Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines

Article abstract of DOI:10.3762/bjoc.15.41

The synthesis of novel fluorescent N(9)-alkylated 2-amino-6-triazolylpurine and 7-deazapurine derivatives is described. A new C(2)-regioselectivity in the nucleophilic aromatic substitution reactions of 9-alkylated-2,6-diazidopurines and 7-deazapurines wi

Full text of DOI:10.3762/bjoc.15.41

Synthesis and fluorescent properties of N(9)-alkylated
2-amino-6-triazolylpurines and 7-deazapurines
Andrejs Šišuļins1, Jonas Bucevičius2, Yu-Ting Tseng3, Irina Novosjolova1,
Kaspars Traskovskis1, Ērika Bizdēna1, Huan-Tsung Chang3, Sigitas Tumkevičius*2
and Māris Turks*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 474–489.
1Faculty of Materials Science and Applied Chemistry, Riga Technical
University, P. Valdena Str. 3, LV-1048 Riga, Latvia, 2Department of
Organic Chemistry, Faculty of Chemistry and Geosciences, Vilnius
University, Naugarduko Str. 24, 03225 Vilnius, Lithuania and
3Department of Chemistry, National Taiwan University No.1, Section
4, Roosevelt Road, Taipei 106, Taiwan
doi:10.3762/bjoc.15.41
Received: 02 November 2018
Accepted: 31 January 2019
Published: 15 February 2019
Associate Editor: J. Aubé
Email:
Sigitas Tumkevičius* - sigitas.tumkevicius@chf.vu.lt; Māris Turks* -
© 2019 Šišuļins et al.; licensee Beilstein-Institut.
maris.turks@rtu.lv
License and terms: see end of document.
* Corresponding author
Keywords:
7-deazapurines; fluorescence; nucleophilic aromatic substitution;
purines; push–pull systems; pyrrolo[2,3-d]pyrimidines
Abstract
The synthesis of novel fluorescent N(9)-alkylated 2-amino-6-triazolylpurine and 7-deazapurine derivatives is described. A new
C(2)-regioselectivity in the nucleophilic aromatic substitution reactions of 9-alkylated-2,6-diazidopurines and 7-deazapurines with
secondary amines has been disclosed. The obtained intermediates, 9-alkylated-2-amino-6-azido-(7-deaza)purines, were trans-
formed into the title compounds by CuAAC reaction. The designed compounds belong to the push–pull systems and possess prom-
ising fluorescence properties with quantum yields in the range from 28% to 60% in acetonitrile solution. Due to electron-with-
drawing properties of purine and 7-deazapurine heterocycles, which were additionally extended by triazole moieties, the com-
pounds with electron-donating groups showed intramolecular charge transfer character (ICT/TICT) of the excited states which was
proved by solvatochromic dynamics and supported by DFT calculations. In the 7-deazapurine series this led to increased fluores-
cence quantum yield (74%) in THF solution. The compounds exhibit low cytotoxicity and as such are useful for the cell labelling
studies in the future.
Introduction
Purine [1-7] and 7-deazapurine (IUPAC name: pyrrolo[2,3- push–pull systems is a promising direction in the development
d]pyrimidine) [8-11] derivatives have been progressively of various fluorescent (7-deaza)purine derivatives [12-16]. The
studied for decades due to their wide range of biological activi- push–pull effect arises by adding electron-donating and elec-
ties and photophysical properties. Currently, the synthesis of tron-withdrawing groups at the opposite ends of π-conjugated
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systems. Large Stokes shifts and high quantum yields are 7-deazapurine derivatives containing heterocyclic substituents
usually characteristic for this type of molecules. Traditionally, at various attachment points [26,27] have been actively studied
fluorescent purine nucleoside analogs were recognized as valu- for their fluorescent properties. Among others, also azole con-
able fluorescent probes for DNA and RNA research [17]. This taining compounds of type E [28] and F [29] have been de-
paved a way for development of various adenosine and guano- scribed.
sine analogs which in many cases contained an additional sub-
stituent at C(8) like compounds A and B (Figure 1) [18,19]. The Similarly, to purine derivatives also 7-deazapurines are used in
latter attachment does not significantly affect the natural DNA labeling [30]. On the other hand, modified purines have
Watson–Crick base-pairing abilities of the modified com- found also applications as cell imaging tools [31,32], biosen-
pounds. In this context, other important structural modifica- sors and sensors for detection of heavy metals [33]. The tenden-
tions in such a series include 8-vinyladenosine [20], 8-styryl- cy of these structures to form hydrogen bonds, to respond to
adenosine [13,21] and 8-heteroarylguanosine [22] derivatives medium effects (solvatochromism) [34] and to certain impuri-
which revealed good to excellent quantum yields. Useful levels ties (e.g., coordination complexes with metal ions) make these
of fluorescence were reported also for purine nucleos(t)ides compound classes very attractive for sensor design [33,35]. It is
bearing azole-type substituents at C(2) or C(6) (e.g., 6-thiazol- interesting to note, that push–pull type purine non-nucleos(t)ide
2-yl derivative C [23] and 2-(1,2,3-triazol)-1-yladenosines D derivatives have not been actively studied in the context of ma-
[24,25] (Figure 1).
terials science. The few available examples include the design
of methyl 9-benzyl-2-N,N-dimethylamino-9H-purine-8-carbox-
ylate and the corresponding 2,6-bis(dialkylamino) derivatives as
fluorescent materials for preparation of organic light-emitting
diodes [12,36-38].
In light of the aforementioned facts, we proceeded to design
novel and structurally related classes of 2-amino-6-(1,2,3-
triazol-1-yl)purines and 7-deazapurines (Figure 1 compounds of
type G and H) in order to determine and to compare their fluo-
rescent properties. The synthetic approach towards 7-deaza-
purine derivatives H has been recently disclosed by us [39], but
the photophysical properties of these compounds have not been
studied thus far. In this full account we report the newly de-
veloped C(2)-regioselective nucleophilic aromatic substitution
of 2,6-diazidopurines, transformation of the intermediate
2-amino-6-azidopurines into the title compounds and compara-
tive photophysical study of originally yet identically substituted
fluorescent push–pull purines and 7-deazapurines.
