Synthesis and structure of dihydroberberine nitroaryl derivatives – Potential ligands for G-quadruplexes

Article abstract of DOI:10.1007/s10593-017-2055-3

(Figure Presented) A method was developed for the synthesis of dihydroberberine nitroaryl derivatives on the basis of dihydroberberine reactions with aromatic electrophiles (picryl chloride, 4-chloro-7-nitrobenzofurazan, 4-chloro-5,7-dinitrobenzofurazan, and 7-chloro-4,6-dinitrobenzofuroxan). The obtained 13-substituted dihydroberberine derivatives represent structures with significant intramolecular charge transfer and, according to the results of molecular docking analysis, can effectively bind with G-quadruplexes of telomeric DNA fragments.

Full text of DOI:10.1007/s10593-017-2055-3

DOI 10.1007/s10593-017-2055-3
Chemistry of Heterocyclic Compounds 2017, 53(3), 335–340
Synthesis and structure of dihydroberberine nitroaryl derivatives –
potential ligands for G-quadruplexes
1
1
1
Oleg N. Burov *, Sergey V. Kurbatov , Mikhail E. Kletskii ,
1
1
Alexander D. Zagrebaev , Igor E. Mikhailov
1
Southern Federal University,
7
Zorge St., Rostov-on-Don 344090, Russia; e-mail: bboleg@gmail.com
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
017, 53(3), 335–340
Submitted September 8, 2016
Accepted November 1, 2016
2
A method was developed for the synthesis of dihydroberberine nitroaryl derivatives on the basis of dihydroberberine reactions with
aromatic electrophiles (picryl chloride, 4-chloro-7-nitrobenzofurazan, 4-chloro-5,7-dinitrobenzofurazan, and 7-chloro-4,6-dinitro-
benzofuroxan). The obtained 13-substituted dihydroberberine derivatives represent structures with significant intramolecular charge
transfer and, according to the results of molecular docking analysis, can effectively bind with G-quadruplexes of telomeric DNA
fragments.
Keywords: berberine, dihydroberberine, 4,6-dinitrobenzofurazan, 4,6-dinitrobenzofuroxan, G-quadruplex, molecular docking,
nucleophilic aromatic substitution, DFT calculations.
Berberine (1) and its derivatives exhibit a broad range of
biological activity, which has been described in review
articles1 and continues to motivate further research in the
areas of organic synthesis and medicinal chemistry toward
developing new routes for structural modification of this
alkaloid. In our opinion, one of the most attractive areas for
the application of berberine derivatives relies on their
ability to bind with G-quadruplexes found in telomeric
carbonyl groups can additionally interact with planar
organic cations and/or Lewis acids.7
,2
Berberine derivatives have significant affinity for
various types of G-quadruplexes due to the presence of
positively charged extended π-system in their molecules.3
Berberines, similarly to other planar polycondensed
heterocyclic systems, form intercalation complexes with
G-quadruplexes,8 which are stabilized by hydrophobic,
ionic, and van der Waals interactions. More distant, non-
specific binding between anionic or neutral ligands and
DNA is also possible, mediated by electrostatic interactions
(including via hydrogen bonds) of the ligand with the sugar-
phosphate backbone of DNA.
,7
3
regions of DNA, which provide universal biological
4
,5
targets in systemic therapy of oncological diseases. The
formation of noncovalent complexes with G-quadruplexes
in promoter regions of oncogenes, as well as in telomeric
regions of chromosomes in combination with telomerase
inhibition provides opportunities for blocking uncontrolled
division of cancer cells and leads to their apoptosis.6
G-quadruplexes are a specific secondary structure type
observed in DNA regions that are enriched in
deoxyguanosine and are composed of four coplanar
guanine bases. These guanine bases are stabilized by
hydrogen bonds in a way that the oxygen atoms of guanine
Analysis of the main types of coordination between
small molecules and G-quadruplexes led to the known
requirements for the structure of potential ligands, which
have been presented in review articles.9
,10
First, the
molecule of potential ligand must contain planar poly-
condensed cyclic structures, capable of stacking. Second, it
is desirable to have additional charged groups able of
0
009-3122/17/53(03)-0335©2017 Springer Science+Business Media New York
335

Chemistry of Heterocyclic Compounds 2017, 53(3), 335–340
Scheme 1
1
forming complexes not only by intercalation, but also by
ionic interactions.
