Design and one-pot synthesis of α-aminophosphonates and bis(α-aminophosphonates) by iron(III) chloride and cytotoxic activity

Article abstract of DOI:10.1016/j.ejmech.2009.07.009

In this study, we used a solution of FeCl₃ in THF to facilitate the Mannich-type reaction of aldehyde, amine and phosphite compounds to form corresponding α-aminophosphonates in a one-pot, three-component reaction. Selected α-aminophosphonates

Full text of DOI:10.1016/j.ejmech.2009.07.009

European Journal of Medicinal Chemistry 44 (2009) 4266–4275
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design and one-pot synthesis of
a-aminophosphonates and bis
(
a-aminophosphonates) by iron(III) chloride and cytotoxic activity
,
b
b
c
a
Zahra Rezaei a , Habib Firouzabadi , Nasser Iranpoor , Abbas Ghaderi , Mohammad Reza Jafari ,
*
Abbas Ali Jafari d, Hamid Reza Zare c
a Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
b Department of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran
c Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
d Department of Chemistry, Faculty of Sciences, Yazd University, Yazd, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, we used a solution of FeCl3 in THF to facilitate the Mannich-type reaction of aldehyde,
Received 24 January 2009
Received in revised form
17 June 2009
Accepted 9 July 2009
Available online 16 July 2009
amine and phosphite compounds to form corresponding
a-aminophosphonates in a one-pot, three-
component reaction. Selected -aminophosphonates were entered into a biological assay test and were
a
studied by docking methods, using Autodock 3.0.
The results showed that the reactions were carried out mildly and eco-friendly to form
a-amino-
phosphonates in high yields. Some were found to have cytotoxic activity on the cell lines RAJI, JURKAT
and MCF-7. An indole derived bis( -aminophosphonates) showed maximum cytotoxic effect comparable
a
Keywords:
to doxorubicin. Although the FDE (Final Docking Energy) for the most cytotoxic compound was of the
most negative value, there is no correlation between FDE and cytotoxicity.
Ó 2009 Elsevier Masson SAS. All rights reserved.
a
-Aminophosphonates
FeCl3
Cytotoxicity
Docking
1. Introduction
preparation of diverse a-aminophosphonates have been published
since the first synthesis by Fields [17] in 1952: addition of imines to
di- or trialkyl phosphite derivatives [18], nucleophilic amination of
Organophosphorus compounds have found a wide range of
applications in the areas of industrial, agricultural, and medicinal
chemistry owing to their biological and physical properties as well
as their utility as synthetic intermediates [1–5]. As a kind of natural
a-hydroxyphosphonate derivatives [19], electrophilic amination
of -alkylphosphonamides [20], hydrogenation of dehy-
a
droaminophosphonate derivatives [21], aldol-type reactions of
(isocyanomethyl)phosphonates with aldehydes [22], hydrogena-
tion of aziridinylphosphonate [23], addition of phosphites to sulfi-
mines [24] and catalyzed Mannich-type one-pot procedures [25].
amino acid analogues,
important class of compounds with diverse biological activities.
The activity of -aminophosphonates as peptidomimetics [6],
a-aminophosphonates constitute an
a
enzyme inhibitors [7], pharmacogenic agents [8], haptens of cata-
lytic antibodies [9], herbicidals [10], inhibitors of serine hydrolases
[11], inhibitors of UDP-galactopyranose mutase [12] and antitumor
agents [13–15] is reported in literature.
Catalytic synthetic methods that allow the limits of fine organic
synthesis to be expanded considerably play a special role in
synthetic organic chemistry. Catalytic methods are currently used
in synthetic organophosphorus chemistry to obtain various
organophosphorus compounds, in particular, functionalized phos-
phonates and phosphinates, which attract a special attention due to
their biological activities [16]. A large number of methods for the
However, one-pot synthesis of a-aminophosphonates remains
a favor due to its versatile route and high yielding reactions.
Recently, three-component synthesis starting from aldehydes,
amines and diethylphosphite or triethylphosphite have been
reported by using Lewis and Brønsted acid catalysts such as LiClO4
[26], InCl3 [27a], ZrCl4 [27b], AlCl3 [27b], lanthanide triflates/
magnesium sulfate [28], SbCl3/Al2O3 [29a], TaCl5–SiO2 [29b],
amberlyst-15 [30a], montmorillonite clay-MW [30b], Al2O3-MW
[31], CF3CO2H [32a], sulfamic acid [32b], scandium (tris-dodecyl
sulfate) [33], BF3$Et2O [34], M(OTf)n [35] and M(ClO4)n [36]. Though,
many of these methods suffer from some drawbacks such as long
reaction times, low yields of the products, requiring stoichiometric
amounts of catalysts, costly and moisture sensitive catalysts and use
of highly toxic or toxic catalysts. More recently, ZrOCl2$8H2O [37]
or ZrO(ClO4)2$6H2O [38] and TiO2 [39] are reported to be effective
* Corresponding author. Tel.: þ98 711 2425305; fax: þ98 711 2424126.
E-mail address: rezaeiza@sums.ac.ir (Z. Rezaei).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.07.009

Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 4266–4275
4267
catalysts for the formation of
component system composing of aldehydes/ketones, amines and
diethylphosphite under neat conditions.
a
-aminophosphonates using a three-
probable mechanism of anti-proliferative action of the synthesized
bis( -aminophosphonates). The breadth and the relatively planar
structure of the synthesized compounds were suggestive of
intercalating properties of these bis( -aminophosphonates).
Moreover, the presence of phosphonate groups in the ends of
molecule and the presence of NH in the middle of the structure
tempted us to study the probable intercalating activity of the
compounds. In order to find most probable intercalating agents,
first we used Autodock to estimate the most negative energy of
docking for all of the compounds which means the most probable
ability of compounds to intercalate with DNA. Then the selected
compounds were entered into a biological assay. Doxorubicin was
selected as reference intercalating agents.
a
FeCl3 has emerged as a potential catalyst in effecting various
organic transformations due to its high catalytic ability, economic
viability, and easy availability [40]. However, FeCl3 suffers from
being hygroscopic and is also a corrosive material. These limit the
use of this compound as a reagent or catalyst in organic synthesis,
especially for the large-scale operation. On the other hand, dis-
solved FeCl3 in THF (tetrahydrofuran) produces a yellow to green
colour solution which can be bottled and stored at room temper-
ature for months without being hygroscopic. Transformation of this
solution to the reaction mixture is easily performed by a pipette or
by an eye dropper without any serious precaution.
a
As a part of our continued interest in the development of
synthetic methods for the preparation of phosphonate derivatives
[35,41], we have found that FeCl3$THF solution catalyzes highly
efficient preparation of a-aminophosphonates via a three-compo-
nent system composing of aldehydes, amines, and diethylphosphite
(Scheme 1). We have also applied this protocol for the one-pot
2. Chemistry
At the outset it was investigated the three-component reac-
tion of benzaldehyde, aniline, and diethylphosphite in the pres-
ence of a catalytic amount of FeCl3$THF solution. The best
reaction condition was resulted when the molar ratio of benz-
aldehyde (2.0 mmol)/aniline (2.0 mmol)/diethyl phosphate
(2.2 mmol)/FeCl3$THF (1.0 mL, 5 mol%) were used at 60 ꢀC. At this
condition, the reaction proceeded well and completed after
0.75 h to produce the desired diethyl phenyl(phenylamino)-
methylphosphonate (1a) in 95% isolated yield. The merit of the
catalyst has been shown by conducting the reaction of benzal-
preparation of bis(
hydes, amines, and diethylphosphite as a three-component system.
