Synthesis, fluorescence properties and the promising cytotoxicity of pyrene-derived aminophosphonates

Article abstract of DOI:10.3762/bjoc.12.117

A large series of variously substituted amino(pyren-1-yl)methylphosphonic acid derivatives was synthesized using a modified aza-Pudovik reaction in 20-97% yields. The fluorescence properties of the obtained compounds were investigated revealing that N-alk

Full text of DOI:10.3762/bjoc.12.117

Synthesis, fluorescence properties and the promising
cytotoxicity of pyrene–derived aminophosphonates
Jarosław Lewkowski*1, Maria Rodriguez Moya1, Anna Wrona-Piotrowicz1,
Janusz Zakrzewski*1, Renata Kontek*2 and Gabriela Gajek2
Full Research Paper
Open Access
Address:
Department of Organic Chemistry, Faculty of Chemistry, University of
Beilstein J. Org. Chem. 2016, 12, 1229–1235.
1
doi:10.3762/bjoc.12.117
Łódź, Tamka 12, 91-403 Łódź, Poland and 2Laboratory of
Cytogenetics, Faculty of Biology and Environmental Protection,
University of Łódź, Banacha 12/16, 90-237 Łódź, Poland
Received: 08 March 2016
Accepted: 01 June 2016
Published: 16 June 2016
Email:
Jarosław Lewkowski* - jlewkow@uni.lodz.pl; Janusz Zakrzewski* -
janzak@uni.lodz.pl; Renata Kontek* - renkon@biol.uni.lodz.pl
Associate Editor: C. Stephenson
©
2016 Lewkowski et al.; licensee Beilstein-Institut.
*
Corresponding author
License and terms: see end of document.
Keywords:
aminophosphonic derivatives; cytotoxicity; fluorescence properties;
MTT test; pyrene-1-carboxaldehyde
Abstract
A large series of variously substituted amino(pyren-1-yl)methylphosphonic acid derivatives was synthesized using a modified aza-
Pudovik reaction in 20–97% yields. The fluorescence properties of the obtained compounds were investigated revealing that
N-alkylamino(pyren-1-yl)methylphosphonic derivatives are stronger emissive compounds than the corresponding N-aryl deriva-
tives. N-Benzylamino(pyren-1-yl)methylphosphonic acid displayed strong fluorescence (ΦF = 0.68) in phosphate-buffered saline
(
PBS). The influence of a series of derivatives on two colon cancer cell lines HT29 and HCT116 was also investigated. The most
promising results were obtained for N-(4-methoxyphenyl)amino(pyren-1-yl)methylphosphonate, which was found to be cytotoxic
for the HCT116 cancer cell line (IC50 = 20.8 μM), simultaneously showing weak toxicity towards normal lymphocytes
(
IC50 = 230.8 µM).
Introduction
The biological activity of aminophosphonic systems is very acid derivatives have been described only twice in the chemical
well known and described, in aspect of their crop protective [1], literature. Firstly, Harry Hudson’s team [8] published the syn-
antibacterial [2] or anticancer properties [3]. Various C-aryl thesis of diethyl N-benzhydrylamino(pyrene-1-yl)methylphos-
substituted derivatives of phosphonoglycine have been synthe- phonate in a series of N-benzhydryl substituted aminomethyl
sized including those of benzene and several polycyclic aromat- phosphonates. Recently, an Indian group [9] reported the syn-
ic hydrocarbons [4], five- [5] and six-membered [6] heteroaro- thesis of a number of N-aryl substituted, diethyl amino(pyrene-
matic compounds and even ferrocene [7]. In contrast, pyrene- 1-yl)methyl phosphonates and some preliminary studies on their
based derivatives, e.g., amino(pyrene-1-yl)methyl phosphonic fluorescence properties.
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Beilstein J. Org. Chem. 2016, 12, 1229–1235.
