Organotin(IV) compounds derived from ibuprofen and cinnamic acids, an alternative into design of anti-inflammatory by the cyclooxygenases (COX-1 and COX-2) pathway

Article abstract of DOI:10.1016/j.jorganchem.2018.02.049

New tributyl-, dibutyl- and diphenyl-tin(IV) complexes derived from ibuprofen and cinnamic acids were synthesized. All compounds were structurally characterized by FT-IR, multinuclear ¹H, ¹³C, ¹⁹F and ¹¹⁹Sn NMR and corroborated by 2D spectra. The NMR data in CDCl₃ revealed several hexacoordinated compounds with octahedral geometry. Moreover, in DMSO-d₆ some of these complexes switched to heptacoordination with a pentagonal-bipyramidal geometry due to the inclusion of a solvent's molecule; their ¹¹⁹Sn signals moved up field by around 58 ppm compared to their chemical shifts in non-coordinated solvent CDCl₃. The structural results were supported by Density Functional Theory (DFT) computational calculations. In addition, a docking study was performed to evaluate the ability of ligands to interact within the active site of cyclooxygenases (COX-1 and COX-2). Docking results showed a possible binding of stannoxanes theoretically more selective towards COX-2 than ibuprofen.

Full text of DOI:10.1016/j.jorganchem.2018.02.049

Accepted Manuscript
Organotin(IV) compounds derived from ibuprofen and cinnamic acids, an alternative
into design of anti-inflammatory by the cyclooxygenases (COX-1 and COX-2)
pathway
Maria M. Romero-Chávez, Kayim Pineda-Urbina, David J. Pérez, Fernando Obledo-
Benicio, Angelina Flores-Parra, Zeferino Gómez-Sandoval, Ángel Ramos-Organillo
PII:
S0022-328X(18)30155-4
10.1016/j.jorganchem.2018.02.049
JOM 20348
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 23 January 2018
Revised Date: 23 February 2018
Accepted Date: 28 February 2018
Please cite this article as: M.M. Romero-Chávez, K. Pineda-Urbina, D.J. Pérez, F. Obledo-
Benicio, A. Flores-Parra, Z. Gómez-Sandoval, Á. Ramos-Organillo, Organotin(IV) compounds
derived from ibuprofen and cinnamic acids, an alternative into design of anti-inflammatory by the
cyclooxygenases (COX-1 and COX-2) pathway, Journal of Organometallic Chemistry (2018), doi:
10.1016/j.jorganchem.2018.02.049.
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ACCEPTED MANUSCRIPT
Organotin(IV) compounds derived from ibuprofen and cinnamic acids, an alternative
into design of anti-inflammatory by the cyclooxygenases (COX-1 and COX-2)
pathway
Maria M. Romero-Cháveza, Kayim Pineda-Urbinaa, David J. Pérezb, Fernando Obledo-
Benicioa, Angelina Flores-Parrac, Zeferino Gómez-Sandovala and Ángel Ramos-
Organilloa*.
a
Facultad de Ciencias Químicas, Universidad de Colima, Km. 9 Carr. Colima-
Coquimatlán, C.P. 28400, Coquimatlán, Colima, México. mariaromerochavez@ucol.mx;
aaramos@ucol.mx.
b Faculty of Pharmacy and Pharmaceutical Sciences , University of Alberta , Edmonton,
Alberta, Canada, T6G 2E1.
c
Departamento de Química, Centro de Investigación y de Estudios Avanzados-IPN.
Apartado Postal 14-740. México 07000, D. F. México
Abstract
New tributyl-, dibutyl- and diphenyl-tin(IV) complexes derived from ibuprofen and
cinnamic acids were synthesized. All compounds were structurally characterized by FT-IR,
1
13
19
multinuclear H, C, F and 119Sn NMR and corroborated by 2D spectra. The NMR data
in CDCl3 revealed several hexacoordinated compounds with octahedral geometry.
Moreover, in DMSO-d6 some of these complexes switched to heptacoordination with a
pentagonal-bipyramidal geometry due to the inclusion of a solvent’s molecule; their 119Sn
signals moved up field by around 58 ppm compared to their chemical shifts in non-
coordinated solvent CDCl3. The structural results were supported by Density Functional
Theory (DFT) computational calculations. In addition, a docking study was performed to
evaluate the ability of ligands to interact within the active site of cyclooxygenases (COX-1
and COX-2). Docking results showed a possible binding of stannoxanes theoretically more
selective towards COX-2 than ibuprofen.
Keywords: Stannoxanes; Ibuprofen; Coordination; DFT; Docking; Cyclooxygenase.
1. Introduction
Tin compounds offer a large structural variety due to the range of coordination
numbers that the tin atom can adopt (4-8). This leads to different chemical shifts in 119Sn
NMR spectroscopy, ranging of +800 to -600 ppm [1-3]. The type and size of the
substituents attached to the tin(IV) atom determines the spatial geometry, as well as their
industrial and biological applications. It is well known that an increase in the coordination
number of the tin atom is related to an increase in electron shielding around the nucleus,
n
that is monitored by the NMR spectra of 119Sn, as well as the J(13C-117/119Sn) coupling
1