The efficient methods for the preparation of bis-( -amino-
a-aminophosphonates) by the reaction of alde-
a
phosphonates) are rather limited in the literature (Scheme 1).
At present, cancer is the leading cause of death worldwide. It
accounted for 7.9 million deaths (around 13% of all deaths) in 2007
[42]. Despite recent progresses in cancer chemotherapy, high
toxicity and low specificity of current medications are motivating
the scientists to search for safer and more effective anticancer
drugs. Along with the extensive worldwide research, we decided to
dehyde
(2.0 mmol)/aniline
(2.0 mmol)/diethyl
phosphate
(2.2 mmol) under similar conditions as mentioned above in the
absence of the catalyst. The reaction did not proceed even after
24 h. In order to show the general application of the method,
several aldehydes, amines and diethyl phosphate with similar
molar ratios as above, were reacted smoothly for the appropriate
study antitumor activity of some new bis(
to expand our survey in anticancer drug research. To the best of our
knowledge, the biological studies are not extended to bis( -ami-
a-aminophosphonates)
a
reaction times (0.5–2 h) to yield the corresponding
a-amino-
nophosphonates), yet. This group of compounds may have even
more effect and range of bioactivity, due to an increased number of
phosphonate and amine functionality in a unique molecule.
Computer docking techniques play an important role in the
drug design as well as in the mechanistic study by placing
a molecule into the binding site of the target macromolecule in
a non-covalent fashion [43]. DOCK [44] and AutoDock [45] as
flexible docking programs enable us to predict favorable protein–
ligand complex structures with a reasonable accuracy and speed.
These docking programs, when used prior to experimental
screening, can be considered as powerful computational filters to
reduce labor and cost needed for the development of potent
medicinal compounds. When used after experimental screening,
they can help to a better understand of bioactivity mechanisms.
AutoDock is said to offer a reasonable result in comparison with
other popular docking programs [46]. The docking technique will
undoubtedly continue to play an important role in drug discovery
[47]. Several drugs that were designed by intensive use of
computational methods are currently under investigation for
clinical trials [48] Therefore, we utilized AutoDock 3.0 to interpret
phosphonates in excellent isolated yields (80–95%). The exam-
ples studied cover electron-rich and electron-deficient aromatic
aldehydes with aniline as an aromatic amine and also showing
that N-methyl aniline reacts smoothly to give the corresponding
a
-aminophosphonate carrying a secondary amine moiety. The
results are summarized in Table 1.
We have also compared the catalytic activity of FeCl3$THF with
respect to the other catalysts used for the reaction of p-methox-
ybenzaldehyde and aniline with diethylphosphite as presented in
Table 2.
Bis(a-aminophosphonates) are interesting compounds, as they
are multidentate ligands which may be used for the extraction of
metals from solutions and they can be employed as the monomers
for the preparation of macrocyclic or polymeric compounds
carrying phosphonate and amine moieties. In addition, and more
importantly, investigation of their biological activity would be of
great interest. Through this study, it was also investigated the
applicability of the catalyst solution for the preparation of bis(a-
aminophosphonates) via a one-pot three-component reaction of
structurally diverse diamines (1.0 mmol), electron-rich and
Scheme 1. Three-component reaction of aromatic aldehydes with amine and diethylphosphite in FeCl3$THF solution.

Table 1
FeCl3$THF solution catalyzed synthesis of
a
-aminophosphonates by using a three-component system.
Entry
Aldehyde
Amine
a
-Aminophosphonate
Time (h)
0.75
Yield (%)
O
OEt
H
N
P
OEt
1a
PhCHO
PhNH2
95
H
O
OEt
H
N
P
OEt
1b
1c
1d
1e
1f
4-Me–PhCHO
4-MeO–PhCHO
4-HO–PhCHO
4-Cl–PhCHO
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
PhNH2
0.5
0.75
0.5
1
95
92
95
95
90
91
H
Me
OMe
OH
O
OEt
H
P
N
OEt
H
O
OEt
H
P
N
OEt
H
O
OEt
H
P
N
OEt
H
Cl
O
OEt
H
P
N
OEt
4-NO2–PhCHO
1
H
NO2
O
OEt
H
P
MeO
HO
CHO
N
OEt
OMe
OH
1g
1
H
O
OEt
H
N
P
OEt
1h
1i
PhCH]CHCHO
PhNH2
2
2
87
80
H
O
OEt
Me
N
P
OEt
PhCHO
Ph(Me)NH
H

Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 4266–4275
4269
Table 2
Comparison of the effect of catalysts in preparation of
a
-aminophosphonate by the reaction of 4-methoxybenzaldehyde, aniline and diethylphosphite.
OEt
O
O
H
P
N
OEt
Cat.
H
PhNH2
+
+ HPO(OEt)2
H
MeO
OMe
Yield (%)
Entry
Catalyst (mol%)
Solvent
Time (h)
Ref.
1
2
3
4
5
6
7
8
9
TaCl5–SiO2 (10)
InCl3 (10)
Sulfamic acid (20)
ZrCl4 (10)
CH2Cl2
THF
–
CH3CN
CH3CN
CH3CN
–
–
–
THF
19
11
2
8.5
8.5
3.5
2.5
3
88
92
87
85
80
92
98
90
78
92
[15]
[13]
[18b]
[13]
[13]
[15]
[25]
[21]
[21]
–
AlCl3 (10)
SbCl3/Al2O3 and molecular sieves 5 Å (10)
TiO2 (20)
Al(OTf)3 (10)
Ce(OTf)4 (10)
FeCl3 (5)
4
0.75
10
electron-deficient aromatic aldehydes (2.0 mmol) and dieth-
ylphosphite (2.2 mmol) in the presence of FeCl3$THF solution
(2.0 mL, 5 mol%). The reactions progressed well at 60 ꢀC and the
desired bis(a-aminophosphonates) were produced in excellent
isolated yields (90–95%). 1,4-Phenylenediamine also reacted
successfully under similar reaction condition and the correspond-
ing bis(a-aminophosphonates) were produced in 92% in 1 h.
However, 1,2-phenylenediamine failed to react under similar
reaction conditions (Table 3).
Doxorubicin was added to individual wells of fresh cells at the same
concentrations as the positive control. Treated cells were incubated
in 37 ꢀC incubator, supplemented with 5% CO2 and 95% humidity
for 48 h (RAJI, JURKAT) to 72 h (MCF-7). In parallel, the cells were
treated with 0.6% of DMSO as negative control. MTT was added
after the incubation period and the cells were incubated for an
extra 4 h. Formazan crystals were then dissolved in 2-propanol/
DMSO/HCl (30:20:2). Absorbance was read by ELISA spectropho-
tometer (TitertekPlus, NS2 Reader, ICN Biomedical, Canada) at
570 nm.
We were also interested to prepare bis(a-aminophosphonates)
carrying a nucleoside moiety in a molecule. For this purpose,
guanosine (a nucleoside containing guanine) was reacted with
phenylene dicarboxaldehyde and diethyl phosphate under similar
reaction conditions. The reaction proceeded smoothly with the
cleavage of the sugar moiety of the nucleoside to produce the
5. Results and discussion
5.1. Molecular docking
corresponding bis(a-aminophosphonate) 3 in a moderate isolated
yield (58%) as shown in Scheme 2.