importance of Н NMR data for the majority of chemists,
as well as the reliability of information thus obtained about
the chemical shifts of protons located near the cationic
The goal of this work was to synthesize and study
nitroaryl derivatives of berberine, with structures that satisfy
these requirements and feature significant intramolecular
charge transfer, offering possibilities for additional polar
interactions. The great value of nitroarylation of berberine
derivatives that contain enamine moiety was demonstrated
1
center, in this work we relied on H NMR spectroscopy.
In order to determine the contribution of bipolar compo-
nent in the structures of the obtained compounds 4a–d, we
performed a computational study within the framework of
density functional theory, using the B3LYP exchange-
correlation functional with 6-31G** basis set. This level of
approximation has been found to be adequate for
evaluating the electronic and geometry characteristics of
1
1
previously for acetonylberberine. However, this method
did not allow us to obtain planar structures necessary for
binding with G-quadruplexes.
14
16
In this work, we report the first use of dihydroberberine
2) as a substrate for the introduction of nitroaryl
nitro derivatives of oxazoles and berberines.
(
The most significant parameters that we selected for
evaluating the contribution of bipolar structures were
intramolecular charge transfer to the nitroaryl group, the
bond length between berberine and nitroaryl groups, and
the rotation angle of the nitroaryl substituent relative to the
plane of berberine ring system (Table 1).
substituents at position 13. Our selected arylating reagents
were highly electrophilic chloronitroarenes: picryl
chloride (3a), 4-chloro-7-nitrobenzofurazan (3b), 4-chloro-
5
,7-dinitrobenzofurazan
(3c),
and
7-chloro-4,6-di-
nitrobenzofuroxan (3d) (Scheme 1). The reduction of
berberine chloride (1) to dihydroberberine (2) was
The selected criterion for evaluating the extent of charge
transfer was the total Mulliken charge on the nitroaryl
(berberine) moiety of compounds 4a–d. As shown in Table 1,
there is a significant charge transfer in compounds 4a–d in
the direction from dihydroberberine ring system to the
nitroaryl group (Fig. 1). Besides that, the significant charge
transfer in the aforementioned direction was evidenced also
performed according to
a
previously described
procedure.12
The reactions of dihydroberberine (2) with equivalent
amounts of chloronitroarenes 3a–d were performed in
xylene at room temperature. This led to rapid formation of
dihydroberberine 13-nitroaryl derivatives 4a–d in the form
of deeply colored crystals (Scheme 1). The selection of
xylene as reaction medium was based on the good
solubility of the starting compounds and reaction by-
products in this solvent. The target products formed
precipitates that were relatively pure.
Table 1. The chemical shifts of characteristic protons and the
main physical characteristics of compounds 4a–d according to
calculations using the B3LYP method with 6-31G** basis set
Our previously synthesized diaryls of similar type,
containing both electron-donating and highly electrophilic
moieties, showed significant intramolecular charge transfer
Compound
Parameter
4
a
4b
4c
4d
1
3,14
Chemical shift of 6-CH
2
2
, δ, ppm
, δ, ppm
3.18 3.26 4.05–4.12 4.12–4.17
.30–4.37 4.98–5.04
4.55 4.62 4.97–5.14 5.32–5.37
through a conjugated system of chemical bonds.
The
4
substantial contribution of resonance structures of type 4'a–d
in the electron density distribution was experimentally
demonstrated by the chemical shifts of signals due to pro-
tons located next to the berberine nitrogen atom (Table 1,
Fig. 1). It should be noted that structural characterization of
Chemical shift of 8-CH
Charge transfer, ē
Dipole moment, D
Length of С(13)–С(7') bond, Å*
Dihedral angle
С(12')–С(13)–С(7')–С(6'), deg.**
0.254 0.304
4.56 8.72
1.480 1.471
0.398
8.26
1.461
55
0.425
8.38
1.460
57
72
54
1
nitrogen-containing compounds requires not only Н NMR
15
spectra, but also N NMR spectra, which can be highly
important.15 However, taking into account the particular
*
The length of С(13)–С(1') bond is given for compound 4a.