Such a poor knowledge about these compounds is astonishing moiety [21] were found to be fluorescence-based sensors of
in the light of the fact that the phosphonic analogues of phenyl- Cu(II) and Mg(II) cations.
glycine, exhibited their herbicidal activity [10], and are used as
plant growth regulators [10], agrochemical fungicides [11,12] Considering all above, we decided to synthesize a series of
and glutamate receptor modulators [13]. It is therefore N-substituted derivatives of C-(pyren-1-yl)phosphonoglycine
expectable that C-pyrene derivatives may have similar or even and to investigate their cytotoxic and fluorescence properties.
more promising biological properties.
Results and Discussion
Synthesis of aminophosphonic acid deriva-
This expectation is supported by the biological activity of azo-
methine derivatives of pyrene-1-carboxaldehyde. They show tives 3, 4 and 5
antimicrobial action, e.g., 1-phenytoinylacetic acid hydrazone Schiff bases 1a–h were prepared by refluxing pyrene-1-carbox-
of pyrene-1-carboxaldehyde demonstrated a moderate antimi- aldehyde with an amine in methanol, hexane or dichloro-
crobial activity towards Escherichia coli and Staphylococcus methane for 24 hours and were used for further conversions as
aureus [14]. Azomethine derivatives of pyrene-1-carboxalde- obtained. This harsh method to prepare imines had to be used,
hyde have shown enzyme inhibitory activity, as, e.g., its thio- because the simple mixing of reagents in methanol at room tem-
semicarbazone, which is able to inhibit the action of urease perature, which is the common mode d’emploi in such cases
[
15].
[5,7], did not provide satisfactory results. The reaction comple-
tion was monitored by 1H NMR and obtained imines 1a–h were
Although fluorescence properties of pyrene-based aminophos- isolated by simple evaporation of the solvent and were used for
phonic derivatives have been mentioned only once in a prelimi- the further reaction without purification.
nary form [9], fluorescence emission of their azomethine pre-
cursors was reported for pyrene-1-carboxaldehyde thiosemi- Aminophosphonates 3Aa–h, 3Ba–e and 3Ca–d, 3Cg have been
carbazone and Schiff bases as well as their metal complexes synthesized via an aza-Pudovik reaction [22], i.e., the addition
[
16-21]. Such properties were described for, e.g., ruthenium(II) of the appropriate phosphite 2A–C to the azomethine bond of
complexes of (5-chloropyridin-2-yl)-(pyren-1-yl)methyle- the Schiff bases 1a–h. Nevertheless, the important modifica-
neamine [17], a N-(1-pyrene)methylideneglucosamine mercury tions had to be introduced to the described procedures [22,23].
complex [18], a N-(pyren-1-ylidene)-2-hydroxyaniline- The 1-pyrene moiety is a troublesome substituent due to its
copper(II) and -zinc(II) complexes [19] or N-(pyren-1-ylidene)- spatial volume, which tends to disturb in the course of the reac-
4
-carboxyaniline-Fe(II) and -Cr(III) complexes [20]. Several tions. Attempts to use any of common solvents failed as no or
phosphorus-supported ligands containing a pyrene-1-carbimino only a weak progress of the reaction was noticed (Scheme 1).
Scheme 1: Synthesis of aminophosphonates 3Aa–j, 3Ba–e, 3Ca–d, 3Cg, aminophosphonic acids 4a, 4c and hydroxyphosphonate 5A.
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Beilstein J. Org. Chem. 2016, 12, 1229–1235.
The best solution was to apply phosphites simultaneously as product could be obtained only when tert-butylamine (or iso-
solvents and reactants, which however forced to use them in a propylamine) was present in the reaction mixture (Scheme 1).
high excess. This necessity resulted in troubles with purifica-
tion, implicating a particular approach to each case.
All obtained aminophosphonates 3Aa–j, 3Ba–e, 3Ca–d and
Cg as well as the hydroxyphosphonate 5A gave satisfactory
3
Dimethyl aminophosphonates 3Aa–Ah were purified by results of in the elemental analysis and were characterized by
washing their dichloromethane solutions with a saturated means of 1H, 13C and 31P NMR and IR spectroscopy with all
aqueous sodium bicarbonate solution, which allowed to remove signals attributed to each nucleus. Compounds were also char-
dimethyl phosphite. This procedure was followed by column acterized by melting point measurements.