According to the data of FDEs, compound 2m had the
maximum negative FDE, after doxorubicin. Therefore, in the case
of compound 2m, the result of docking was in agreement with the
result of biological assay. The reason of the potent cytotoxic
activity of compound 2m could be explained by taking advantage
of docking results. As it is illustrated in Fig. 1, compound 2m can
be placed in the middle of the two strands of DNA double strands.
The nitrogen atom of indole in one end of the molecule can make
a hydrogen bond with the O4 atom of the Tym4 form one strand of
3. Molecular docking
The ligand was drawn in the Hyperchem 7.5. The geometry was
optimized through the molecular dynamic method AMBER and
semi-empirical method AM1. The DNA receptor structure was
extracted from Protein Data Bank (PDB code 1D12). The Autodock
software version 3.0.5 was used for the molecular docking process.
The grids were constructed around the DNA double strands. The
Lamarckian Genetic Algorithm method was used for the global
optimum binding position search. A number of 80 cycles of calcu-
lation were used in order to get a final binding position as accurate
as possible. The complex of ligand/DNA was viewed by Accelry’s
Discovery Studio Visualizer. The docking procedure was run and
the maximum negative Final Docking Energy (FDE) was calculated
(Table 4).
0
DNA. This nitrogen can also make a hydrogen bond with the O2 of
the deoxyribose of Cyt5 in the same strand of DNA (Fig. 2). At the
other end of the molecule, the nitrogen of NH can make
a hydrogen bond with O2 of Cyt5 in one strand and N2 of Gua2
from the other strand (Fig. 3). These numerous hydrogen binding
may be the reason of a probable intercalating properties and
observed cytotoxicity.
Compound 2f had IC50 ¼ 58.6
m
M for RAJI (r2 ¼ 0.967). However,
the FDE of compound 2f, that showed moderate toxicity, was less
negative than some other compounds that showed no cytotoxicity.
On the other hand, there were a number of compounds which had
a more negative FDE than 2f, but showed no cytotoxicity. Despite
the exact reason of this controversy needs more mechanism
including studies, it may be justified by limitations of docking
software, incorrect selection of the ligand’s target and effect of cell
metabolism pathways that can activate or deactivate exotic mole-
4. Biological assay
MTT assay was performed on the cell lines RAJI, JURKAT and
MCF-7 which were cultivated in RPMI 1640, enriched with 10% fetal
bovine serum (Gibco). All compounds tested were dissolved in
DMSO and subsequently diluted in the culture medium before
treatment of the cultured cells. Fresh cells were plated in 96-well
plates at a density of 104 cells/well/100
mL of the proper culture
cules. A comparison of maximum inhibition percentage of
medium and treated with the compounds at the concentrations of
0.1, 1, 10, 25, 50, 75 and 100 to maximize the precision of tests.
compounds tested at 100
Table 4.
mM vs. Final Docking Energy is shown in

4270
Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 4266–4275
Table 3
FeCl3$THF solution catalyzed synthesis of bis(
sponding phosphonates.
a
-aminophosphonates) by using a three-component system. In all the reactions, diethylphosphate is used to form the corre-
Entry
Aldehyde
Amine
Bis(a
-aminophosphonate)
Time (h)
Yield (%)
2a
PhCHO
0.75
96
2b
PhCHO
1
93
2c
PhCHO
2
90
2d
PhCHO
1
92
2e
4-CH3C6H4CHO
1
95
2f
1
94
2g
4-(CH3)2NPhCHO
1
95
2h
1.5
92

Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 4266–4275
4271
Table 3 (continued )
Entry
Aldehyde
Amine
Bis(a
-aminophosphonate)
Time (h)
Yield (%)
2i
4-NO2C6H4CHO
1.5
90
2j
PhCHO
1
93
2k
0.5
82
2l
CHOPhCHO
PhNH
0.85
88
2m
CHOPhCHO
3
68
2n
CHOPhCHO
12
53
5.2. Biological assay
were selected to cover different tumor lines and were purchased
from Pasteur Institute of Iran. The Media RPMI 1640 were used and
10% fetal calf serum was added to the media. Compounds 2b, 2c, 2d,
2f, 2g, 2h, 2i, 2k, 2l, 2m, 2n were selected to be evaluated by in vitro
cytotoxicity test.
The antitumor activity of the synthesized compounds was
measured by MTT method. Three different cell lines JURKAT (T-cell
lymphoma), RAJI (Burkit’s lymphoma) and MCF-7 (breast cancer)
Scheme 2. Formation of bis(a-aminophosphonate) starting from guanosine.

4272
Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 4266–4275
Table 4
Maximum percentage of inhibition for compound tested at 100
Final Docking Energy.
m
M, comparing to
FDEa (kcal/mol)
Entry
Inhibition (%) of cell lines
Jurkat
MCF-7
RAJI
2b
2c
2d
2f
2g
2h
2i
2k
15.75
6.84
27.98
40.11
17.8
20.05
10.66
15.55
36.79
68.39
0
10.19
0
13.95
29.15
12.7
3.5
12.16
16.63
25.4
54.2
12.7
65.47
0b
0
6.41
56.18
0.78
0
ꢁ12
ꢁ11.2
ꢁ12.2
ꢁ10.5
ꢁ10.2
ꢁ8.6
0
0
ꢁ10.1
ꢁ11.9
ꢁ12.15
ꢁ15.4
ꢁ10.5
ꢁ17.2
2l
2m
2n
27.23
64.78
64.78
66.66
Doxorubicin
82.28
a
FDE: Final Docking Energy.
The score 0 shows no inhibition of growth or stimulation of growth.
b
The MTT studies showed that the most cytotoxic compound was
2m which has an indole moiety in its structure, with IC50 ¼ 24.3
mM
for JURKAT (r2 ¼ 0.982), IC50 ¼ 45.2
m
M for RAJI (r2 ¼ 0.997) and
IC50 ¼ 67.5
IC50 ¼ 58.6
m
m
M
for MCF-7 (r2 ¼ 0.999). Compound 2f showed
M for RAJI (r2 ¼ 0.967). All other tested compounds
showed IC50 > 100 mM. The maximum inhibition percentage of the
compounds at 100 mM concentration is presented in Table 4.
0
Fig. 2. The hydrogen bonding of O4 of thymidine 4 (Tym4) and O2 of cytosine 5 (Cyt5)
of DNA with the indole ring of compound 2m. The indole ring is scaled up to clarify the
picture. The yellow tubes show the backbone of DNA double strands. (For interpre-
tation of the references to colour in this figure legend, the reader is referred to the web
version of this article.)
6. Conclusion
Bis-a-aminophosphonates are valuable compounds to be inves-
tigated as bioactive molecules and pharmacological agents. The
amine and phosphonate substitutions can interact with enzymes,
DNA and receptors to start a pharmacological effect. The synthesis of
bis(a-aminophosphonates) is hardly reported in literature.
In this study, the non-hygroscopic and easy handling solution of
FeCl3 in THF has been introduced as a highly efficient bench top
catalyst for one-pot synthesis of a-aminophosphonates in excellent
yields via a three-component coupling reaction of aldehydes,
amines, and diethylphosphite. We have also applied this method for
the preparation of biologically active bis(a-aminophosphonates) in
excellent yields.