Results and Discussion
We have recently observed significant fluorescence in the tria-
zolylpurine and triazolyl-7-deazapurine series [25,29,40,41].
Therefore, we developed synthetic methods that can provide
structurally related chromophores of the purine and 7-deaza-
purine series possessing identical substitution pattern (struc-
tural congeners G and H, Figure 1). The easy access to the title
compounds opened a possibility for a comparative study of their
photophysical properties.
Figure 1: Examples of fluorescent purine/7-deazapurine derivatives.
Synthesis
N(9)-Alkylated-2,6-diazidopurine 2a was synthesized in two
7-Deazapurines can be regarded as structurally close congeners steps from commercially available 2,6-dichloropurine (1a) by
to purines with an extra attachment point at their “artificially subsequent alkylation of the N(9) position and azido group
introduced” C(7). Therefore, it comes as no surprise that also introduction in C(2) and C(6) positions. The N(9) position of
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Beilstein J. Org. Chem. 2019, 15, 474–489.
purine was alkylated in two different ways: 1) using alkyl Mitsunobu reaction (method B, Scheme 1) was performed be-
halides in the presence of a strong base, and 2) using alcohols tween the corresponding alcohol and 2,6-dichloropurine in an-
under Mitsunobu conditions.
hydrous THF at 0–20 °C for 1–1.5 h, resulting in average yields
of 66% for N(9)-alkylated products. Both methodologies pro-
In the first approach (method A, Scheme 1), the purine was duced a mixture of N(9)- and N(7)-alkylated isomers from
deprotonated with a base (NaH or K2CO3) and alkylated with which the major N(9) product was easily separated by column
alkyl halides such as 1-iodoheptane, 1-bromononane and chromatography [42-47]. Alkylated products were used in SNAr
1-bromododecane. The main disadvantages of this approach are reactions with NaN3 in acetone or DMF, giving good to excel-
suboptimal yields, which varied from 48% to 52%, and long lent yields of 2,6-diazidopurines 2a–c in the range from 66 to
reaction times. For example, in the case of 1-bromododecane, 93%. In several cases chromatographic separation of the
the reaction required 72 hours to complete. On the other hand, N(9)/(7) isomers was easier at the stage of diazido products 2a
Scheme 1: General synthetic routes for the compounds 5, 7–9, 10 and 11. Method A: alkyl halogenide, MeCN or DMF, NaH, 1–3 days, 20–55 °C;
method B: alcohol, Ph3P, THF, DIAD, 1 h, 0→20 °C.
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Beilstein J. Org. Chem. 2019, 15, 474–489.
and 2a’. Diazido products 2 are light and temperature sensitive These results are summarized in Figure 2. The temperature
[48], but can be stored without degradation in refrigerator at increase caused the disappearance of signals at 7.92 (s, α), 4.23
−20 °C for a prolonged period of time. In addition, DSC mea- (t, β) and 4.01–3.95 (m, γ) and the broadening of signals at 7.69
surements for compounds 2a–c were done. Diazides 2a–c (s, a), 4.04 (t, b) and 3.84–3.74 (m, c). A similar type of the
melted at 67 °C, 75 °C and 82 °C, respectively, and showed an ring–chain tautomerism is expected to occur in 6-azido-2-
exothermic effect only if heated above 190 °C (Figures S5–S7 amino-7-deazapurines (synthetic intermediates on the way
in Supporting Information File 1).
3→10/11), but it was not studied in detail due to their relatively
low stability [39]. Regarding the tautomerism in 2,6-diazido-
In the 7-deaza series deprotonated starting material 1b was substituted starting materials, it has been studied previously for
methylated with MeI and further submitted to SNAr reaction both purine [41] and 7-deazapurine [52] derivatives. In both
with NaN3 according to a previously published procedure [39]. cases practically only the diazido forms are observed in chloro-
The expected 2,6-diazido-7-deazapurine (3) was obtained in form solution, but the proportion of the tetrazole tautomer in-
78% yield.
creases with the increase of solvent polarity. Additionally,
X-ray analysis of 2,6-diazidopurine 2'-deoxyribonucleoside
It should be noted that the medium size alkyl chains at N(9) revealed the exclusive existence of the azido tautomer in the
were chosen for several reasons: a) they help to solubilize the solid state [41].
target compounds in the organic medium; b) they are consid-
ered as a good compromise to achieve both “membrane-like
character”, which helps for cell membrane permeability, and
sufficient solubility in the aqueous (biological) media [49].
With the key intermediates 2 and 3 in hand, we proceeded with
the synthesis and structure elucidation of the designed struc-
tures G and H (Figure 1) which are represented by compounds
7–11 in Scheme 1. Firstly, we prepared a regioisomeric com-
pound 5 by repeating the previously elaborated sequence of
double CuAAC reaction (2→4) followed by a SNAr process
(4→5) which showcases the use of 1,2,3-triazoles as leaving
groups. It is well established during our previous research in the
purine nucleoside series that such an approach provides
6-amino-2-(1,2,3-triazol-1-yl) derivatives [25]. On the other
hand, it was also reported that 2,6-diazidopurine nucleosides ex-
hibit opposite regioselectivity with aliphatic thiols, which do
SNAr reactions at C(2) position of purines [50,51]. Taking this
information into account, we performed an SNAr reaction be-
tween 2,6-diazidopurine 2a and piperidine and obtained the
C(2)-substitution product 6b as the major isomer. To the best of
our knowledge, this is the first report on such regioselectivity
involving combination of 2,6-diazidopurines and N-nucleo-
philes.
It should be noted that in solution, azides 6 exist in equilibrium
between the azidopurine and tetrazolopurine forms. This equi-
librium was studied in different deuterated solvents by 1H NMR
spectroscopy on the example of 6-azido-9-heptyl-2-piperidino-
purine 6b. Experiments were performed in CDCl3, THF-d8,
CD3CN and DMSO-d6. The 1H NMR spectrum in CD3CN
showed the presence of the tetrazole form and has been used for
NMR studies in the temperature range from 30 to 60 °C using
Figure 2: 1H NMR spectra of compound 6b in CD3CN at different tem-
peratures (300 MHz, c = 12.5 mg/mL); a, b, c – signals for azide form
6b-A; α, β, γ – signals for tetrazole form 6b-T).
two different concentrations – 12.5 mg/mL and 25.0 mg/mL.