chromatography, and, in a case of N-benzyl derivative 3Aa, trit-
urating the product with diethyl ether until the precipitation of a Jayaprakash et al. [9] reported the synthesis of several
solid was additionally carried out.
pyrene-derived aminophosphonates via a silica-catalyzed
Kabachnik–Fields reaction. Among others, they synthesized
The isolation and purification of diethyl aminophosphonates three amino-phosphonates 3Bb–d, reporting their melting point
Ba–e required a different method. To isolate them, the crude values and their spectral characterizations. Melting point values
3
reaction mixtures were dissolved in a minimum amount of quoted by the authors differed from values measured by us. The
diethyl ether and triturated until a yellow precipitate formed. reason of such a discrepancy remains unclear, it might be
This operation was repeated twice. Aminophosphonates 3Ba–e caused by the different eluents used – we eluted products using
were purified by column chromatography.
chloroform, while Jayaprakash et al. [9] used hexane and ethyl
acetate (2:3).
The most complex procedure was used to isolate and to purify
the dibenzyl aminophosphonates 3Ca–d and 3Cg. The crude The other discrepancy concerns the 1H NMR spectra, and par-
reaction mixtures were dissolved in small amounts of pyridine ticularly their aromatic regions. In all three cases, Jayaprakash
and then, treated with elemental iodine to decompose dibenzyl et al. [9] quoted all aromatic signals as broad multiplets, where-
phosphite. This was followed by washing the mixture dissolved as we were capable to distinguish clearly signals of pyrene
in dichloromethane with saturated aqueous solutions of sodium protons as a series of distinct doublets and approximate triplets.
thiosulfate and then sodium bicarbonate. The purification with Phenyl ring signals were also visible, e.g., the non-substituted
column chromatography allowed to afford pure products in phenyl ring gave a triplet, doublet of doublets and a doublet, the
satisfactory yields.
4-methyl substituted phenyl moiety demonstrated a distinct
AA’XX’ system, whereas the 4-methoxy derivative shows an
Due to the fact that we were not able find proper conditions to AA’BB’ system. All these phenomena are clearly visible in the
prepare N-(pyren-1-ylidene)-tert-butylamine (1j) and dimethyl 1H NMR spectra and scans of them are collected in Supporting
N-(tert-butyl)amino(pyren-1-yl)methylphosphonate (3Aj) via Information File 1.
the aza-Pudovik reaction, the Kabachnik–Fields reaction was
used as an alternative method [23]. The three-component reac- Aminophosphonic acids 4a and 4c were prepared using the
tion without any catalyst was carried out first in dichloro- classical cleavage of dimethyl aminophosphonates 2Aa and
methane then, in methanol. In both cases, to our surprise, no 2Ac with trimethylsilyl bromide in dry dichloromethane. After
traces of the desired aminophosphonate 3Aj have been found in 24-hours reaction, the reaction was quenched by methanol to
the reaction mixture. Instead, dimethyl hydroxy(pyren-1- give, after routine work-up the desired acids 4a and 4c
yl)methylphosphonate (5A) was obtained in quite satisfactory (Scheme 1). They were characterized by NMR spectroscopy
yield. Dimethyl N-(tert-but-yl)amino(pyren-1-yl)methylphos- (1H, 13C and 31P), IR spectroscopy, melting point measure-
phonate (3Ai) was obtained, when the Kabachnik–Fields reac- ments and elemental analysis.
tion was carried out in the presence of a catalytic amount of tri-
fluoroacetic acid in refluxing acetonitrile. The same procedure, The obtained phosphonic derivatives were then selected and
i.e., the Kabachnik–Fields reaction in the presence of trifluoro- their biological and photophysical properties were studied.
acetic acid, but in refluxing methanol has been successfully
Luminescent properties of pyrenyl amino-
used for the preparation of dimethyl N-(m-methylphen-
yl)amino(pyren-1-yl)methylphosphonate (3Ai) (Scheme 1). phosphonates
The widespread use of pyrene derivatives as luminescent probes
Interestingly, attempts to obtain the hydroxyphosphonate 5A in in biological research [24-27] prompted us to study emissive
conditions typical for the Pudovik (not aza) reaction failed – the properties of the synthesized aminophosphonates. We have
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Beilstein J. Org. Chem. 2016, 12, 1229–1235.