The biological assays showed that indole containing bis(
a-ami-
nophosphonates) had high to moderate cytotoxic activity.
a
Although the FDE for the most cytotoxic compound 2m was of the
most negative value, there is no correlation between FDE and
cytotoxicity.
7. Experimental
All solvents and reagents were purchased from Sigma or Merck
Chemical Companies. The products were purified by column
chromatography techniques. NMR spectra were recorded on
a Brucker Avance DPX 500 MHZ and 250 MHZ instrument. FT-IR
spectroscopy was performed using a Shimadzu 8100.
7.1. General procedure to synthesis of tetraethyl[4,40-methylene
bis(4,1-phenylene) bis(azanediyl)] bis(phenylmethylene)
diphosphonate (1a)
To a mixture of aldehyde (2 mmol), diamine (1 mmol), and
diethylphosphite (2.2 mmol) was added FeCl3$THF (2.0 mL,
5.0 mol%) and stirred at 60 ꢀC for the appropriate reaction time.
After completion of the reaction (TLC), EtOAc (10 mL) was added to
Fig. 1. Compounds 2m can intercalate into DNA double strand so that one of the indole
ring makes a distance in sequential bases.

Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 4266–4275
4273
7.1.3. Tetraethyl[4,40-carbonyl bis(4,1-phenylene) bis(azanediyl)]
bis(phenylmethylene) diphosphonate (2b)
M.p. ¼175–176 ꢀC. Elemental analysis for C37H48N2O10P2
requires C: 6.37%, H: 63.25%, found: C: 62.77%; H: 6.34%; 1H NMR
(CDCl3, TMS, 250 MHz): 7.56 (d, 4H, J ¼ 8.7 Hz, Ar-H), 7.29–7.47 (d,
4H, J ¼ 8.7 Hz, Ar-H), 6.57 (m, 10H, Ar-H), 5.51 (b, 2H, NH), 4.86 (d,
2H, 2JPH ¼ 24.2 Hz, CHP), 4.07–4.15 (m, 4H, CH2CH3), 3.90–3.94 (m,
2H, CH2CH3), 3.62–3.69 (m, 2H, CH2CH3), 1.10 (t, 6H, J ¼ 7 Hz, CH3),
1.29 (t, 6H, J ¼ 7 Hz, CH3) ppm. 13C NMR (CDCl3, TMS, 62.9 MHz):
193.81, 149.62, 149.40, 135.25, 128.80, 128.76, 127.82, 127.73, 112.52,
2
63.30 (d, JPC ¼ 27.2 Hz), 56.78, 54.39 (JCP ¼ 149.3 Hz), 16.22 (d,
3JPC ¼ 5.7 Hz), 16.13 (d, 3JPC ¼ 5.7 Hz) ppm; IR (KBr): 3278.8, 2973.9,
1612.4, 1596.2, 1527, 1234.3, 1029.8 cmꢁ1
.
7.1.4. Tetraethyl[4,40-oxy bis(4,1-phenylene) bis(azanediyl)]
bis(phenylmethylene) diphosphonate (2c)
M.p. ¼115–116 ꢀC. Elemental analysis for C34H42N2O7P2 requires
C: 62.57%, H: 6.49%, found: C: 62.48%; H: 6.44%; 1H NMR (CDCl3,
TMS, 250 MHz): 7.47–7.43 (m, 4H, C6H5), 7.30–7.19 (m, 6H, C6H5),
6.65 (4H, d, JCH ¼ 8.9 Hz, C6H4), 6.50 (4H, d, JCH ¼ 8.9 Hz, C6H4), 4.90
1
(b, 2H, NH), 4.69 (2H, d, JPH ¼ 24 Hz, CH), 4.13–4.06 (m, 4H,
CH2CH3), 3.92–3.85 (m, 2H, CH2CH3), 3.66–3.63 (m, 2H, CH2CH3),
1.24 (t, 6H, J ¼ 6.88 Hz, CH2CH3), 1.07 (t, 6H, J ¼ 6.88 Hz, CH2CH3)
ppm; 13C NMR (CDCl3, TMS, 62.9 MHz): 150.2 (d, 3JPC ¼ 16.6), 142.1,
2
Fig. 3. The hydrogen bonding of N2 of guanine 2 (Gua2) and O2 of cytosine 5 (Cyt5,
upper) of DNA with the NH of compound 2m. The yellow tubes show the backbone of
DNA double strands. (For interpretation of the references to colour in this figure
legend, the reader is referred to the web version of this article.)
141.9, 136.0 (d, JPC ¼ 2.3), 128.4, 127.3, 119.2, 116.3, 63.2 (d,
2
2JPC ¼ 6.9), 63.1 (d, JPC ¼ 6.9), 56.5 (d, JCP ¼ 151.0 Hz), 16.4 (d,
3JPC ¼ 5.7), 16.1 (d, 3JPC ¼ 5.7) ppm; IR (KBr): 3294, 2985, 1604, 1496,
1226, 1026 cmꢁ1
.
the mixture. The mixture was washed with H2O (10 mL). The
organic phase was separated and dried over anhydrous Na2SO4. The
solvent was evaporated in vacuo and the resulting crude material
was purified by chromatography on a short column of silica gel
(EtOAc:petroleum ether, 1:3) and then recrystallized from petro-
7.1.5. Tetraethyl[4,40-methylene bis(4,1-phenylene) bis(azanediyl)]
bis(phenylmethylene) diphosphonate (2d)
M.p. ¼151–152 ꢀC. Elemental analysis for C35H44N2O6P2 requires
C: 64.61%, H: 6.82%, found: C: 64.51%; H: 6.80%; 1H NMR (CDCl3,
TMS, 250 MHz): 7.46–7.43 (4H, m, C6H5), 7.31–7.20 (m, 6H, C6H5),
6.83 (4H, d, JCH ¼ 8.3 Hz, C6H4), 6.48 (4H, d, JCH ¼ 8.3 Hz, C6H4), 4.76
leum benzine/dichloromethane (4:1) to afford the pure bis(a-
aminophosphonates). The procedure for the preparation of
compounds 2l, 2m and 2n is similar to the above protocol with the
ratio of dialdehyde (1.0 mmol)/amine (2.0 mmol)/diethyl phos-
phate (2.2 mmol)/FeCl3$THF (2.0 mL, 5.0 mol%) for the appropriate
reaction times.
1
(b, 2H, NH), 4.71 (2H, d, JPH ¼ 24.2 Hz, CH), 4.13–4.04 (m, 4H,
CH2CH3), 3.92–3.85 (m, 2H, CH2CH3), 3.66–3.61 (m, 2H, CH2CH3),
3.62 (2H, s, CH2), 1.26 (t, 6H, J ¼ 6.9 Hz, CH2CH3), 1.07 (t, 6H,
J ¼ 6.9 Hz, CH2CH3) ppm; 13C NMR (CDCl3, TMS, 62.9 MHz): 144.4 (d,
3JPC ¼ 15.1), 136.1, 131.2, 128.9, 128.5, 128.2, 113.9, 63.23 (d,
2
2JPC ¼ 6.9), 63.2 (d, JPC ¼ 7.0), 56.2 (d, JCP ¼ 150.3 Hz), 40.1, 16.4 (d,
7.1.1. Diethylmethyl(phenyl) amino-phenylmethylphosphonate (1i)
Elemental analysis for C18H24NO3P requires C: 64.85, H: 7.26%,
found: C: 64.78%; H: 7.24%; 1H NMR (250 MHz, CDCl3, TMS): 7.5 (d,
2H, J ¼ 6.3 Hz, C6H5), 7.30–7.20 (m, 5H, C6H5), 6.87 (d, 2H, J ¼ 8.1 Hz,
C6H5), 6.77 (t, 1H, J ¼ 7.1 Hz, C6H5), 5.33 (1H, d, 1JPH ¼ 24.8 Hz, CH),
4.24–3.92 (m, 4H, CH2CH3), 2.94 (s, 3H, CH3), 1.22–1.16 (m, 6H,
CH2CH3) ppm; 13C NMR (62.9 MHz, CDCl3, TMS): 150.2 (d,
3JPC ¼ 7.3 Hz), 134.4, 130.2, 129.6, 129.2, 128.9, 128.8, 128.5, 127.9,
3JPC ¼ 6.3),16.2 (d, 3JPC ¼ 5.8) ppm; 31P NMR (DMSO, TMS, 200 MHz):
23.46 ppm; IR (KBr): 3298, 2981, 1612, 1517, 1242, 1027 cmꢁ1
.