** The dihedral angle С(12)–С(13)–С(1')–С(2') is given for compound 4a.
3
36

Chemistry of Heterocyclic Compounds 2017, 53(3), 335–340
Figure 1. The direction of dipole moment (charge transfer) and the possible resonance structures of compounds 4a–d.
by the calculated dipole moments of compounds 4a–d
Table 1, the directions of dipole moments are shown in
It is interesting to note that the С(13)–С(7') bond,
(
formed as a result of the discussed reactions, is activated
with respect to both electrophilic and nucleophilic attack.
The calculation of Parr's indices21 showed that this bond is
Fig. 1). The increasing extent of charge transfer in
compounds 4a–d from berberine moiety to the nitroaryl
group is apparently associated with increased contribution
of resonance structures 4'a–d with separated charges.
The negative charge in the nitroaryl moiety was mostly
concentrated on the oxygen atoms of nitro groups. As
shown in Figure 2, the carbon skeleton of the nitroaryl
moiety in compounds 4b–d was positively charged,
similarly to the berberine ring system.
+
strongly polarized: the maximum index of electrophilicity fk
corresponded to the С(7') atom of compounds 4b–d (С(1')
atom of compound 4a), while the maximum index of
nucleophilicity f was found on the С(13) atom of
–
k
berberine fragment. The aforementioned findings mean
that the significant non-coplanarity of compounds 4a–d
(Table 1) makes the С(13)–С(7') bond highly active in
addition reactions. This fact can be quite useful for the
formation of weak associative bonds with enzymes or
nucleic acid fragments.
In the case of compounds 4a–d, the significant charge
1
transfer correlated with changes in H NMR chemical shift
of 6-CH
2
and 8-CH protons which were the closest to the
2
N-7 nitrogen atom (Table 1). This observation also pointed
to the substantial contribution of structures with separated
Molecular docking of compounds 4a–d. Nucleic acid
regions capable of G-quadruplex formation create obstacles
for DNA synthesis by polymerases and reverse
transcriptases.22 It has been shown ex vivo that
1
charges. The downfield H NMR shift for the protons
located in the cationic part of the molecule is often used to
estimate the extent of charge transfer in bipolar
23
quadruplexes cause apoptosis in tumor cells. Ligands that
stabilize DNA quadruplexes in oncogen promoter regions
can suppress their hyperexpression.24 Deactivation of
oncogens deprives the cell of proteins associated with the
pathological process.25 As noted above, the structures with
intramolecular charge transfer on the basis of berberine
may serve as promising ligands for binding with G-quadru-
plexes. In order to confirm this hypothesis, we performed
modeling of docking processes between compounds 4a–d
spirocycles1 and intramolecular π-complexes.
7,18
19
Compounds 4a–d belong to the class of pseudo-cross-
2
0
conjugated systems, as evidenced by the results of our
quantum-chemical calculations. Thus, the negatively charged
nitroaryl fragment is rotated relatively to the positively
charged berberine ring system by 54–72° (Table 1). It is
interesting to note that the length of the С(13)–С(7')
bond (С(13)–С(1') in compound 4а), according to the
calculations, is intermediate between that of ordinary and
double bonds. At the same time, the length of bond
between the nitroaryl and berberine moieties correlates
with the extent of charge transfer.
7
and some G-quadruplexes from the G4LDB database. We
selected as targets such types of quadruplexes as 3QSC,
3MIJ, and 2JWQ.
Figure 2. Electrostatic potential surfaces of oxadiazoles 4b–d. The areas of maximum negative potential are marked in blue, while the
areas of maximum positive potential are red.