Temperature increase caused the increase of the azido form.
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Beilstein J. Org. Chem. 2019, 15, 474–489.
The discovered ability of the azido group to be substituted with parison showed two main differences in the spectra (Figure 3):
amines at C(2) position was used for the synthesis of a novel 1) the H–C(triazole) signal of product 8a is shifted downfield
library of 9-alkyl-2-amino-6-triazolylpurine derivatives. Thus, from 8.69 to 9.10 ppm and 2) the appearance of a CH2 signal
copper-catalyzed azide–alkyne 1,3-dipolar cycloaddition reac- near the N atom is changed from multiplet at 3.96–3.87 ppm to
tion of compounds 6a–c with different para-substituted phenyl- broad singlet at 4.60–3.95 ppm. Furthermore, a significant
acetylenes produced the expected compounds 7a–f, 8a–f and 9 difference is observed also in the UV spectra. Product 8a has an
(Scheme 1). The yields of 1,3-dipolar cycloadditions varied additional absorption maximum at 370 nm (Figure 4).
from 51% to 76% in the case of pyrrolidinyl purines 7a–f and
from 53% to 86% for piperidinyl purines 8a–f (Table 1 and In the 7-deazapurine series the SNAr reactions between 2,6-
Table 2). To gain an insight into the structure–photophysical diazido-9-methyl-7-deazapurine (3) and pyrrolidine or piperi-
properties relationship of the newly obtained structures, various dine were more regioselective than in the purine series. In the
EDG and EWG at the para-position of the phenyl rings were latter case the purine products 6a–c had to be chromatographi-
installed. It can be concluded that 2,6-diazidopurines are versa- cally separated to remove the 2-azido-6-amino isomer as the
tile intermediates for the synthesis of both the 2-amino-6-tria- purification at the stage of final products was not effective. The
zolylpurine and 6-amino-2-triazolylpurine derivatives. Compar- observed C(2)-selectivity in the 7-deazapurine series allowed to
ison of both synthetic methods (2→4→5 versus 2→6→7/8/9) combine the SNAr and CuAAC reactions into an sequential one-
reveals that the newly developed approach towards 2-amino-6- pot process producing target products 10 and 11 directly from
triazolylpurine derivatives was performed in a more atom diazide 3. The 7-deazapurine structural analogs 10a–f and
economic way. The latter synthesis does not require a double 11a–f to every purine entry were obtained with 58–80% isolat-
cycloaddition followed by replacement of one of the triazole ed yields.
moieties.
UV–vis and fluorescence data
The final structural proof for the compounds of the series 7a–f The optical properties of the synthesized compounds were
and 8a–f was obtained by spectral comparison between com- assessed by performing absorption and fluorescence spectrosco-
pound 8a and regioisomeric compound 5. The 1H NMR com- py and fluorescence quantum yield measurements. The quan-
Table 1: Diversity of 9-alkyl-2-pyrrolidino-6-triazolylpurine 7 and 7-deazapurine 10 derivatives obtained in reactions 6a→7a–f and 3→10a–f accord-
ing to Scheme 1.
Entry
General structure
Compound
R
Yield, %
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
-H
-OMe
-NMe2
-F
51
57
53
64
76
63
CF3
-CN
7
7
8
10a
10b
10c
10d
10e
10f
-H
-OMe
-NMe2
-F
71
66
68
80
76
79
9
10
11
12
-CF3
-CN
10
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Table 2: Diversity of 9-alkyl-2-piperidino-6-triazolylpurine 8 and 7-deazapurine 11 derivatives obtained in reactions 6b→8a–f and 3→11a–f according
to Scheme 1.
Entry
General structure
Compound
R
Yield, %
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
-H
-OMe
-NMe2
-F
71
60
53
74
84
86
-CF3
-CN
8
7
8
11a
11b
11c
11d
11e
11f
-H
-OMe
-NMe2
-F
65
60
58
68
63
75
9
10
11
12
-CF3
-CN
11
Figure 3: Comparison of 1H NMR spectra of compounds 8a and 5 (300 MHz, CDCl3).
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Beilstein J. Org. Chem. 2019, 15, 474–489.
Figure 4: a) Experimental UV–vis absorption spectra (lines) with computed theoretical absorption bands (columns) of compounds 5 and 8a
(c = 10−4 M). b) Energy diagram and spatial distribution of frontier molecular orbitals (at isosurface value 0.02) of compounds 5 and 8a.
tum yields were determined using a fluorescence standard of was red-shifted for 7-deazapurine series to 468–472 nm, more-
quinine sulfate in 0.1 M H2SO4 as a reference [53]. Absorption over most of the studied compounds possessed very similar
and fluorescence data of the investigated compounds in MeCN quantum yields 0.56–0.61 for purine and 0.50–0.56 for 7-deaza-
solutions are summarized in Table 3. The newly developed purine series, with only a few exceptions from a trend (Table 3,
purine and 7-deazapurine derivatives exhibit similar photophys- entries 3, 9, 12, 15, 21 and 24). Compounds 10f and 11f from
ical properties to previously reported push–pull systems con- the 7-deazapurine class (Table 3, entries 12 and 24), which pos-
taining the same central molecular scaffold (see Table 3 versus sess -CN substituents on the para position of the phenyl ring,
Figure 1). There are only few other modified purines and showed slightly lower quantum yields of 0.36–0.38 and a red
7-deazapurines known for which higher quantum yields were shift of the emission maxima by 10–15 nm, whilst similar
reported. The latter include Castellano’s purines (QY up to purine class compounds (Table 3, entries 6 and 18) remained on
95%) containing electron-withdrawing substituents at C(8) a previously discussed trend, thus probably indicating a minor
[36,37] and 2-halo-7-deazapurine derivatives (QY up to 83%) change in electronic structure for compounds 10f and 11f. Also,
reported by Hocek et al. [28].