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constants [3-5]. These increases involve intra- or inter-molecular interactions by varying
the solvent, temperature or steric factors of substituents at the metal center. An increase in
the coordination number depends of the acidity of tin atom and the availability of the
substituents as electron donors [3, 4]. Diverse studies have determined that an increase in
the size and number of the substituents on the tin atom, increases the lipophilicity and
decreases the toxicity of the compound in biological systems [6-11]. Particularly,
organotin(IV) carboxylates’ monomers have shown a wide variety of coordination
geometries, such as tetrahedral, trigonal bipyramidal and octahedral [12, 13].
The study of organotin’s biological activity began with Gielen and coworkers, who
tested a set of compounds as antitumor agents [14-17]. Some organotin(IV) compounds
exhibit a better in vitro antitumor activity than the cisplatin or carboplatin [3,7]. In addition,
organotin compounds have been explored as acaricide [3], anthelmintic [18], cytotoxic
[19,20], antibacterial [21,22], antifungal [22], antimicrobial [23], anti-tuberculosis [24],
antioxidants and anti-inflammatory [25], agents.
Ibuprofen (Figure 1) is one of the best-selling NSAIDs (Nonsteroidal anti-
inflammatory drugs) worldwide and it is marketed as a racemic mixture, but its
overconsumption has been linked to gastric ulcers and other side effects [26,27].
O
OH
Figure 1. Chemical structure of (R,S)-ibuprofen.
On the other hand, the trans-cinnamic acids and their derivatives have received
attention because their functional properties like antioxidant, antibacterial, antifungal, and
their importance in food supplements, cosmetics and pharmaceuticals [28-32]. Furthermore,
these compounds offer a great structural diversity when attached to metals [33]. Moreover
the spacer groups play an important role in prodrug conjugation and design, as well as in
drug delivery systems. The glycol spacers increase the degrees of freedom and modify the
solubility with the aim of reduce adverse effects, in some NSAIDs the use of these groups
decreases gastric damage by esterification of the carboxylic acid [34-35]. Based on the
aforementioned, the present work reports the synthesis and structural characterization of a
new group of organotin(IV) compounds by means the NMR spectra in CDCl3 and DMSO-
d6. This study focuses on the ability of the tin atom to increase its coordination number in
the presence of a coordinating agent, in addition, a study to the in silico affinity and
selectivity was carried out of each complex towards cyclooxygenases, important enzymes
of the inflammatory process.
2