3
37

Chemistry of Heterocyclic Compounds 2017, 53(3), 335–340
2
6
i
Table 2. The inhibition constants (pK ) for several G-quadru-
The sequence 2JWQ represents a DNA fragment
d[T AG ], composed of three aggregated G-tetrads,
connected by loops with different spatial configuration.
plexes by compounds 4a–d according to the docking models
2
3
27–29
3
0
Compound
The sequence 3QSC
d(AG TUAG ), also composed of three aggregated
G-tetrads. The sequence 3MIJ represents a RNA fragment
r(UAG AG U), capable of forming two-chain associates.
represents a DNA fragment
G-quadruplex*
3
T
3 2
4a
4b
4c
4d
3
1
3
3
2
QSC
MIJ
6.62
4.91
6.54
7.08
4.83
0.21
7.75
5.09
6.57
8.68
5.23
7.21
3
U
2
3
It was established that molecules which interacted with
any of the first two tetrads, stabilizing the quadruplex
structure, led to telomer dysfunction due to disruption of
JWQ
*
The abbreviations are given according to the protein database (PDB ID).
32,33
telomer-protein interactions
and, in particular, altered
the binding with telomerase. The compounds that formed
complexes with the structure of 3MIJ also caused
inhibition of telomerase. It is known that telomerase is a
key enzyme for proliferation of cancer cells, as it is
involved in the process of their immortalization by
preventing the normal process of telomer shortening.
Remarkably, this enzyme is active in the majority of cancer
cells (85%) and shows little or no activity in healthy
somatic cells.3
several DNA strands (Fig. 3). It is interesting to note that
the activity in series of oxadiazoles 4b–d was directly
dependent on the extent of intramolecular charge transfer.
At the same time, in the case of some G-quadruplexes
compound 4a gave larger pK
i
values compared to
compound 4b, although there is a higher degree of charge
transfer in the latter molecule. This observation can be
explained by the less planar structure of compound 4a,
which interacts more readily with DNA fragments.
4,35
The effectiveness of interaction between ligand and
G-quadruplex was expressed by using the widely accepted
The strongest binding in docking was observed between
compound 4d and sequence 3QSC (Table 2, Fig. 3). As
shown in Figure 3, the dinitrofuroxan derivative 4d formed
an intercalation complex, in which the berberine ring
system was located between two loops of nucleic acid and
was coordinated with four guanine residues. The nitroaryl
group in this complex was rotated at a significant angle
relative to the berberine skeleton and formed two additional
hydrogen bonds with NH groups of thymine residues.
Obtained molecular docking results showed that the
significant intramolecular charge transfer in berberine
derivatives can lead to the formation of stable inclusion
complexes with G-quadruplexes, which are additionally
stabilized by binding between the anionic part of the
molecule and the non-guanine fragments of quadruplexes.
Thus, we have developed a method for the modification
of berberine molecule by introducing highly electrophilic
aromatic substituents through the formation of a new
pK value as criterion, which is equal to the negative
i
decimal logarithm of "inhibition" constant K , representing
i
a ratio between the product of ligand and G-quadruplex
concentrations and the concentration of the formed
complex. Generalization of the experimental results
allowed to formalize the requirements to the characteristics
of potential quadruplex ligands. Promising ligands of
G-quadruplexes must exhibit high affinity for
G-quadruplex and a good "quadruplex/duplex" selectivity
(
the ligand binding constant with G-quadruplex (1/K ) must
i
6
–1
36
not be lower than 10 M , therefore pK ≥ 6).
i
The zwitterionic berberine derivatives 4a–d showed the
highest affinity for DNA quadruplexes upon complex
formation by intercalation mechanism (Table 2, Fig. 3).
The strongest binding of compounds 4a–d occurred with
loose G-quadruplexes of telomerases that were formed by
Figure 3. A complex of compound 4d and G-quadruplex 3QSC with symbolic representation of DNA (left) and taking into account the
7
van der Waals radii in quadruplex (right), according to the results obtained from online modeling service g4ldb.com.
3
38

Chemistry of Heterocyclic Compounds 2017, 53(3), 335–340
carbon–carbon bond at position 13. According to quantum-
chemical calculations, the obtained compounds are
characterized by a high degree of intramolecular charge
transfer and, according to molecular docking models, can
be used as promising ligands for G-quadruplexes in
telomeric DNA fragments. The presence of a planar
electron-withdrawing moiety can enable the coordination
with additional binding sites of DNA molecules.