measured their electronic absorption and emission spectra in
chloroform solution. Although photodecomposition of pyrene in
this solvent has been reported [28], we found that this is not the
case of the compounds under study. To avoid excimer forma-
tion, spectra were recorded at low sample concentrations
(
1 μM). We have found that all compounds under study were
emissive albeit emission quantum yields varied from ≈0.01 to
0.7 (Table 1). The typical absorption and emission spectrum
those of compound 3Aj), compared with the spectra of pyrene
≈
(
are shown in Figure 1. The spectra are closely similar and show
vibronic structure characteristic for monomeric fluorophores.
The spectra of 5 are slightly shifted bathochromically (9 nm and
4
nm for the absorption and emission spectrum, respectively) in
comparison to the spectra of pyrene. In this context, it should be
noticed that spectra reported in [9] were measured at signifi-
cantly higher concentrations (0.5 mM) and are broad and struc-
tureless. Therefore, they should rather be assigned to fluoro-
phore aggregates (excimers).
Figure 1: Normalized electronic absorption and emission spectra of
3Aj and pyrene in chloroform (c = 1 μM).
Table 1: Absorption and emission maxima and fluorescence quantum
yields (ΦF) for the synthesized compounds in chloroform solution
(c = 1 μM).
Compd. Absorption
Emissiona
ΦFb
λmax (nm)
λmax (nm)
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
4
5
Aa
Ba
Ca
Ab
Bb
Cb
Ac
Bc
Cc
Ad
Bd
Cd
Ae
Be
Af
304, 317, 330, 347 378, 388, 399
304, 316, 331, 347 378, 388, 398
304, 316, 331, 348 378, 389, 399
0.06
0.06
0.06
304, 317, 331, 348 382, 397, 424, 444 <0.01
304, 318, 330, 348 382, 397, 443
305, 318, 332, 349 382, 397, 455
304, 317, 331, 348 380, 395, 485
304, 316, 330, 448 380, 395, 484
304, 317, 330, 448 380, 396, 485
304, 317, 331, 348 380, 398,
304, 317, 330, 348 380, 398
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
0.10
Figure 2: Emission spectra of compound 3Aj in various solvents. The
spectra are normalized at ≈378 nm (pyrene band I).
The highest emission quantum yield (0.68) was found for
aminophosphonic acid 4a in aqueous buffer (pH 7.4). A similar
phenomenon of higher emission efficiency of 1-(pyrene-1-
carboxamido)methylphosphonic acid in comparison to a corre-
sponding aminophosphonate was earlier reported [29].
304, 317, 331, 348 381, 398
303, 316, 330, 347 378, 390, 398
303, 316, 330, 346 377, 389, 397
303, 317, 330, 347 378, 390, 398
0.10
0.09
Ag
Ai
316, 330, 347
378, 390, 398
0.05
303, 316, 330, 347 380, 395
<0.01
0.11
Aj
318, 331, 347
378, 389, 397
The aforementioned data suggest possible application of com-
pound 3Aj (and other exhibiting similar emission quantum
yield) as molecular probes monitoring micropolarity of the
fluorophore environment. On the other hand, water-soluble 4a
might be used for biological imaging.
ac
303, 316, 329, 345 378, 397, 419
0.68
A
317, 330, 347
377, 388, 396
0.13
aExcitation was set at the maximum of the lowest energy absorption
band. bMeasured for aerated solutions. Quenching by dissolved
dioxygen was not observed. cMeasured for an aqueous 0.01 PBS
(
phosphate-buffered saline) solution (pH 7.4)
Investigation of cytotoxic effects of studied
The spectra of 3Aj were run in solvents of varied polarity compounds
Figure 2) and display the well-known Ham effect (dependence The cytotoxic effects of dimethyl aminophosphonates 3Aa,
of the ratio of intensities of III/I vibronic bands on the medium 3Ab, 3Ac, 3Ad, 3Ai and dimethyl [hydroxy(pyren-1-
polarity) [26]. yl)methyl]phosphonate (5A) were investigated with two human
(
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Beilstein J. Org. Chem. 2016, 12, 1229–1235.