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2. Results and discussion
2.1 Synthesis
A series of ibuprofen and cinnamic acid derivatives organotin(IV) carboxylates
compounds (1-13) were synthesized according to Scheme 1 and Scheme 2 (see
experimental section). All compounds were air-stable, soluble in common organic solvents
and they could be isolated up to 82% of yield. Some of n-butyl derivatives (2, 3, 4, 7, 8 and
9) were solids and melted at range of 45-90 °C, the rest of the compounds were liquids.
This is because the presence of two n-butyl groups bonded to tin atom, these groups
decrease the formation of intermolecular interactions by steric hindrance [3]. The NMR
1
spectra of H, 13C and 119Sn indicate the presence of only one species in solution, these
were obtained in a noncoordinating solvent (CDCl3) and a coordinating (DMSO-d6), with
the aim of analyze the tin atom ability to increase its coordination sphere and the chemical
behavior of this metal in different conditions.
2.2 Spectroscopy
In the infrared spectra, an explicit feature of all the studied compounds is the band
that corresponds to the Sn-O bond, which appears in the region of 400 to 500 cm-1. This,
along with the absence of a broad band in the region 2600-3000 cm-1 corresponding to the
stretching vibration of the hydroxyl group ν(O-H) in carboxylic acids, is an indication of
the deprotonation of the COOH moiety [36,37]. Furthermore, the bands in the 507-594 cm-1
and 511-631 cm-1 regions are assigned to the symmetrical and asymmetrical stretching of
the Sn-C bond [38]. In addition, dicarboxylic stannoxanes (1-9) displayed two intense
bands in the range of 1550 to 1700 cm-1 due to the stretching vibration of the carbonyl
groups ν(C=O). However, one of these carbonyl stretching bands disappears for compounds
10-13.
A comparative analysis of the ∆ν (νasymCOO- νsym COO-) values of the sodium
carboxylates and complexes 1-9 indicates the type of coordination between the tin atom and
the carboxylate substituent, differentiating between monodentate, bidentate and bidentate
bridge modes [39]. The ∆ν for compounds 1-4, 7 and 8 is lower than those corresponding to
the respective free ligands by 84 to 124 cm-1. This is representative of the bidentate
chelating mode. In the case of 5, 6 and 9 complexes, the values of ∆ν correspond to those
found in a bidentate bridge mode for the carboxylic ligands in them (see experimental
section) [40,41].
The signal corresponding to the COOH proton of the raw organic acids is absent in
the H NMR spectra of compounds 1-13 (CDCl3) and 1a-13a (DMSO-d6). This coincides
1
with the observed data in IR. The chemical shifts for n-butyl protons show a shielding
3

ACCEPTED MANUSCRIPT
effect in DMSO-d6 solution, which may be related to the changes in the electronic
environment of the tin atom caused by coordinating solvent. The H7, H7', H8 and H8'
protons of the α, β-unsaturated double bonds do not exhibit significant changes in
molecules 1-4, 1a-4a, 6-9 and 6a-9a. For compounds 5, 10-13, 5a, and 10a-13a, the
positions H7 and H8 exhibit a deshielding effect, because of the tin atom presence. Figure 2
shows the numbering scheme for the stannoxanes.
11
3
9
10
4
2
1
O
O
9
O
9'
O
9'
2
5
7
7'
7'
6'
6'
3'
5
1
7
8
1'
3
1'
2'
O
Sn
13
O
O
Sn
10
O
5'
4'
12
5'
4'
6
8'
8
8'
6
4
14
11
2'
3'
15
12
16
13
5
1
11
3
9
10
4
2
O
9
O
9'
O
O
9'
2
5
7
7'
7'
6'
1
6'
3'
5
1
7
3
1'
2'
1'
O
Sn O
O
Sn
O
5'
12
5'
8
6
8'
8'
6
13
10
4
11
14
2'
8
4'
4'
X
X
3'
15
12
16
13
2 (X=F); 3 (X=Cl); 4 (X=Br)
6 (X=H); 7 (X=F); 8 (X=Cl); 9 (X=Br)
8
8
2
2
O
1
O
1
O
3
3
11
10
11
10
7
7
12
12
4
4
6
6
O
O
n
Sn
O
O
n
Sn
O
O
n
9
9
5
5
13-14 (n=2)
13-15, (n=3)
13-14 (n=2)
13-15, (n=3)
12 (n=2); 13 (n=3)
10 (n=2); 11 (n=3)
Figure 2. Organotin(IV) compounds and numbering sequence.
The 13C NMR spectra data confirms the exchange of the acidic proton (-COOH) by
tin atom (-COOSn-) with the carbonyl signals appearing between 172.1 and 185.0 ppm,
because of the substituent (Table 1). For compounds 1-9, the carbonyl chemical shifts give
important information of the chemical environment surrounding the tin atom when is
compared to the raw materials. The carbonyl chemical shifts in CDCl3 show a deshielding
effect in comparison with their free ligands. For the hydrocinnamic and ibuprofen carbonyl
groups, displacements of 4-6 ppm to higher frequencies were observed, whereas this
change was greater than 10 ppm for the trans-cinnamic ligands. The above changes suggest
that the trans-cinnamic carboxylates had a stronger coordination with tin(IV) atom, due to a
4