lower quantum yields of 0.28–0.35 and highly red-shifted emis-
sion maxima to 528–581 nm were recorded for the compounds
In our case the lowest-energy absorption band was observed possessing strong electron-donating -NMe2 groups (Table 3,
approximately at 360 nm for the purine class compounds entries 3, 9, 15, 21). In addition, it was found that these com-
(Table 3, entries 1–6 and 13–18), whereas for the 7-deaza- pounds possess a strong positive solvatochromic effect, which
purine series (Table 3, entries 7–12 and 19–24) the lowest- was studied in detail in solvents of different polarity (THF,
energy absorption band was slightly red-shifted by 15 nm to CHCl3, DMSO, MeCN and MeOH). The study was performed
≈375 nm. A similar trend was observed in the fluorescence on two model compounds, 8c from the purine class and 11c
spectra of the studied compounds – emission maxima for the from the 7-deazapurine class (Figure 5 and Figure 6). As illus-
purine class compounds was observed at 442–452 nm, whilst it trated in Figure 5 and Figure 6 the emission of compounds 8c
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Beilstein J. Org. Chem. 2019, 15, 474–489.
Table 3: Photophysical properties of 6-triazolyl compounds 7a–f, 10a–f, 8a–f and 11a–f.a
Entry
Structure
Compound
R
λabs, nm
λemb, nm
Δλ, nm
Φ
1
2
3
4
5
6
7a
7b
7c
7d
7e
7f
-H
-OMe
-NMe2
-F
360
359
361
360
362
363
444
442
577
444
452
453
84
83
0.59
0.61
0.32
0.57
0.58
0.58
216
84
-CF3
-CN
90
90
7
7
8
10a
10b
10c
10d
10e
10f
-H
-OMe
-NMe2
-F
375
374
369
375
377
378
472
466
528
472
468
482
97
92
0.52
0.56
0.35
0.53
0.54
0.36
9
159
97
10
11
12
-CF3
-CN
91
104
10
13
14
15
16
17
18
8a
8b
8c
8d
8e
8f
-H
-OMe
-NMe2
-F
357
357
360
360
357
360
445
444
88
87
0.57
0.59
0.28c
0.56
0.57
0.60
445; 581
449
85; 221
89
-CF3
-CN
453
96
456
96
8
19
20
21
22
23
24
11a
11b
11c
11d
11e
11f
-H
-OMe
-NMe2
-F
372
371
368
373
375
376
472
471
536
473
481
485
100
100
168
100
106
109
0.54
0.52
0.35d
0.50
0.51
0.38
-CF3
-CN
11
aAll spectra were recorded in MeCN solutions (c = 10−4 M) at room temperature; bcompounds 7 and 8 were excited at 360 nm and compounds 10
and 11 were excited at 370 nm; cfluorescence lifetime: 7.79 ± 0.03 ns; dfluorescence lifetime: 8.77 ± 0.03 ns.
and 11c showed pronounced changes with solvent polarity in solvent polarity indicating small dipole moment in the ground
terms of emission maxima and quantum yields, though the state. A good linear correlation between the fluorescence QY
absorption spectra showed minor or no changes with increasing and the Dimroth–Reichardt polarity parameter (ET(30)) [54]
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Beilstein J. Org. Chem. 2019, 15, 474–489.
Figure 5: Photos of compound 8c (A and B) and compound 11c (C and D) in THF, CHCl3, DMSO, MeCN and MeOH before excitation (A and C) and
under excitation (B and D) of UV (366 nm).
Figure 6: a) Fluorescence spectra of compounds 8c (λexc = 360 nm) and 11c (λexc = 370 nm) in solvents of different polarity, c = 10−4 M. b) Quan-
tum yield dependence on the Dimroth–Reichardt polarity parameter ET(30) with a linear fit for compounds 8c and 11c.
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Beilstein J. Org. Chem. 2019, 15, 474–489.
was observed (Figure 6) for both classes of compounds. For ex- polarity media. The charge transfer nature of the transitions for
ample, the fluorescence QY of 7-deazapurine 11c in THF were the compounds 8c and 11c, compared to reference compounds
determined to be 0.76 and non-detectable in methanol. Simi- 8a and 11a, was confirmed by quantum chemical calculations.
larly, QY of purine 8c dropped from 0.56 to <0.01 by switching Computed spatial distributions of FMO’s and comparison of
between the same solvents (Table 4). Non-linear dependency in electronic structures revealed that where is almost no change in
increase of emission maxima is observed (Table 4) with in- energy and distribution of LUMO, which is localized over the
creasing polarity parameter (ET(30)), thus indicating that the extended triazolyl(deaza)purine core (Figure 7). However, a
sensitivity to solvent polarity is not the only major solute–sol- major change in HOMO localization and energy is observed:
vent interaction and the emission maxima are also influenced by 1) the HOMO is mostly localized on the central (deaza)purine
other solvent properties such as viscosity or hydrogen bonding. core and piperidino substituent for the reference compounds 8a
Interestingly, purine class compound 8c showed a dual-fluores- and 11a; 2) the HOMO is mostly distributed over the electron-
cence character in the solvents of higher polarity (DMSO, donating Me2N groups, phenyl ring and the 1,2,3-triazolyl
MeCN) arising from the locally excited and charge transfer moiety for compounds 8c and 11c. Thus, these findings support
excited states, however, dual-fluorescence was not evident for an enhanced ICT character of the excited states for the com-
the 7-deazapurine class, which could be explained by a better pounds possessing strong electron-donating Me2N groups.
stabilization of the ICT excited state by the solvatic shell. A de-
crease of QY accompanied by a high red shift of the emission In summary, moderate to high quantum yields were observed
maxima with increasing polarity of the surrounding media is a for the studied purine and 7-deazapurine compounds. Accord-
typical characteristic for the enhanced ICT of the excited states ing to the expectations, the choice of alkyl chains and tertiary
with a possible character of TICT [55], which could explain a amine (piperidine or pyrrolidine) substituents did not signifi-
dual-fluorescence and fluorescence quenching in the high cantly influence fluorescent properties. The preliminary study
Table 4: Emission maxima and quantum yields of compound 8c and 11c in solvents of different polarity.