colorectal carcinoma cell lines: HT29 and HCT116 and also on against both colon cancer cell lines, but in contrast to 3Ad, was
the normal human lymphocytes. For this a standard MTT also toxic for lymphocytes. Paradoxally, compound 3Ac, bear-
(
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) ing a 4-C6H4-CH3 moiety, exhibited the most potent cytotoxici-
test was used and results presented as IC50 values (i.e., the con- ty from all tested compounds: IC50 (HT29) = 15.8 µM and
centration of the compound that inhibits 50% growth). The ac- IC50 (HCT116) = 15.9 µM. On the other hand, 3Ac had the
tivity of the tested compounds was studied in the concentration highest IC50 value against normal cells from all tested com-
range from 5 to 600 µM. The obtained IC50 values are summa- pounds. The compound 3Ab was the less toxic for normal cells
rized in Table 2.
(IC50 = 334.2 µM) from among all tested compounds. However,
Ab was also the least toxic against both tested cancer cell lines
3
The activity of tested compounds varied from IC50 = 15.8 µM HT29 (IC50 = 105.8 µM) and HCT116 (IC50 = 70.8 µM). Com-
to 105.8 µM. As it can be seen, the most interesting results were pound 5A has exhibited a significant cytotoxicity against HT29
obtained for compound 3Ad, bearing the p-methoxyphenyl (IC50 = 25.8 µM). For compounds 3Aa and 3Ai, the received
moiety (Figure 3). It has exhibited significant cytotoxicity results were comparable, except for the results against HT29,
against both tested cancer cell lines HT29 (IC50 = 24.2 µM) as the level of the cytotoxicity was slightly higher for 3Ai. Simul-
well as HCT116 (IC50 = 20.8 µM) cells, and it simultaneously taneously, cytotoxicities of both aminophosphonates (3Aa and
was not strongly toxic for normal human lymphocytes 3Ai) against normal lymphocytes were rather high (IC50 = 89.2
(
IC50 = 230.8 µM). However, HT29 cells were more resistant to and 75.8 µM, respectively).
Ad than HCT116 cells. Therefore, the aminophosphonate 3Ad
3
showed a carcinoma-specific cytotoxicity against human colon On the basis of the results presented in Table 1, it can be con-
cancer cells. A similar correlation was observed for the cluded that the type of functional group has a large influence on
aminophosphonic derivative 3Ac, which was strongly cytotoxic the biological properties of the tested compounds. These results
Table 2: IC50 values on studied compounds.
Compound
R1
lymphocytes
HT29
HCT116
3
3
3
3
3
5
Aa
Ab
Ac
Ad
Ai
CH2Ph
IC50 = 89.2 ± 2.9 µM
IC50 = 334.2 ± 2.59 µM
IC50 = 17.5 ± 4.15 µM
IC50 = 230.8 ± 3.43 µM
IC50 = 75.8 ± 4.02 µM
IC50 = 135.8 ± 1.73 µM
IC50 = 29.2 ± 3.84 µM
IC50 = 105.8 ± 3.37 µM
IC50 = 15.8 ± 3.44 µM
IC50 = 24.2 ± 5.12 µM
IC50 = 57.5 ± 5.19 µM
IC50 = 25.8 ± 4.99 µM
IC50 = 29 ± 2.37 µM
IC50 = 70.8 ± 2.99 µM
IC50 = 15.9 ± 4.85 µM
IC50 = 20.8 ± 3.48 µM
IC50 = 20.21 ± 5.63 µM
IC50 = 40.4 ± 4.53 µM
Ph
4-C6H4-CH3
4-C6H4-OCH3
3-C6H4-CH3
–
A
Figure 3: IC50 values of studied compounds.
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Beilstein J. Org. Chem. 2016, 12, 1229–1235.
indicate that the presence of a methylphenyl group causes a References
compound to be toxic for normal lymphocytes (3Ac and 3Ai); a
1. Kafarski, P.; Lejczak, B.; Tyka, R.; Koba, L.; Pliszczak, E.;
Wieczorek, P. J. Plant Growth Regul. 1995, 14, 199–203.
Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon Relat. Elem. 1991,
3, 193–215. doi:10.1080/10426509108029443
Kafarski, P.; Lejczak, B. Curr. Med. Chem.: Anti-Cancer Agents 2001,
, 301–312. doi:10.2174/1568011013354543
similar phenomenon was observed for N-benzyl substitution
2
.
.
(
(
3Aa). Results obtained for the α-hydroxyphosphonate 5A
6
IC50 = 25.8 µM against HT29) give the impact to look for
3
potential anticancer agents among the α-hydroxyphosphonic de-
1
rivatives.
4. Mohd-Pahmi, S. H.; Hussein, W. M.; Schenk, G.; McGeary, R. P.
Bioorg. Med. Chem. Lett. 2011, 21, 3092–3094.
doi:10.1016/j.bmcl.2011.03.024
Conclusion
A large series of various amino(pyren-1-yl)methylphospho-
5
.
Klimczak, A. A.; Kuropatwa, A.; Lewkowski, J.; Szemraj, J.
Med. Chem. Res. 2013, 22, 852–860. doi:10.1007/s00044-012-0065-3
Boduszek, B. Tetrahedron 1996, 52, 12483–12494.
doi:10.1016/0040-4020(96)00727-2
nates was prepared using the aza-Pudovik reaction (3Aa–h,
6.
3
Ba–e, 3Ca–d, 3Cg) or in the course of the Kabachnik-Fields
reaction (3Ai and j). Amino(pyren-1-yl)methylphosphonic acids
a and 4c were prepared using Boduszek’s methodology [6]
7. Lewkowski, J.; Rzeźniczak, M.; Skowroński, R.; Zakrzewski, J.
J. Organomet. Chem. 2001, 631, 105–109.
4
doi:10.1016/S0022-328X(01)01011-7
and dimethyl hydroxy(pyren-1-yl)methylphosphonate (the
Pudovik reaction). The fluorescence properties of the obtained
compounds were investigated and N-benzylamino(pyren-1-
8.
Hudson, H. R.; Lee, R. J.; Matthews, R. W.
Phosphorus, Sulfur Silicon Relat. Elem. 2004, 179, 1691–1709.
doi:10.1080/10426500490466274
yl)methylphosphonic acid showed a quantum yield of 68%, 9. Jayaprakash, S. H.; Rao, K. U. M.; Krishna, B. S.; Prasad, S. S.;
Sundar, C. S.; Reddy, C. S. Phosphorus, Sulfur Silicon Relat. Elem.
while dimethyl tert-butylamino(pyren-1-yl)methylphosphonate
2
015, 190, 449–460. doi:10.1080/10426507.2014.948621
(
3Aj) gave 11% quantum yield.
1
0.Hudson, H. R. Aminophosphonic and Aminophosphinic Acids and their
Derivatives as Agrochemicals. In Aminophosphonic and
Aminophosphinic Acids: Chemistry and Biological Activity;
Kukhar, V. P.; Hudson, H. R., Eds.; John Wiley and Sons: Chichester,
2000; pp 443–482.
The influence of a series of derivatives on two colon cancer cell
lines HT29 and HCT116 was also investigated. The most inter-
esting results were obtained for dimethyl N-(4-methoxyphen-
yl)amino(pyren-1-yl)methylphosphonate 4d, which was found
to be cytotoxic for these two colon cancer cell lines
1
1
1
1.Maier, L.; Diel, P. J. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 57,
5
7–64. doi:10.1080/10426509108038831
2.Hudson, H. R. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 144,
41–444. doi:10.1080/10426509908546276
(
IC50 ≈ 20 μM), but showed nearly no toxicity towards lympho-
4
cytes (IC50 ≈ 230 μM). Although, dimethyl N-(4-methylphen-
yl)amino(pyren-1-yl)methylphosphonate 4c demonstrated im-
portant cytotoxicity (IC50 ≈ 15 μM) for both cancer cell lines, it
was unfortunately found to be toxic towards normal lympho-
cytes (IC50 ≈ 17 μM).