ACCEPTED MANUSCRIPT
lesser steric hindrance. These data confirmed the carboxylate oxygen’s bidentate chelating
and bridge modes of coordination with the tin atom, as previously observed through FT-IR
spectra. On the other hand, for the compounds 10-13 was not observed the interaction and
coordination of the carboxylate oxygen with the tin atom.
Table 1. Chemical shifts δ (ppm) of the carbonyl groups in CDCl3 y DMSO-d6 for the 1-13
compounds.
1
1a
2
2a
3
3a
4
4a
176.2 173.0 176.1 173.8 176.3 173.3 176.4 172.6
182.9 180.0 176.3 173.8 175.9 174.1 175.9 172.7
9
9'
5
5a
6
6a
7
7a
8
8a
9
9a
185.0 181.6 184.8 181.0 185.0 172.3 185.0 172.7 184.9 172.1
183.0 179.4 176.1 172.5 175.9 172.3 175.9 172.7 172.7 172.1
12
9'
10
10a
11
11a
12
12a
13
13a
175.1 175.0 175.2 175.0 175.1 175.1 175.3 175.1
12
#a = chemical shifts in DMSO-d6
When this analysis was done in a coordinating solvent, DMSO-d6, the carbonyl
groups had a deshielding effect with respect to the free ligands. However, compounds 1a-
13a carbonyl signals appear at lower frequency than those of 1-13, an effect attributed to
DMSO-d6 interaction to the tin atom. This disturbs the structure’s geometry around the
metallic nucleus, weakening the interaction between the carboxylate oxygen and the tin
atom. The ibuprofen carbonyl of compounds 7a-9a display the largest changes; 12.7 ppm,
12.3 ppm and 12.8 ppm respectively.
The 119Sn spectroscopy data of the studied compounds (1-13 and 1a-13a) are
presented in Table 2. The 119Sn chemical shifts for compounds 1-9 appear in the region of -
+145 ppm to -150 ppm confirming that all of them are hexacoordinate systems. For
compounds 10-13, simple signals were observed around of +156 ppm for tributyltin
derivatives and chemical shifts at -46 ppm for diphenyltin derivatives, both in accord with
reported tetracoordinate tin atom [25, 32]. The 119Sn signals are shifted to lower frequencies
in DMSO-d6, because of a shielding effect by the solvent surrounding the metal.
Comparing the 119Sn chemical shifts in both solvents, compounds 1 and 4 had the largest
differences, ∆δ119Sn = 57.7 and ∆δ119Sn = 58.8 respectively. These changes have been
previously related to changes in the coordination number of the metal, with the solvent
acting as a ligand in this case (Table 2) [4].
The carbon atoms (α, β and γ) coupled with the metallic nucleus in systems 1-13 are
n
shown in Figure 3. The corresponding J(13C-117/119Sn) coupling constants are quite
informative regarding the interactions between the nuclei, their chemical and magnetic
5