7.1.6. Tetraethyl[4,40-methylene bis(4,1-phenylene) bis(azanediyl)]
bis(p-tolylmethylene)diphosphonate (2e)
Elemental analysis for C37H48N2O6P2 requires C: 65.47%, H:
7.13%, found: C: 65.42%; H: 7.11%; 1H NMR (CDCl3, TMS): 7.33 (d, 4H,
JCH ¼ 7.9 Hz, p-Me-C6H4), 7.10 (d, 4H, JCH ¼ 7.9 Hz, p-Me-C6H4), 6.84
(4H, d, JCH ¼ 8.4 Hz, C6H4), 6.48 (4H, d, JCH ¼ 8.4 Hz, C6H4), 4.67 (b,
2H, NH), 4.67 (2H, d, 1JPH ¼ 24 Hz, CH), 4.13–4.05 (m, 4H, CH2CH3),
3.95–3.88 (m, 2H, CH2CH3), 3.69–3.63 (m, 2H, CH2CH3), 3.63 (s, 2H,
CH2), 2.29 (s, 3H, CH3), 1.26 (t, 6H, J ¼ 6.88 Hz, CH2CH3), 1.11 (t, 6H,
J ¼ 6.88 Hz, CH2CH3) ppm; 13C NMR (CDCl3, TMS): 144.4 (d,
3JPC ¼ 15.2), 137.5, 132.8, 131.6, 129.3, 127.7, 113.9, 63.24
(d, 2JPC ¼ 7.0), 63.2 (d, 2JPC ¼ 7.0), 55.9 (d, JCP ¼ 151.2 Hz), 40.0, 21.0,
2
3
118.0, 113.4, 63.1 (d, JCP ¼ 6.4 Hz), 62.1 (d, JPC ¼ 7.1 Hz), 61.8 (d,
1JCP ¼ 159.8 Hz), 16.5 (d, JPC ¼ 5.5 Hz), 16.3 (d, JPC ¼ 5.7 Hz) ppm;
3
3
IR (KBr): 3294, 2970, 1612, 1242, 1027 cmꢁ1
.
7.1.2. Tetraethyl (1,4-phenylene bis(azanediyl))
bis(phenylmethylene) diphosphonate (2a)
Elemental analysis for C28H38N2O6P2 requires C: 59.99%, H:
6.83%, found: C: 60.02%; H: 6.79%; 1H NMR (CDCl3, TMS): 7.47–7.39
(m, 4H, C6H5), 7.31–7.22 (m, 6H, C6H5), 6.41 (s, 4H, C6H4), 4.65 (b,
2H, NH), 4.6 (2H, d, 1JPH ¼ 24 Hz, CH), 4.12–4.05 (m, 4H, CH2CH3),
3.92–3.3.85 (m, 2H, CH2CH3), 3.70–3.63 (m, 2H, CH2CH3), 1.24 (t,
6H, J ¼ 7.1 Hz, CH2CH3), 1.08 (t, 6H, J ¼ 7.1 Hz, CH2CH3) ppm; 13C
NMR (CDCl3, TMS): 139.1 (d, 3JPC ¼ 15.9 Hz),136.1,130.0,127.8,127.7,
3
3
16.2 (d, JPC ¼ 5.8), 16.4 (d, JPC ¼ 5.8) ppm; IR: 3294, 2980, 1612,
1517, 1242, 1027 cmꢁ1
.
7.1.7. Tetraethyl[4,40-methylene bis(4,1-phenylene)
bis(azanediyl)]bis[(3-hydroxy-4-methoxyphenyl)-
methylene]diphosphonate (2f)
2
2
115.4, 63.2 (d, JPC ¼ 7.5 Hz), 63.1 (d, JPC ¼ 7.2 Hz), 57.3 (d,
M.p. ¼158–159 ꢀC. Elemental analysis for C37H48N2O10P2
JCP ¼ 150.3 Hz), 16.4 (d, 3JPC ¼ 5.8 Hz), 16.1 (d, 3JPC ¼ 5.8 Hz) ppm; IR
requires C: 59.83%, H: 6.51%, found: C: 59.69%; H: 6.38%; 1H NMR
(KBr): 3294, 2970, 1612, 1242, 1027 cmꢁ1
.

4274
Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 4266–4275
(CDCl3, TMS, 250 MHz): 6.97–6.86 (m, 10H, Ar-H þ 1H, OH), 6.51–
6.47 (d, 4H, JCH ¼ 8.3 Hz, C6H4 þ1H, OH), 4.61 (b, 2H, NH), 4.61
J ¼ 6.88 Hz, CH2CH3) ppm; 13C NMR (CDCl3, TMS): 150.0 (d,
3JPC ¼ 13.7), 134.9, 130.9, 128.9, 128.7, 128.2, 127.8, 113.0, 63.6 (d,
2
2
(2H, d, JPH ¼ 23.7 Hz, CH), 4.13–4.08 (m, 4H, CH2CH3), 3.95–3.89
2JPC ¼ 6.7), 63.3 (d, JPC ¼ 6.7), 56.6 (d, JCP ¼ 151.5 Hz), 16.3 (d,
3
(m, 2H, CH2CH3), 3.84 (s, 6H, OCH3), 3.70–3.65 (m, 2H, CH2CH3),
3.66 (s, 2H, CH2), 1.27 (t, 6H, J ¼ 6.88 Hz, CH2CH3), 1.13 (t, 6H,
J ¼ 6.88 Hz, CH2CH3) ppm; 13C NMR (CDCl3, TMS, 62.9 MHz):
146.9, 146.2, 144.5 (d, JCP ¼ 150.9 Hz), 131.5, 129.3, 128.5, 119.2 (d,
3JPC ¼ 5.6), 16.1 (d, JPC ¼ 5.6) ppm; 31P NMR (DMSO, TMS,
200 MHz): 22.90 ppm; IR: 3248, 2978, 1594.3, 1506.7, 1287, 1237,
1100, 1029.8 cmꢁ1
.