Entry
Compound
Solvent
λem, nma
Δλ
Φ
1
2
3
4
5
THF
504
147
76
0.56
0.51
0.28
0.28
<0.01
CHCl3
DMSO
MeCN
MeOH
442
443; 604
445; 581
460; 619
80; 241
85; 221
96; 255
8c
6
7
THF
449
461
572
536
-b
76
88
0.74
0.62
0.54
0.35
0b
CHCl3
DMSO
MeCN
MeOH
8
196
166
-b
9
10
11c
aCompound 8c was excited at 360 nm and compound 11c at 370 nm. bFluorescence was lower than the detection limit.
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Beilstein J. Org. Chem. 2019, 15, 474–489.
Figure 7: Energy diagram for the frontier molecular orbitals of compounds 8a, 8c, 11a and 11c.
showed that introduction of other aliphatic amines at C(2) does were compared with those obtained on normal breast epithelial
not significantly affect the photophysical properties of the target cell line (MCF-10A). All compounds showed low cytotoxicity
substances either. On the other hand, the present synthetic de- on all tested cell lines (for Figure S81 see Supporting Informa-
velopment does not allow yet to introduce arylamino moieties at tion File 1). Bearing in mind fluorescent properties and low
C(2) due to the diminished nucleophilicity of anilines.
cytotoxicity of the newly obtained compounds, we tested their
potential application in cell staining. The preliminary experi-
The 7-deazapurine derivatives were characterized with a some- ments revealed that the compounds went through the cell mem-
what larger Stokes shift and bathochromic shift of the lowest brane after 1 h or 2 h incubation period and localized uniformly
energy absorption band in comparison to purine derivatives, but in the cytoplasm. The representative fluorescent image of the
resulted in slightly lower quantum yields. Except for the com- labeled MCF-7 cells with compound 9 is shown in Figure 8 (for
pounds with strong electron-donating Me2N substituents and other examples see Figure S82 in Supporting Information
ICT/TICT character, where QY were slightly higher for File 1).
7-deazapurine derivatives. As the emission properties of com-
pounds (7c, 8c, 10c and 11c) possessing the ICT/TICT char- Based on the recent investigation of metabolic labelling of
acter of the excited states are environment-dependent it makes DNA [30,56] by deaza-7-ethenyl-2'-deoxyguanosine and
these fluorophores interesting as potential sensors of the 7-deaza-7-ethenyl-2'-deoxyadenosine or 5-(azidomethyl)-2'-
surroundings such as polarity or (micro)viscosity sensors. Other deoxyuridine, we can assume that nucleoside analogs bearing
purine and 7-deazapurine derivatives, which efficiently emit fluorophores of our type would be susceptible to metabolic
light in the blue region with respect to the structural biocompat- phosphorylation and incorporation into DNA in the living cells.
ibility could be applied for the cell staining in fluorescence
microscopy.
Further studies are required to develop the newly described
N(9)-alkylated-2-amino-6-triazolylpurines and 7-deazapurines
as cell labeling agents for biological chemistry applications.
Applications in the cell studies
The newly prepared compound library with purine and 7-deaza-
purine derivatives was submitted to the screening of their bio- Conclusion
logical activity. The compounds of interest were studied on two A group of novel and structurally related N(9)-alkylated
cancer cell lines – luminal A breast cancer cell line MCF7 and 2-amino-6-triazolylpurines and 7-deazapurines was obtained,
triple negative breast cancer cell line MDAMB231. The results using the corresponding 2,6-diazido derivatives as key starting
484

Beilstein J. Org. Chem. 2019, 15, 474–489.
Figure 8: Labeled MCF-7 cells using compound 9 (C,D) and unlabeled MCF-7 cells (A,B) in microscope (2 h, c(9) = 100 μM, B and D passed sepa-
rately through filter (365 ± 20 nm)).
Experimental
materials. We have reported here for the first time that 9-alkyl-
2,6-diazidopurines exhibit C(2)-selectivity in nucleophilic aro- General information
matic substitution reactions with amines. A similar selectivity Reactions and purity of the synthesized compounds were moni-
was observed also for 9-alkyl-2,6-diazido-7-deazapurines. We tored by TLC using Silica gel 60 F254 aluminum plates (Merck).
have also demonstrated that the synthetic intermediates ob- Visualization was accomplished by UV light. Column chroma-
tained in the SNAr reaction (e.g., 6-azido-9-heptyl-2-(piperidin- tography was performed using silica gel 60 (0.040–0.063 mm)
1-yl)purine (6b)) exists in both tetrazolo- and azido-tautomeric (Merck). Yields of products refer to chromatographically and
forms in CD3CN solution. The presence of the latter permits the spectroscopically homogeneous materials. Anhydrous methy-
CuAAC reaction with terminal acetylenes and gave a rise to the lene chloride, dimethylformamide and acetonitrile were ob-
title compounds.
tained by distillation over CaH2, tetrahydrofuran was obtained
by distillation over sodium. Commercial reagents were used as
The obtained compounds possess useful levels of fluorescence received.
in acetonitrile solution with quantum yields ranging from 28%
to 60% with emission maxima positioned at 442–581 nm. It NMR spectra were recorded on Bruker Avance 300 or Bruker
should be noted that still the biggest challenge in manufac- Ascend 400 spectrometers (300 MHz, 400 MHz for 1H and
turing of affordable OLEDs is emission of the color blue. Most 75 MHz, 100 MHz for 13C, respectively). The proton signals for
of here reported compounds emit blue light and thus are impor- residual non-deuterated solvents (δ 7.26 ppm for CDCl3, δ
tant novel structural entities to be studied in the context of 2.50 ppm for DMSO-d6) and carbon signals (δ 77.1 ppm for
OLEDs in the future. Compounds containing a 4-(4-dimethyl- CDCl3, δ 39.5 ppm for DMSO-d6) were used as an internal
aminophenyl)-1,2,3-triazol-1-yl substituent have shown a strong reference for 1H NMR and 13C NMR spectra, respectively.
solvatochromic effect including the increase of fluorescence Coupling constants are reported in Hz. Chemical shifts of
quantum yield to 74% in the case of 7-deazapurine derivative signals are given in ppm and multiplicity assigned as follows: s
11c. The solvent change provided a fluorescence shift from dark – singlet, d – doublet, t – triplet, m – multiplet.
blue (≈440 nm) to orange (≈620 nm) color.