ACCEPTED MANUSCRIPT
environments, as well as the geometry, hybridization and number of substituents of the tin
2
atom. In CDCl3, the alpha carbon has an average J(13C-117/119Sn) coupling constant of 580
Hz for products 1-9, 337 Hz for 10 and 11, and 620 Hz in systems 12 and 13. In
comparison, the same coupling constant was greater than 850 Hz in compounds 1a-9a.
Figure 3. Important positions near the tin atom for 1-13 compounds.
Table 2. Selected Chemical shifts δ (ppm) of 13C and 119Sn for 1-13 and 1a-13a
compounds.
Compounds
1
δ119Sn
α
25.2
β
26.3
γ
∆δ119Sn
26.6
-146.9
(569.5/562.4) (95.5) (35.2)
29.9 26.2 27.2
(855.2/827.1) (138.8) (50.3)
25.4 26.4 26.6
(586.8/560.5) (97.6) (34.5)
26.2 26.2 27.3
(835.1/820.0) (137.8) (62.3)
25.9 26.4 26.7
(585.6/561.5) (98.6) (35.2)
30.0 26.1 27.2
(851.2/814.0) (137.8) (57.3)
25.4 26.4 27.7
(584.6/559.4) (99.6) (35.2)
29.3 26.2 27.2
(855.2/854.2) (139.8) (72.4)
25.0 26.3 25.6
(580.5/554.4) (93.5) (37.2)
30.2 26.1 27.2
(867.3/847.2) (142.8) (27.6)
26.5 26.2 25.1
(583.6/557.5) (97.6) (36.2)
30.3 26.2 27.3
(856.3/839.1) (144.8) (34.1)
26.6 26.4 25.1
(584.6/559.5) (98.6) (36.2)
30.2 27.4 26.2
(857.3/813.0) (140.8) (35.1)
25.1 26.2 26.6
(568.5/555.5) (97.6) (37.2)
30.3 26.1 27.5
(850.2/825.1) (139.8) (36.2)
25.1 26.2 26.4
(571.5/558.2) (96.5) (36.2)
57.7
-204.6
-147.4
-193.4
-147.8
-205.8
-149.6
-198.4
-145.9
-167.4
-150.1
-172.1
-149.5
-168.9
-149.4
-169.9
-149.3
1a
2
46.0
58.0
48.8
21.5
22.0
19.4
2a
3
3a
4
4a
5
5a
6
6a
7
7a
8
20.5
33.8
8a
9
6

ACCEPTED MANUSCRIPT
0.3
(868.3/822.0) (138.8) (37.3)
17.6 26.9 27.8
(337.1/332.0) (63.4) (22.1)
7.7 26.8 27.9
(343.2/327.0) (64.3) (23.1)
18.3 26.8 27.7
(337.1/332.0) (64.4) (22.1)
26.1
27.4
-183.1
+156.4
+148.9
+156.2
+143.8
-46.6
9a
10
7.5
10a
11
12.4
17.1
27.4
17.9
(339.1/NA)
137.4
(619.8/NA)
137.5
26.8
(64.6) (23.1)
129.2 136.5
(58.3) (48.3)
27.8
11a
12
129.1
(62.4)
129.2
136.1
(42.3
136.1
-63.7
12a
13
(627.9/NA)
137.4
-46.2
(631.9/NA)
138.3
(63.4) (49.3)
129.1 136.2
(104.6) (49.3)
-73.6
13a
(NA)
#a (DMSO-d6); (nJ(13C-117/119Sn))
For compounds 1a-4a, the difference between the coupling constants in DMSO-d6 and
CDCl3 is 285.7, 248.3, 265.6 and 270.6 Hz respectively. This, jointly with a change in the
chemical shift of tin (∆δ119Sn) larger than 45 ppm and slight variations in the carbonyl
groups’ chemical shifts, confirm the coordination of a dimethylsulfoxide’s oxygen atom
with the tin atom [42, 43]; a contrast of hexacoordination in chloroform with
heptacoordination in DMSO-d6.
Figure 4. Coordination for compound 1 in CDCl3 and DMSO-d6. This change in the
coordination number was observed for 2a-4a compounds as well.
The coupling constant (2J(13C-117/119Sn)) is around 300 Hz for compounds 5a and
6a. However, ∆δ119Sn is smaller than 25 ppm and the chemical shifts for the, respectively,
carbonyl groups do not show any significant changes. This indicates a weak interaction
between a DMSO-d6 molecule and these compounds, contrary to the coordination with the
metallic nucleus presented in 1a-4a. To further support these conclusions, DFT theoretical
computations were performed. Figure 5 shows the resulting optimized geometry for
compound 5a with a DMSO molecule. Of all the atoms interacting with the tin atom, the
solvent’s oxygen atom is the furthest from the metallic nucleus, in concordance with the
NMR data.
7