2
2JPC ¼ 6.2), 114.6, 113.9, 111.1, 63.25 (d, JPC ¼ 6.6), 63.23 (d,
7.1.12. Tetraethyl[4,40-sulfonyl bis(4,1-phenylene) bis(azanediyl)]
bis((4-hydroxy-3-methoxyphenyl)methylene)diphosphonate (2k)
M.p. ¼158–159 ꢀC. Elemental analysis for C34H42N2O8P2S
requires C: 54.54%, H: 5.85%, found: C: 54.12%; H: 5.83%; 1H NMR
(CDCl3, TMS, 250 MHz): 7.575 (d, 4H, J ¼ 8.7 Hz, Ar-H), 6.824–6.905
(m, 6H, Ar-H), 6.572 (d, 4H, J ¼ 8.7 Hz, Ar-H), 5.332 (b, 2H, NH),
4.8656 (d, JPH ¼ 23.8 Hz, 2H, CHP), 4.033–4.129 (m, 4H, CH2CH3),
3.9069–3.9474 (m, 2H, CH2CH3), 3.621–3.697 (m, 2H, CH2CH3),
1.2902 (t, 6H, J ¼ 7 Hz, CH3), 1.1047 (t, 6H, J ¼ 7 Hz, CH3) ppm. 13C
NMR (CDCl3, TMS, 62.9 MHz): 147.7, 131.0, 129.0, 126.2, 120.9, 114.6,
3
2JPC ¼ 6.7), 55.7, 55.6 (d, JCP ¼ 153.0 Hz), 40.0, 16.3 (d, JPC ¼ 5.9),
3
16.1 (d, JPC ¼ 5.7) ppm; IR (KBr): 3297, 3128, 2979, 1608, 1505,
1234, 1147, 1030 cmꢁ1
.
7.1.8. Tetraethyl[4,40-methylene bis(4,1-phenylene) bis-(azanediyl)]
bis[(4-(dimethylamino)phenyl)methylene]diphosphonate(2g)
M.p. ¼150–151 ꢀC. Elemental analysis for C37H48N2O10P2
requires C: 63.57%, H: 7.39%, found: C: 63.09%; H: 7.35%; 1H NMR
(CDCl3, TMS, 250 MHz): 7.27 (d, 4H, J ¼ 8.7 Hz, Ar-H), 6.85 (d, 4H,
J ¼ 8.4 Hz, Ar-H), 6.68 (d, 4H, J ¼ 8.7 Hz, Ar-H), 6.49 (d, 4H,
2
113.0, 110.0, 63.414 (d, JPC ¼ 6.9 Hz), 55.182 (d, JCP ¼ 151.75 Hz),
2
J ¼ 8.4 Hz, Ar-H), 4.52–4.63 (b, 2H, NH), 4.60 (d, 2H, JPH ¼ 25 Hz,
55.9, 16.478 (d, 3JPC ¼ 5.1 Hz), 16.213 (d, 3JPC ¼ 5.1 Hz) ppm; IR (KBr):
CHP), 4.03–4.12 (m, 4H, CH2CH3), 3.87–3.94 (m, 2H, CH2CH3), 3.63–
3.68 (m, 2H, CH2CH3), 3.65 (s, 2H, CH2), 2.91 (s, 12H, NCH3), 1.26 (t,
6H, J ¼ 7 Hz, CH2CH3), 1.12 (t, 6H, J ¼ 7 Hz, CH2CH3); 13C NMR
(CDCl3, TMS, 62.9 MHz): 131.4, 129.3, 128.6, 128.5, 123.2, 112.5,
3248, 2978, 1594, 1506, 1287, 1237, 1100, 1029 cmꢁ1
.
7.1.13. Tetraethyl-1,4-phenylenebis[(phenylamino)
methylene]diphosphonate (2l)
2
112.5, 113.9, 63.0 (d, JP–C ¼ 3.75 Hz), 55.5 (d, JCP ¼ 152 Hz), 40.5,
M.p. ¼159–160 ꢀC. Elemental analysis for C28H38N2O6P2
requires C: 59.99%, H: 6.83%, found: C: 59.63%; H: 6.80%; 1H NMR
(CDCl3, TMS, 250 MHz): 7.40 (s, 4H, C6H4), 7.22–7.15 (m, 4H, C6H5),
6.87–6.75 (m, 2H, C6H5), 6.70–6.65 (m, 4H, C6H5), 4.79 (b, 2H, NH),
4.78 (d, J ¼ 23.3 Hz, 2H, CH), 4.18–3.88 (m, 4H, CH2CH3), 3.91–3.76
(m, 2H, CH2CH3), 3.68–3.55 (m, 2H, CH2CH3), 1.04 (t, J ¼ 7.0 Hz, 6H,
CH2CH3), 0.93 (t, J ¼ 7.0 Hz, 6H, CH2CH3), 13C NMR (CDCl3, TMS,
62.9 MHz): 135.8, 129.1, 128.2, 118.4, 113.9, 63.3, 55.8 (d,
JPC ¼ 150.1 Hz), 16.4 ppm; IR (KBr): 3294, 2978, 1605, 1497, 1242,
3
3
40.0, 16.5 (d, JPC ¼ 5.75 Hz), 16.3 (d, JPC ¼ 5.75 Hz) ppm. IR (KBr):
3263, 2987, 1613, 1516, 1516, 1227, 1329, 1029 cmꢁ1
.
7.1.9. Tetraethyl(4,40-methylene bis(4,1-phenylene)) bis(azanediyl)
bis((3,4,5-trimethoxyphenyl)methylene)diphosphonate (2h)
M.p. ¼ 72–73 ꢀC. Elemental analysis for C37H48N2O10P2 requires
C: 59.13%, H: 7.02%, found: C: 58.68%; H: 6.99%; 1H NMR (CDCl3,
TMS, 250 MHz): 6.904 (d, 4H, J ¼ 8.25, Ar-H), 6.714 (s, 4H, Ar-H),
2
6.527 (d, 4H, J ¼ 8.25 Hz, Ar-H), 4.598 (d, 2H, JPH ¼ 24.1 Hz, CHP),
1027 cmꢁ1
.
4.053–4.135 (m, 4H, OCH2CH3), 3.915–3.984 (m, 2H, CH2CH3),
3.687–3.765 (m, 2H, CH2CH3), 3.826 (s, 18H, OCH3), 3.704 (s, 2H,
7.1.14. Tetraethyl-1,4-phenylene bis((2-(1H-indolyl)
ethylamino)methylene)diphosphonate (2m)
CH2), 1.275 (t, 6H, J ¼ 7 Hz, CH3), 1.141 (t, 6H, J ¼ 7 Hz, CH3) ppm. 13
C
NMR (CDCl3, TMS, 62.9 MHz): 153.2, 144.7, 131.8, 131.7, 129.4, 113.9,
Yellow oily liquid. Elemental analysis for C28H38N2O6P2 requires
C: 62.24%, H: 6.96%, found: C: 61.77%; H: 6.93%; 1H NMR (CDCl3,
TMS, 500 MHz): 8.57 (d, JNH ¼ 7.5 Hz, 2H, Ar-NH), 6.79–7.54 (m,
14H, Ar-NH), 4.32 (dd, 2H, J ¼ 19.5, J ¼ 20.1 Hz, CHP), 4.01–4.10 (m,
4H, CH2CH3), 3.92–3.98 (m, 2H, CH2CH3), 3.798–3.834 (m, 2H,
CH2CH3), 2.88–2.94 (m, 8H, CH2CH2N), 2.085 (b, 2H, CH2NH), 1.26–
1.20 (m, 6H, CH3), 1.1 (m, 6H, CH3). 13C NMR (CDCl3, TMS, 125 MHz):
136.8, 128.9, 127.8, 127.5, 122.5, 122.116, 119.4, 119.0, 113.5, 111.6,
63.3 (d, JPC ¼ 6.75 Hz), 61.1 (d, JCP ¼ 151.2 Hz) 48.479, 25.8,
16.8 ppm; 31P NMR (DMSO, TMS, 200 MHz): 24.02 ppm; IR (KBr):
3118.4, 2973.2, 1224.7, 1018.3.