The infrared spectra were recorded on a Perkin Elmer Spec-
Finally, the purines and 7-deazapurines were tested in live cell trum BX spectrometer. Wavelengths are given in cm−1. The
imaging on breast cancer cell lines MCF-7 and MDAMB231. UV–vis absorption spectra of all compounds were acquired
They are biocompatible, cell-permeable, not cytotoxic and do using a Perkin-Elmer 35 UV–vis spectrometer. Emission spec-
not influence cell proliferation. Thus, one can predict that the tra were measured on QuantaMaster 40 steady state spectrofluo-
developed purine and 7-deazapurine derivatives possessing the rometer (Photon Technology International, Inc.). Absolute
novel substitution pattern may find their application also in cell photoluminescence quantum yields were determined using
labeling in the future besides the potential use as materials in QuantaMaster 40 steady state spectrofluorometer (Photon Tech-
organic light emitting diodes. The latter study which uses struc- nology International, Inc.) equipped with 6 inch integrating
turally related fluorescent purine derivatives containing steri- sphere by LabSphere, using a florescence standard of quinine
cally bulky amorphousing groups at position N(9) for forma- sulfate in 0.1 M H2SO4 as a reference. High-resolution mass
tion of fluorescent molecular glasses are underway in our labo- spectrometry (HRMS) analyses were carried out on a Dual-ESI
ratories and will be reported in due course.
Q-TOF 6520 (Agilent Technologies) mass spectrometer and
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Beilstein J. Org. Chem. 2019, 15, 474–489.
Agilent 1290 Infinity series UPLC system equipped with (s, 1H, H-C(8)), 4.23 (t, 3J = 7.2 Hz, 2H, -CH2-), 1.88 (quintet,
column Extend C18 RRHD 2.1 × 50 mm, 1.8 µm connected to 3J = 7.2 Hz, 2H, -CH2-), 1.36–1.13 (m, 8H, 4 × -CH2-), 0.82 (t,
an Agilent 6230 TOF LC/MS masspectrometer.
3J = 6.8 Hz, 3H, -CH3) ppm; 13C NMR (75.5 MHz, CDCl3) δ
153.3, 152.9, 151.7, 145.9, 130.8, 44.7, 31.6, 29.8, 28.6, 26.6,
For HPLC analysis we used an Agilent Technologies 1200 22.5, 14.0 ppm; HRMS–ESI (m/z): [M + H]+ calcd for
Series chromatograph equipped with an Agilent XDB-C18 C12H17Cl2N4, 287.0825; found, 287.0826.
(4.6 × 50 mm, 1.8 µm) column and a Phenomenex Gemini NX
(4.6 × 100 mm, 3 µm) column. Eluent A: 0.01 M KH2PO4 solu- Azidation: NaN3 (5.88 g, 90.5 mmol, 3.0 equiv) was added to a
tion with 6% v/v MeCN added; eluent B: 0.1% TFA solution solution of 9-alkyl-2,6-dichloro-9H-purine (30 mmol,
with 5% v/v MeCN added; eluent C – MeCN.
1.0 equiv) in acetone (50 mL) and stirred for 14 h at 50 °C, pro-
tected from the daylight. Then, the reaction mixture was evapo-
rated and suspended in water (30 mL). The resulting precipitate
was filtered and dried in vacuum.
General procedures and product characteri-
zation
2,6-Bistriazolyl derivative 4 was synthesized using previously
reported procedure of Cu(I)-catalyzed azide–alkyne cycloaddi- 2,6-Diazido-9-heptyl-9H-purine (2a): Colorless solid; reac-
tion reaction on 2,6-diazidopurine derivatives [25]. Synthesis of tion time – 14 h; yield 8.4 g, 93%. IR (KBr) ν (cm−1): 2932,
7-deazapurine derivatives 3, 10a, 11a and their characterization 2858, 2170, 2123; 1H NMR (300 MHz, CDCl3) δ 7.87 (s, 1H,
are described in our preliminary communication [39].
H-C(8)), 4.15 (t, 3J = 7.2 Hz, 2H, -CH2-), 1.93–1.77 (m, 2H,
-CH2-), 1.39–1.15 (m, 8H, 4 × -CH2-), 0.84 (t, 3J = 6.8 Hz, 3H,
-CH3) ppm; 13C NMR (75.5 MHz, CDCl3) δ 155.9, 154.1,
153.7, 143.7, 121.5, 44.2, 31.6, 29.8, 28.7, 26.6, 22.6, 14.1
Synthesis of 9-alkyl-2,6-diazido-9H-purine deriva-
tives 2a–c
Alkylation, method A: A solution of 2,6-dichloropurine (1a, ppm; HRMS–ESI (m/z): [M + H]+ calcd for C12H17N10,
1.0 g, 5.4 mmol, 1.0 equiv) in anhydrous MeCN or anhydrous 301.1632; found, 301.1646.
DMF (30 mL) was cooled to 0 °C and 57% suspension of NaH
(0.3 g, 7.0 mmol, 1.3 equiv) was added in small portions Synthesis of 9-alkyl-6-azido-2-pyrrolidino-9H-purine or
(50 mg). The resulting reaction mixture was stirred for 30 min. 9-alkyl-6-azido-2-piperidino-9H-purine derivatives 6a,b:
After that, the corresponding 1-iodoalkane or 1-bromoalkane 9-Alkyl-2,6-diazido-9H-purine 2 (8.3 mmol, 1.0 equiv) was dis-
(11 mmol, 2.1 equiv) was added and the reaction mixture was solved in DMF (30 mL), pyrrolidine or piperidine (11.7 mmol,
stirred for 1–3 days at 20–55 °C. The excess of NaH was neu- 1.4 equiv) was added and the reaction mixture was stirred iso-
tralized with MeOH or EtOH. The reaction mixture was evapo- lated from the daylight at 30 °C for 5 h. After that, the mixture
rated under reduced pressure and the residue was dissolved in was evaporated and silica gel column chromatography (DCM/
DCM (30 mL), the organic phase was washed with brine MeCN 50:1) was used to provide the desired product.