ACCEPTED MANUSCRIPT
Figure 5. Optimized geometry of compound 5a with a DMSO molecule. Displayed
interatomic distances in angstroms.
Systems 7a-9a (Figure 6) had similar (2J(13C-117/119Sn)) coupling constants, and
∆δ119Sn, however, the chemical shift for the ibuprofen’s carbonyl group was displaced to
lower frequencies by 12 ppm (Table 1). This reflects the molecules’ structural
rearrangement due to the DMSO’s oxygen atom taking the tin atom to heptacoordination.
The structure of compound 8a was optimized utilizing computational calculations, where a
single solvent molecule was included. The results show the solvent oxygen atom and the
carbonyl oxygen atoms are at a similar distance from the tin nucleus (Figure 7). When
compared with the calculations for compound 5a, the solvent has a stronger interaction with
the tin atom in 8a. These results further supports the heptacoordination suggested by NMR
data.
8

ACCEPTED MANUSCRIPT
Figure 6. Coordination number for 7-9 and 7a-9a compounds in CDCl3 and DMSO-d6.
Figure 7. Optimized geometry of compound 8a.
Compounds 10a through 13a did not show any significant changes that would
indicate an alteration in the tin’s coordination number. The spacer group pushes the
carbonyl fragment away from the metallic nucleus, effectively inhibiting any possible
coordination. Furthermore, the three butyls present on systems 10a and 11a, hinders any
approach to the tin center by any DMSO molecule.
2.3 Molecular docking
To explore the effect of the tin atom in combination with the trans-cinnamic acid
(TCA), hydrocinnamic acid (HCA) and ibuprofen a docking study towards cyclooxygenase
(COX) isoforms was carried out.
Only compounds which bear at least one (S)-ibuprofen moiety –which is
biologically active in COX inhibition− were selected to discuss their binding modes [44,
45]. Additionally, as a second criteria, only those systems that were able to interact with
Arg513 and His90 residues, were discussed; these residues are only reached by COX-2
selective inhibitors [46]. Arg513 and His90 are key residues, which provide access to the
lipophilic pocket formed by Val523, hence a COX-2 selective inhibitor needs to interact
favorably with them to accommodate into the pocket [46, 47].
9