2
104.7, 104.7, 63.2 (d, JPC ¼ 4.4 Hz, CH2CH), 56.6 (d, JCP ¼ 187.2 Hz),
56.1, 40.1,16.4 (d, 3JPC ¼ 5.8 Hz),16.2 (d, 3JPC ¼ 5.8 Hz) ppm; 31P NMR
(DMSO, TMS, 200 MHz): 23.46 ppm; IR (KBr): 3263.5, 2973.2,
1594.2, 1477.4, 1527, 1228.1, 1234.4, 1029.8 cmꢁ1
.
7.1.10. Tetraethyl[4,40-methylene bis(4,1-phenylene) bis(azanediyl])
bis[(4-nitrophenyl)methylene]diphosphonate (2i)
M.p. ¼184–185 ꢀC. Elemental analysis for C35H42N4O10P2
requires C: 56.76%, H: 5.72%, found: C: 56.71%; H: 5.70%; 1H NMR
(CDCl3, TMS, 250 MHz): 8.18 (d, 4H, JCH ¼ 8.2 Hz, p-NO2–C6H4), 7.64
(d, 4H, JCH ¼ 8.18 Hz, p-NO2–C6H4), 6.86 (4H, d, JCH ¼ 8.4 Hz, C6H4),
6.42 (4H, d, JCH ¼ 8.4 Hz, C6H4), 4.80 (2H, d, 2JPH ¼ 25.3 Hz, CH), 4.75
(b, 2H, NH), 4.15–3.85 (m, 8H, CH2CH3), 3.65 (s, 2H, CH2), 1.28 (t, 6H,
J ¼ 6.88 Hz, CH2CH3), 1.17 (t, 6H, J ¼ 6.88 Hz, CH2CH3) ppm; 13C NMR
7.1.15. Tetraethyl-1,4-phenylene bis[(6-oxo-6,7-dihydro-1H-purin-
2yl-amino)methylene]diphosphonite (2n)
M.p. ¼ 73–74 ꢀC. Elemental analysis for C26H34N10O8P2 requires
C: 46.16%, H: 5.07%, found: C: 45.81%, H: 5.05%; 1H NMR (CDCl3,
TMS, 500 MHz): 9.98 (s, 2H, NH), 7.84 (s, 2H, NH), 7.83 (s, 2H), 7.63
(d, 4H, J ¼ 6.7 Hz, C6H4), 5.45 (b, 2H, NH), 5.10 (d, 2H, JPH ¼ 12.7 Hz,
CH), 4.08–4.00 (m, 8H, CH2CH3), 1.24–1.17 (m, 12H, CH2CH3) ppm;
13C NMR (CDCl3, TMS, 125 MHz): 192.5, 144.4, 136.2, 129.9, 128.00,
3
(CDCl3, TMS, 62.9 MHz): 147.5, 144.1 (d, JPC ¼ 3.1), 143.7 (d,
2JPC ¼ 14.6), 132.2, 131.6, 129.6, 128.7, 128.6, 123.7, 113.9, 63.7 (d,
2JPC ¼ 7.0), 63.4 (d, 2JPC ¼ 6.8), 56.1 (d, JCP ¼ 148.2 Hz), 40.0, 21.0, 16.4
3
3
(d, JPC ¼ 5.7), 16.2 (d, JPC ¼ 5.7) ppm; IR (KBr): 3290, 2979, 1610,
1514, 1344, 1234, 1029 cmꢁ1
.
2
127.9, 70.8 (d, JCP ¼ 157.8 Hz, CH), 64.2 (d, JPC ¼ 7.1 Hz), 63.6
2
3
3
7.1.11. Tetraethyl[4,40-sulfonyl bis(4,1-phenylene) bis(azanediyl)]
bis(phenylmethylene)diphosphonate (2j)
(d, JPC ¼ 7.6 Hz), 16.8 (d, JPC ¼ 4.7 Hz), 16.7 (d, JPC ¼ 5.0 Hz) ppm;
IR (KBr): 3227, 2973, 1695, 1594, 1232, 1029 cmꢁ1
.
Elemental analysis for C34H42N2O8P2S requires C: 58.28%, H:
6.04%, found: C: 58.23%; H: 6.01%; 1H NMR (CDCl3, TMS): 7.54 (4H,
d, JCH ¼ 7.8 Hz, C6H4), 7.41–7.26 (m, 10H, C6H5), 6.56 (4H, d,
JCH ¼ 7.8 Hz, C6H4), 5.68 (b, 2H, NH), 4.69 (2H, d, 1JPH ¼ 24 Hz, CH),
4.13–4.04 (m, 4H, CH2CH3), 3.92–3.84 (m, 2H, CH2CH3), 3.63–3.55
(m, 2H, CH2CH3), 1.24 (t, 6H, J ¼ 6.88 Hz, CH2CH3), 1.07 (t, 6H,
Acknowledgement
This work was supported by Shiraz University of Medical
Sciences and Shiraz Institute for Cancer Research.

Z. Rezaei et al. / European Journal of Medicinal Chemistry 44 (2009) 4266–4275
4275
[29] (a) Ambica S. Kumar, S.C. Taneja, M.S. Hundal, K.K. Kapoor, Tetrahedron Lett.
49 (2008) 2208–2212;
References
(b) S. Chandrasekhar, S.J. Prakash, V. Jagadeshwar, Ch. Narsihmulu, Tetrahe-
dron Lett. 42 (2001) 5561–5563.
[30] (a) M. Tajbakhsh, A. Heydari, H. Alinezhad, M. Ghanei, S. Khaksar, Synthesis
(2008) 352–354;
[1] R. Engel, Chem. Rev. 77 (1977) 349.
[2] J. Hiratake, J. Oda, Biosci. Biotechnol. Biochem. 61 (1997) 211.
[3] K.A. Schug, W. Lindner, Chem. Rev. 105 (2005) 64.
[4] K. Moonen, I. Laureyn, C.V. Stevens, Chem. Rev. 104 (2004) 6177.
[5] F. Palacios, C. Alonso, J.M. de los Santos, Curr. Org. Chem. 8 (2004) 1481.
[6] P. Kafarski, B. Lejczak, Phosphorus, Sulfur Silicon Relat. Elem. 63 (1991) 1993.
[7] M.C. Allen, W. Fuher, B. Tuck, R. Wade, J.M. Wood, J. Med. Chem. 32 (1989)
1652.
(b) J.S. Yadav, B.V.S. Reddy, Ch. Madan, Synlett (2001) 1131–1133.
[31] B. Kaboudin, R. Nazari, Tetrahedron Lett. 42 (2001) 8211–8213.
[32] (a) T. Akiyama, M. Sanada, K. Fuchibe, Synlett (2003) 1463–1464;
(b) S.D. Mitragotri, D.M. Pore, U.V. Desai, P.P. Wadgaonkar, Catal. Commun. 9
(2008) 1822–1826.
[33] K. Manabe, S. Kobayashi, Chem. Commun. (2000) 669–670.
[34] H.-J. Ha, G.-S. Nam, Synth. Commun. 22 (1992) 1143–1149.