(2 × 15 mL) and subsequently dried over anh. Na2SO4 and
evaporated. Silica gel column chromatography (Hex/EtOAc 6-Azido-9-heptyl-2-pyrrolidino-9H-purine (6a): Slightly
4:1) provided the desired product.
brown solid, reaction time – 4 h; yield 0.88 g, 51%. IR (KBr) ν
(cm−1): 3062, 2927, 2858, 2148, 2122, 1570, 1254; 1H NMR
Alkylation method B: A solution of 2,6-dichloropurine (1a, (300 MHz, CDCl3) δ 7.56 (s, 1H, H-C(8)), 4.03 (t, 3J = 7.0 Hz,
5.0 g, 26.5 mmol, 1.0 equiv), corresponding alcohol 2H, -CH2-), 3.62–3.54 (m, 4H, 2 × -CH2-), 2.00–1.92 (m, 4H,
(31.7 mmol, 1.2 equiv) and Ph3P (9.2 g, 34.9 mmol, 1.3 equiv) 2 × -CH2-), 1.83 (quintet, 3J = 7.0 Hz, 2H, -CH2-), 1.37–1.16
in anhydrous THF (30 mL) was cooled to 0 °C. DIAD (m, 8H, 4 × -CH2-), 0.85 (t, 3J = 6.8 Hz, 3H, -CH3) ppm;
(6.90 mL, 35.0 mmol, 1.3 equiv) was added dropwise, the mix- 13C NMR (75.5 MHz, CDCl3) δ 157.4, 154.8, 152.4, 140.3,
ture was stirred for 1 h at 20 °C, controlled by HPLC, then 117.0, 47.0 (2C)*, 43.4, 31.7, 29.6, 28.8, 26.6, 25.6 (2C)*, 22.7,
evaporated to dryness. Subsequently, EtOH (20 mL) was added 14.1 ppm; HRMS–ESI (m/z): [M + H]+ calcd for C16H25N8,
and the resulting mixture was cooled to −10 °C to form precipi- 329.2197; found, 329.2195.
tate of Ph3PO, which was filtered as a byproduct and the filtrate
was evaporated. The column chromatography (DCM/MeCN Synthesis of 9-alkyl-2-pyrrolidino-6-(1,2,3-triazol-1-
10:1) provided the desired resulting product.
yl)purine derivatives 7a–f and 9-alkyl-2-piperidino-6-(1,2,3-
triazol-1-yl)purine derivatives 8a–f (typical procedure):
2,6-Dichloro-9-heptyl-9H-purine (1a-1): Slightly yellow oil; Alkyne (1.2 equiv) and 10% AcOH water solution (1 mL) were
reaction time (method A) – 1 h; yield 5.0 g, 66%. IR (KBr) ν added to a solution of compound 6a (200 mg, 0.61 mmol,
(cm−1): 2933, 1802, 1733; 1H NMR (300 MHz, CDCl3) δ 8.09 1.0 equiv) in THF (7 mL). The flask was isolated from daylight
486

Beilstein J. Org. Chem. 2019, 15, 474–489.
and CuSO4∙5H2O (10 mol %) and sodium ascorbate (20 mol %) piepridine 2 × CH2), 3.74 (s, 3H, CH3), 3.88 (s, 3H, OCH3),
were added. The reaction mixture was heated for 20 h at 50 °C. 6.88 (d, J = 3.6 Hz, 1H, 6-H), 7.02 (d, J = 8.8 Hz, 2H, ArH),
The reaction mixture was cooled to ambient temperature and 7.08 (d, J = 3.6 Hz, 5-H, 1H), 7.92 ( d, J = 8.8 Hz, 2H,ArH),
the precipitated product (bright yellow/green in color) was 8.79 ( s, 1H,triazole-H); 13C NMR (100 MHz, CDCl3) δ 25.6,
filtered. The product on the filter was washed with water (5 mL) 30.7, 46.9, 55.3, 99.5, 101.6, 114.3, 116.2, 123.1, 126.7, 127.3,
and MTBE (3 × 5 mL). Then the product was transferred into a 146.7, 147.0, 156.6, 156.8, 159.8; HRMS–ESI (m/z): [M + H]+
flask and dissolved in CHCl3 (7 mL). H2S gas was bubbled calcd for C20H22N7O, 376.1880; found, 376.1887.
through the latter solution until dark brown/black suspension
appeared. The resulting mixture was filtered through celite, the Quantum chemical calculations
filtrate was evaporated under reduced pressure and dried in The initial molecular geometries were generated by using a mo-
vacuo. Products can be further purified by silica gel column lecular mechanics method (force field MMF94, steepest descent
chromatography, if required.