J = 8.7, H-11); 7.39 (2H, d, J = 7.8, H-5'); 8.43 (2H, d,
13
J = 7.8, H-6'). C NMR spectrum (DMSO-d ), δ, ppm:
6
26.6; 49.0; 52.0; 55.4; 61.2; 103.1; 109.1; 109.3; 112.0;
115.7; 116.8; 117.8; 121.5; 124.0 (2C); 126.3; 126.6;
132.8; 135.7; 145.0; 146.5; 146.7; 149.2 (2C); 153.8;
+
170.0. Found, m/z: 499.1241 [M–H] .
Calculated, m/z: 499.1248.
C
26
H
20
N
4
7
O .
13-(5,7-Dinitrobenzofurazan-4-yl)-7,8-dihydroberbe-
rine (4с). Yield 397 mg (73%), dark-violet needle-shaped
Experimental
1
crystals, decomp. temp. >119°С. Н NMR spectrum
1Н and 13С NMR spectra were acquired on a Bruker
(DMSO-d
(3H, s, 10-OCH
and 4.30–4.37 (1H, m, 6-СН
), δ, ppm (J, Hz): 3.07–3.16 (2H, m, 5-СН
); 3.83
); 4.05–4.12 (1H, m)
); 4.97–5.14 (2H, m, 8-СН );
6
2
DPX-250 instrument (250 and 63 MHz, respectively), with
3
); 3.86 (3H, s, 9-OCH
3
1
TMS as internal standard. The assignment of Н NMR
2
2
signals was confirmed on the basis of two-dimensional
COSY and NOESY NMR experiments. An overlap of
several 13С NMR signals was observed, reducing their
number to less than theoretically expected. High-resolution
mass spectra were recorded on a Bruker micrOTOF II
instrument (electrospray ionization). Ion signals were
measured in positive ion mode (capillary voltage 4500 V).
The mass scanning range was 50–3000 Da. Decomposition
temperatures were determined in glass capillaries, using a
PTP apparatus. Column chromatography was performed
with Merck Silicagel 60 (70–230 μm). Commercially
available berberine chloride hydrate (1) (Alfa Aesar) and
6.09 (1H, s) and 6.24 (1H, s, OCH O); 7.09 (1H, d, J = 8.8,
2
H-11); 7.13 (1H, s, H-4); 7.56 (1H, d, J = 8.7, H-12); 7.60
13
(1H, s, Н-1); 8.59 (1H, s, H-6'). C NMR spectrum
(DMSO-d ), δ, ppm: 26.4; 49.1; 52.6; 56.5; 61.5; 103.2;
6
109.8; 110.4; 112.7; 115.9; 117.1; 117.6; 121.7; 124.2;
124.5; 126.4; 127.2; 132.9; 135.6; 145.0; 146.5; 147.5;
+
149.7; 152.2; 153.9; 170.0. Found, m/z: 544.1108 [M–H] .
C
26
H
19
N
5
O . Calculated, m/z: 544.1099.
9
13-(5,7-Dinitrobenzofuroxan-4-yl)-7,8-dihydroberbe-
rine (4d). Yield 347 mg (62%), red needle-shaped crystals,
1
decomp. temp. >104°С. Н NMR spectrum (CDCl
(J, Hz): 3.37–3.42 (2H, m, 5-СН ); 4.12–4.17 (1H, m) and
4.98–5.04 (1H, m, 6-СН ); 5.20 (3H, s, 10-OCH ); 5.24
(3H, s, 9-OCH ); 5.32–5.37 (2H, m, 8-СН ); 6.68 (2H, s,
OCH O); 7.47 (1H, s, H-4); 8.18 (1H, d, J = 8.9, H-11); 8.36
(1H, d, J = 8.9, H-12); 8.73 (1H, s, Н-1); 10.17 (1H, s, H-6').
3
), δ, ppm
2
4
-chloro-7-nitrobenzofurazan (3b) (Alfa Aesar) were used
2
3
12
in the syntheses. Dihydroberberine (2), picryl chloride
3
2
37
38
(
3a), 4-chloro-5,7-dinitrobenzofurazan (3c), and 7-chloro-
2
3
9
4
,6-dinitrobenzofuroxan (3d) were synthesized according
1
3
to published procedures.