[35] H. Firouzabadi, N. Iranpoor, S. Sobhani, Synthesis (2004) 2692–2696.
[36] S. Bhagat, A.K. Chakraborti, J. Org. Chem. 72 (2007) 1263–1270.
[37] H. Firouzabadi, M. Jafarpour, J. Iran. Chem. Soc. 5 (2008) 159–183.
[38] S. Bhagat, A.K. Chakraborti, J. Org. Chem. 73 (2008) 6029–6032 and the
references cited therein.
[8] E.K. Baylis, C.D. Campbell, J.G. Dingwall, J. Chem. Soc., Perkin Trans. 1 (1984)
2845.
[9] S.J. Benkovic, R. Hirschmam, Tetrahedron Lett. 35 (1994) 6856.
[10] C.H. Hassal, E.F. Hahn, Antibiotics, vol. VI, Springer, Berlin, 1983, pp. 1–11.
[11] G.F. Makhaeva, V.V. Malygin, A.Yu. Aksinenko, V.B. Sokolov, N.N. Strakhova,
A.N. Rasdolsky, R.J. Richardson, Corresponding Member of RAS I.V. Martynov,
Dockl Biochem. Biophys. 400 (2005) 92–95.
[12] W. Pan, C. Ansiaux, S.P. Vincent, Tetrahedron Lett. 48 (2007) 4353–4356.
[13] M.J. Bloemink, J.J.H. Diederen, J.P. Dorenbos, R.J. Heetebrij, B.K. Keppler,
J. Reedijk, Eur. J. Inorg. Chem. 10 (1999) 1655–1657.
[39] M. Hosseini-Sarvari, Tetrahedron 61 (2008) 5459–5466.
[40] (a) J. Christoffers, J. Chem. Soc., Perkin Trans. 1 (1997) 3141–3149;
(b) J. Christoffers, H. Oertling, Tetrahedron 56 (2000) 1339–1344;
(c) J. Lu, H. Ma, Synlett (2000) 63–64;
[14] L. Jin, B. Song, G. Zhang, R. Xu, S. Zhang, X. Gao, D. Hu, S. Yang, Bioorg. Med.
Chem. Lett. 16 (2006) 1537–1543.
(d) C. Masson, J. Soto, M. Bessodes, Synlett (2000) 1281–1282;
(e) A.M. Chibiryaev, N.D. Kimpe, A.V. Tkachev, Tetrahedron Lett. 41 (2000)
8011–8013;
(f) Z.-p. Zhan, J.-l. Yu, H.-j. Liu, Y.-y. Cui, R.-f. Yang, W.-z. Yang, J.-p. Li, J. Org.
Chem. 71 (2006) 8298–8301;
(g) R. Li, S.R. Wang, W. Lu, Org. Lett. 9 (2007) 2219–2222;
(h) J.S. Yadav, B.V. Subba Reddy, K. Praneeth, Tetrahedron Lett. 49 (2007) 199–
202;
(i) J.S. Yadav, B.V.S. Reddy, A.D. Krishna, Ch. Suresh Reddy, A.V. Narsaiah,
Synthesis (2005) 961–964.
[15] X. Rao, Z. Song, L. He, Heteroat. Chem. 19 (2008) 512–516.
[16] I.P. Beletskaya, M.M. Kabachnik, Mendeleev Commun. 18 (2008) 113–120.
[17] E.K. Fields, J. Am. Chem. Soc. 74 (1952) 1528–1531.
[18] (a) D. Seebach, R. Charczuk, C. Gerber, P. Renaud, Helv. Chim. Acta 72 (1989)
401–425;
(b) H. Kuntz, S. Laschat, Synthesis (1992) 90–95;
(c) S. Shatzmiller, B.-Z. Dolitzky, R. Meirovich, R. Neidlein, C. Weik, Liebigs Ann.
Chem. (1991) 161–164;
(d) A.B. Smith III, K.M. Yager, C.M. Taylor, J. Am. Chem. Soc. 117 (1995) 10879–
10888.
[41] (a) H. Firouzabadi, N. Iranpoor, S. Sobhani, Tetrahedron Lett. 43 (2002) 3653–
3655;
[19] T. Yokommatsu, S. Shibuya, Tetrahedron: Asymmetry 3 (1992) 377–380.
[20] (a) S. Hanessian, Y.L. Bennani, Synthesis (1994) 1272–1274;
(b) U. Schmidt, G. Oehme, H. Kraus, Synth. Commun. 26 (1996) 777–781.
[21] U. Scho¨llkopf, I. Hoppe, A. Thiele, Liebigs Ann. Chem. (1985) 555–559.
[22] M. Sawamura, Y. Ito, T. Hayashi, Tetrahedron Lett. 30 (1989) 2247–2250.
[23] D.Y. Kim, D.Y. Rhie, Tetrahedron 53 (1997) 13603–13608.
[24] I.M. Lefebvre, S.A. Evans Jr., J. Org. Chem. 62 (1997) 7532–7533.
[25] (a) A. Heydari, A. Karimian, J. Ipaktschi, Tetrahedron Lett. 39 (1998)
6729–6732;
(b) R. Yang, R. Zhao, L. Zhao, L. Yun, H. Wang, Synthesis (2003) 887–893.
[26] (a) M.R. Saidi, N. Azizi, Synlett (2002) 1347–1349;
(b) N. Azizi, F. Rajabi, M.R. Saidi, Tetrahedron Lett. 45 (2004) 9233–9236;
(c) N. Azizi, M.R. Saidi, Tetrahedron 59 (2003) 5329–5332;
(d) N. Azizi, M.R. Saidi, Eur. J. Org. Chem. 23 (2003) 4630–4633.
[27] (a) B.C. Ranu, A. Hajra, U. Jana, Org. Lett. 1 (1999) 1141–1143;
(b) A. Manjula, B.V. Rao, P. Neelakantan, Synth. Commun. 33 (2003)
2963–2969.
(b) H. Firouzabadi, N. Iranpoor, S. Sobhani, Tetrahedron 60 (2004) 203–210;
(c) H. Firouzabadi, N. Iranpoor, S. Sobhani, S. Ghassamipour, Synthesis (2005)
595–599;
(d) H. Firouzabadi, N. Iranpoor, S. Sobhani, Z. Amoozgar, Synthesis (2004) 295–
297.
[42] WHO official site, http://www.who.int/mediacentre/factsheets/fs297/en.
[43] M. Kontoyianni, L.M. McClellan, G.S. Sokol, J. Med. Chem. 47 (2004) 558–565.
[44] T.J.A. Ewing, S. Makino, A.G. Skillman, I.D. Kuntz, J. Comput. Aided Mol. Des. 15
(2001) 411–428.
[45] G.M. Morris, D.S. Doodsell, R.S. Holliday, R. Huey, W.E. Hart, R.K. Belew,
A.J. Olson, J. Comput. Chem. 19 (1998) 1639–1662.
[46] Z. Hu, S. Wang, W.M. Southerland, ACS Division of Chemical Information Final
Program, in: 228th ACS National Meeting, Philadelphia, PA, August 2004, pp.
22–26.
[47] R. Wang, Y. Lu, S. Wang, J. Med. Chem. 46 (2003) 2287–2303.
[48] R.C. Jackson, Curr. Opin. Biotechnol. 6 (1995) 646–651.
[28] C. Qian, T. Huang, J. Org. Chem. 63 (1998) 4125–4128.