algorithm) and systematic conformational analysis as imple-
mented in Avogadro 1.1.1 software. The minimum energy
9-Heptyl-6-(4-phenyl-1H-1,2,3-triazol-1-yl)-2-pyrrolidino- conformers found by molecular mechanics were further opti-
9H-purine (7a): Slightly yellow solid, yield 134 mg, 51%. IR mized with the Gaussian 09 program package [57] by the means
(KBr) ν (cm−1): 2952, 2924, 2857, 1622, 1540; 1H NMR of DFT using B3LYP exchange–correlation hybrid functional
(300 MHz, 70 °C, DMSO-d6 + D2O) δ 9.36 (s, 1H, H-C(tri- together with the 6-31G** basis set including the polarizable
azole)), 8.29 (s, 1H, H-C(8)), 8.01 (d, 3J = 7.2 Hz, 2H, Ar), 7.50 continuum model in MeCN. Further, harmonic vibrational
(t, 3J = 7.2 Hz, 2H, Ar), 7.40 (t, 3J = 7.2 Hz, 1H, Ar), 4.15 (t, frequencies were calculated to verify the stability of optimized
3J = 7.0 Hz, 2H, -CH2-), 3.71–3.55 (m, 4H, 2 × -CH2-), geometries. All the calculated vibrational frequencies were real
2.08–1.93 (m, 4H, 2 × -CH2-), 1.88 (quintet, 3J = 7.0 Hz, 2H, (positive), which indicates the true minimum of the total energy
-CH2-), 1.40–1.16 (m, 8H, 4 × -CH2-), 0.84 (t, 3J = 7.0 Hz, 3H, on the potential energy hypersurface. The theoretical absorp-
-CH3) ppm; 13C NMR (75.5 MHz, 70 °C, DMSO-d6 + D2O) δ tion bands were obtained by the means of time-dependent
156.5, 156.3, 146.4, 143.9, 143.7, 129.6, 128.7, 128.2, 125.5, extension of DFT (TDDFT). Spatial distributions of electron
120.0, 114.4, 46.6, 42.8, 30.7, 28.4, 27.7, 25.6, 24.7, 21.6, 13.4 density of calculated HOMOs and LUMOs were obtained at an
ppm; HRMS–ESI (m/z): [M + Na]+ calcd for C24H30N8Na, isosurface value of 0.02 where red and green colors stand for
453.2478; found, 453.2477.
the positive and negative signs of the molecular orbital wave
function, respectively.
Synthesis of 2-dialkylamino-9-methyl-6-[4-(4-substituted
phenyl)-1,2,3-triazol-1-yl]-7-deazapurines 10a–f, 11a–f Experimental procedure for cell studies
(Analogous as described in [39], a typical procedure): A The Human breast adenocarcinoma cell line MCF-7, and
mixture of azide 3 (86 mg, 0.4 mmol) and secondary amine normal mammary epithelial cell line MCF10A were ordered
(1.2 mmol) in CH3CN (2 mL) was protected from daylight and from Food Industry Research and Development Institute
stirred for 8–24 h at 40 °C. After completion of the SNAr reac- (Taiwan). MCF-7 cells were cultured in RPMI medium supple-
tion (TLC control), the reaction mixture was cooled to rt and the mented with fetal bovine serum (10%), antibiotic–antimycotic
corresponding alkyne (0.52 mmol), DIPEA (70 µL, 0.4 mmol), (1.0%). MCF-10A cells were cultured in α-MEM supple-
AcOH (23 µL, 0.4 mmol) and CuI (15 mg, 0.08 mmol) were mented with FBS (10%), and antibiotic–antimycotic (1.0%). All
added. The reaction mixture was stirred under argon atmo- cells were cultured in an environment equilibrated with 5% CO2
sphere at rt for 8–10 h (TLC control). Then the reaction mix- at 37 °C. The cell number and viability of the cells were deter-
ture was poured into aqueous 10% ammonia solution (25 mL), mined by applying the trypan blue exclusion method and
stirred for 10 minutes and extracted with CHCl3 (3 × 20 mL). Alamar Blue assay, respectively. Following the separated incu-
The combined organic layers were washed with water bation of MCF-7 and MCF-10A cells (7.0 × 104 cells per well)
(2 × 30 mL), dried over anhyd Na2SO4 and filtered. After in a culture medium for 24 h at 37 °C containing 5% CO2, each
removal of the solvent in vacuum, the crude products were puri- of the culture media were replaced with 500 μL of cell culture
fied by silica gel column chromatography (CHCl3/EtOAc 6:1) medium containing the compound, and then further cultured for
to afford compounds 10a–f, 11a–f.
an additional 1 h. Those cells were washed twice with 1× PBS
and fixed to the membrane using 4% paraformaldehyde in
6-[4-(4-Methoxyphenyl)-1,2,3-triazol-1-yl]-9-methyl-2- 5.0 mM sodium phosphate buffer (pH 7.4; 1.0 mL) for 10 min.
pyrrolidino-7-deazapurine (10b): Yellow solid, mp 258 °C The fluorescence images of cancer cells were acquired with a
dec, yield 99 mg, 66%. 1H NMR (400 MHz, CDCl3) δ fluorescence microscope (Olympus IX 71, Center Valley, PA,
2.01–2.11 (m, 4H, piperidine 2 × CH2), 3.65–3.72 (m, 4H, USA). Light from an Hg lamp (100 W) passed separately
487

Beilstein J. Org. Chem. 2019, 15, 474–489.
11.De Ornellas, S.; Slattery, J. M.; Edkins, R. M.; Beeby, A.;
through filter (365 ± 20 nm) before it was used to excite the
compound. The emission filters used in this study are long pass
filters, with cut-on wavelengths at 420 nm (Semrock,
Rochester, NY, USA).
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Supporting Information File 1
Full experimental procedures, emission spectra, DSC data,
and copies of 1H and 13C NMR spectra.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-41-S1.pdf]
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This work is supported by the ERDF 1.1.1.1 activity project Nr.
1.1.1.1/16/A/131 "Design and Investigation of Light Emitting
and Solution Processable Organic Molecular Glasses" (Latvia)
and by a grant (No. TAP-LLT-01/2015) from the Research
Council of Lithuania. The authors thank Ms. I. Māliņa for
absorption and emission spectra and Dr. J. Zicāns and R. Merijs
Meri for DSC measurements. Copyrights to the picture “busi-
ness people greet” used in the graphical abstract belong to
Publitek, Inc. dba GoGraph (https://www.gograph.com/).
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Jonas Bucevičius - https://orcid.org/0000-0001-5725-8940
Kaspars Traskovskis - https://orcid.org/0000-0003-1416-7533
Huan-Tsung Chang - https://orcid.org/0000-0002-5393-1410
Sigitas Tumkevičius - https://orcid.org/0000-0002-3279-1770
Māris Turks - https://orcid.org/0000-0001-5227-0369
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