3.Jane, D. Aminophosphonic and Aminophosphinic Acids and their
Derivatives as Agrochemicals. In Aminophosphonic and
Aminophosphinic Acids: Chemistry and Biological Activity;
Kukhar, V. P.; Hudson, H. R., Eds.; John Wiley and Sons: Chichester,
2000; pp 483–536.
1
4.Ali, O. M.; Amer, H. H.; Mosaad, A. A.; Abdel-Rahman, A. A.-H.
Chem. Heterocycl. Compd. 2012, 48, 1043–1049.
doi:10.1007/s10593-012-1097-9
More profound studies on biological properties of selected com-
pounds (necrosis vs apoptosis, mechanism of action) are being
developed and will be published in the near future.
15.Saeed, A.; Imran, A.; Channar, P. A.; Shahid, M.; Mahmood, W.;
Iqbal, J. Chem. Biol. Drug Des. 2015, 85, 225–230.
doi:10.1111/cbdd.12379
1
1
1
1
6.Wang, X. M.; Yan, H.; Feng, X. L.; Chen, Y. Chin. Chem. Lett. 2010,
1, 1124–1128. doi:10.1016/j.cclet.2010.04.029
7.Mandal, S.; Kundi, V.; Seth, D. K.; Srikanth, K.; Gupta, P. Polyhedron
014, 80, 290–297. doi:10.1016/j.poly.2014.06.005
2
Supporting Information
2
Supporting Information File 1
8.Areti, S.; Hinge, V. K.; Rao, C. P. Carbohydr. Res. 2014, 399, 64–69.
doi:10.1016/j.carres.2014.06.014
Experimental procedures, characterization of novel
compounds, and details of the biological and photophysical
study. Scans of 1H, 13C and 31P NMR spectra of all new
synthesized compounds.
9.Pinheiro, D.; de Castro, C. S.; Seixas de Melo, J. S.; Oliveira, E.;
Nuñez, C.; Fernández-Lodeiro, A.; Capelo, J. L.; Lodeiro, C.
Dyes Pigm. 2014, 110, 152–158. doi:10.1016/j.dyepig.2014.04.012
[http://www.beilstein-journals.org/bjoc/content/
20.Obali, A. Y.; Ucan, H. I. J. Fluoresc. 2012, 22, 1357–1370.
doi:10.1007/s10895-012-1075-8
supplementary/1860-5397-12-117-S1.pdf]
2
2
2
1.Chandrasekhar, V.; Pandey, M. D.; Bag, P.; Pandey, S. Tetrahedron
2009, 65, 4540–4546. doi:10.1016/j.tet.2009.03.098
2.Tyka, R. Tetrahedron Lett. 1970, 11, 677–680.
doi:10.1016/S0040-4039(01)97800-1
Acknowledgements
Studies were founded by the National Centre of Science of
3.Zefirov, N. S.; Matveeva, E. D. ARKIVOC 2008, No. i, 1–17.
doi:10.3998/ark.5550190.0009.101
Polish State (NCN), grant no. 2014/13/B/NZ9/02418.
1234

Beilstein J. Org. Chem. 2016, 12, 1229–1235.
2
2
2
2
2
4.Gonçalves, M. S. T. Chem. Rev. 2009, 109, 190–212.
doi:10.1021/cr0783840
5.Sinkeldam, R. W.; Greco, N. J.; Tor, Y. Chem. Rev. 2010, 110,
2
579–2619. doi:10.1021/cr900301e
6.Bains, G.; Patel, A. B.; Narayanaswami, V. Molecules 2011, 16,
909–7935. doi:10.3390/molecules16097909
7
7.Drummen, G. P. C. Molecules 2012, 17, 14067–14090.
doi:10.3390/molecules171214067
8.Aguilera-Sigalat, J.; Sanchez-SanMartín, J.; Agudelo-Morales, C. E.;
Zaballos, E.; Galian, R. E.; Pérez-Prieto, J. ChemPhysChem 2012, 13,
835–844. doi:10.1002/cphc.201100843
29.Wrona-Piotrowicz, A.; Zakrzewski, J.; Gajda, A.; Gajda, T.; Makal, A.;
Brosseau, A.; Métivier, R. Beilstein J. Org. Chem. 2015, 11,
2451–2458. doi:10.3762/bjoc.11.266
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