Synthesis of nitroaryl derivatives 4a–d (General
method). A solution of the appropriate chloronitroarene 3a–d
C NMR spectrum (pyridine-d ), δ, ppm: 29.5; 43.5; 45.3;
5
57.1; 61.8; 103.2; 108.6; 109.6; 112.1; 128.0; 130.9; 131.7;
133.9; 135.8; 137.4; 148.3; 156.9; 165.5. Found, m/z:
+
(
1.0 mmol) in xylene (10 ml) was added to a solution of
562.1188 [M+H] . C26
H
19
N O10. Calculated, m/z: 562.1205.
5
dihydroberberine (2) (337 mg, 1.0 mmol) in xylene
Computational method. Quantum-chemical calcu-
lations were performed for molecules in gas phase within
the framework of the density functional theory using
6-31G** basis set and B3LYP functional, including Beke
(
15 ml). The reaction mixture was stirred for 5 min at room
temperature, the precipitate that formed was filtered off,
dried, and separated by chromatography on silica gel
(
eluent CHCl
were recrystallized from isopropanol.
3-(2,4,6-Trinitrophenyl)-7,8-dihydroberberine (4a).
Yield 412 mg (75%), dark-green needle-shaped crystals,
3
–EtOH, 10:1). The obtained compounds 4а–d
three-parameter exchange functional and Lee–Yang–Parr
correlation functional.4
0,41
The global electrophilicity
1
indices ω were calculated according to the scheme
proposed by Parr.21 This was achieved by using the energy
1
decomp. temp. >157°С. Н NMR spectrum (CDCl
J, Hz): 2.78 (2H, t, J = 7.5, 5-СH ); 3.18 (2H, t, J = 7.5,
-СH ); 3.82 (3H, s, 10-OCH ); 3.88 (3H, s, 9-OCH ); 4.55
2H, s, 8-СH ); 5.89 (2H, s, OCH O); 6.07 (1H, d, J = 8.6,
3
), δ, ppm
of highest occupied (ε
molecular orbitals
ω = μ /2η, where μ = (ε
H
) and lowest unoccupied (ε
L
)
(
6
2
in
the
)/2, η = ε
ground
state:
2
2
3
3
H
+ ε
L
L
– ε . Molecular
H
(
2
2
docking was modeled by using the online service at
H-12); 6.20 (1H, s, H-1); 6.61 (1H, d, J = 8.6, H-11); 6.65
g4ldb.com.7
1
3
(
1H, s, Н-4); 8.72 (2H, s, H-3',5'). C NMR spectrum
CDCl ), δ, ppm: 31.0; 48.1; 49.2; 55.8; 60.8; 98.1; 101.3;
07.5; 108.3; 111.1; 116.2; 122.3; 123.0; 123.1; 126.6;
33.2; 136.4; 142.7; 144.3; 145.6; 145.9; 148.2; 151.3;
(
3
This study was supported by a grant from the Russian
Science Foundation (project 14-13-00103).
1
1
1
+
References
52.7. Found, m/z: 547.1090 [M–H] . C26
H
20
N
O .
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1
2
3
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3-(7-Nitrobenzofurazan-4-yl)-7,8-dihydroberberine (4b).
Yield 339 mg (68%), dark-green needle-shaped crystals,
1
1
decomp. temp. >130°С. Н NMR spectrum (CDCl
J, Hz): 2.93 (2H, t, J = 5.6, 5-СH ); 3.26 (2H, t, J = 5.7,
-СH ); 3.81 (3H, s, 10-OCH ); 3.87 (3H, s, 9-OCH ); 4.62
2H, s, 8-СH ); 5.76 (2H, s, OCH O); 6.14 (1H, s, H-1);
.35 (1H, d, J = 8.6, H-12); 6.60 (1H, s, Н-4); 6.62 (1H, d,
3
), δ, ppm
(
2
6
2
3
3
(
6
2
2
4
3
39

Chemistry of Heterocyclic Compounds 2017, 53(3), 335–340
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