0
arbitrate the
p electron density of the linkage and modulate the
electrophilic power of the chalcone moiety. Generally, as it is
expected the electron-withdrawing groups (EWG), in contrast to
the electron-donating groups (EDG), will decrease the LUMO
energy. In particular, this can be noticed for 9 where presence of
a highly electronegative, that is, strongly electron-withdrawing,
NO2 group, correlates with high electrophilicity.
Chalcone molecule has three reactive sites where a nucleophile
is prone to attack; carbon of the carbonyl group and each hydrogen
of
a and b carbons (Fig. 1). Hence, computed natural charges of the
C
carbonyl, C and Cb were also included to construct the model that
a
examines structure-cytotoxic activity relationships.
The computed orbital energies, ELUMO and EHOMO are key factors
that quantify chemical potential, hardness, softness and electro-
philicity. It is engaging to analyze the frontier orbitals of substi-
8
7
6
9
4
3
2
11 10
Low activity
5
1
High activity
tuted chalcones also in terms of qLUMO
ꢀ
qHOMO, that is, the
Compound
electron density flow upon LUMO to HOMO excitation. As it is
shown for selected compounds in Table 4, molecular regions where
electrons are lost or gained upon excitation are shown in red and
blue, respectively. Seven of tested chalcones (2, 3, 4, 6, 7, 8 and
9) upon excitation show consistently a decrease of electron popu-
lation in the ring A and an increase of the density in the linkage
region. The remaining four compounds (1, 5, 10 and 11) show dis-
tinctively different pattern. In these compounds the electrons leave
the ring B and the link chain shows alternated density changes
over the atoms.
Figure 3. Dendrogram based on standardized cytotoxic activity (expressed as log1/
IC50 in M) against both leukemic HL-60 and NALM-6 cancer cell lines. Ward’s
method of agglomeration, based on Euclidean distance, was used.
l
establish a structure–cytotoxicity relationship based on selected
chalcones 1–11. All quantum-mechanical calculations were per-
formed using the Gaussian 09 software package.14 The orbital
energies were calculated for fully optimized geometries at
B3LYP/6-311G⁄⁄ level of theory, and employed to evaluate reactiv-
These alternated density pattern resonates well with the pat-
tern of electrophilic and nucleophilic atoms in the linkage (Table 4
and S5). Interestingly, these chalcones also display low cytotoxic
activity towards leukemic cancer cell lines (HL-60 and NALM-6).
Classification of chalcones into the two groups can be correlated
with the placement and character of substituents. As long as the
ring A remains most electron-rich region of the compound, the
chalcone will show higher cytotoxic activity. This can be achieved
by placement of electron donating substituents, such as OH and
OCH3 in ring A, but not in ring B (compound 4). Also placement
of strongly electron-withdrawing groups such as NO2 in ring B
(compound 9) correlates with increase of cytotoxic activity.
In order to demonstrate the value and benefit of the reactivity
descriptors to description and explain the structure-cytotoxic
ity descriptors such as chemical potential (
electronegativity ( ), chemical hardness (
electrophilicity ( ). Detailed relations of ELUMO and EHOMO to
l
) which is negative of
v
x
g) and softness ( ), and
r
derived descriptors are presented in Table 3.
All computed values of electron structure descriptors are sum-
marized in Table S3 and DFT natural charges of selected atoms are
shown in Table S4 of the Supplementary material. The graphical
representation of the frontier orbitals (HOMO and LUMO) and
redistribution of electron density (qLUMO
ꢀ
qHOMO) for four repre-
sentatives of chalcones are presented in Table 4 (the other com-
pounds are shown in Table S5). The HOMO orbitals consistently
show the bonding character of the CC double bond of the linkage
that changes to the anti-binding character for the corresponding
LUMO orbital.