ACCEPTED MANUSCRIPT
Compounds 5 (S), 7 (S), 9 (S), 10 (S), 11 (S), 12 (S, S), 12 (S, R) and 13 (S, R) were
found to meet the criteria described. The interactions of tin derivatives with the constriction
channel (CC; Arg120, Glu524 & Tyr355), lateral pocket (LP; Ala527, Leu531, Ser530 &
Val349) and lipophilic pocket (LiP; Val 523) residues of COX-2 are shown in Table 3 and
compare to ibuprofen’s and celecoxib’s, COX-2 reference inhibitors.
Table 3. Summary of the interactions of selected compounds with Arg513 & His90, LP, CC
and LiP (COX-2).
12
12
13
Ibu.
Cel.
5S
7S
9S
10S
11S
(S, S) (S, R) (S, R)
Ala527
-9.92
---
-10.25 -6.30
---
-5.21
-7.00
-17.70 -8.80
-7.80
-7.55
-0.77
-0.32 -10.20 -10.82 -7.30 -13.60 -15.33
-9.64 -22.60 -28.85 -32.60 -18.70 -15.10 -12.90 -9.10
-2.20
-5.08
---
-3.64
-2.70
-4.43
Arg120
Arg513
Glu524
His90
Leu531
Ser530
Tyr355
Val349
Val523
-2.46
-1.44
-2.14
-9.70
-6.33
-2.68
-4.32
-4.31
-3.92
-1.66
-0.37 -11.22 -13.10 -5.06
-1.20
1.70
-0.45
-3.40
---
-5.30
-7.63
-0.95
-8.70
-9.61
-0.98
-3.70
-2.50
-2.20 -15.33 -13.1
-1.11 -13.43 -2.96
-2.02
-1.41
----
-13.72 -4.18
-6.41 -16.84 -13.11 -9.51 -12.60 -13.80 -30.50 -9.80 -10.30 -12.53
---
---
-12.70 -12.20 -6.33 -10.12 -11.80 -7.80
-22.90 -17.70 -16.76 -14.25 -24.40 -22.92 -22.61 -6.80 -18.31
-3.20 -11.43 -11.13
Ibu: ibuprofen; Cel: celecoxib
The stannoxanes bind to COX-2’s active site mainly by forming steric interactions
with key residues; their binding mode is also driven by the formation of hydrogen bonds
(HB). In general terms, the presence of a tin atom, in combination with ibuprofen, HCA
and TCA moieties, exert a favorable influence in their binding modes with COX-2 and
allow them to reach Arg513 and His90.
Figure 8. Binding of selected compounds into COX-2 active site.
Compound 7 (S) and 12 (S, S) displayed remarkable interaction values in
comparison to reference inhibitors and the other stannoxanes (Figure 9). The presence of
fluoro-trans-cinnamic acid and ibuprofen moieties in 7 (S), favors higher interaction
10

ACCEPTED MANUSCRIPT
energies than those of reference inhibitors with Arg513, His90, Leu531, and Val523. Its
binding mode locates the fluoro-trans-cinnamic acid moiety reaching towards the LiP,
His90 and Arg513. The ibuprofen moiety accommodates and interacts with LP’s residues
Ala527 and Leu531. The carboxyls accept HBs from Tyr355 and Ser353. The butyl groups
and tin atom face the Ser530, Val349, and Ala527 residues.
On the other hand, compound 12 (S, S), which bears two phenyl rings bound to the
tin atom, shows higher interaction energy with Arg513, His90, and Leu531 than reference
inhibitors and 7 (S). It binds to COX-2 facing each ibuprofen moiety to opposite directions.
One is facing the Arg513, His90 and Glu524 residues, whereas the other reaches towards
LP residues (Leu531 and Val349). The phenyl groups and tin atom reach the LiP and
Ala527, while also interacting with Val523 and His90.
Figure 9. Comparison of the binding modes of compounds 7 (S), A) and 12 (S, S), B) to
ibuprofen (green). The blue dashed lines represent the HB.
Besides, the interaction with Val523, His90 and Arg513 is often related to a tight
and durable binding to COX-2, which is only achieved by time-dependent and selective
COX-2 inhibitors [46-48]. On the other hand, Leu531 is key to COX-2 selectivity, since it
needs to reach a conformational change that allows the accommodation of an inhibitor [49].
In this sense, compounds 7 & 12 show favorable interactions to the mentioned residues,
which suggest that they may interact with COX-2 in a similar manner to reference
11

ACCEPTED MANUSCRIPT
compounds. The interactions values of compounds with key residues of COX-1 are shown
in Table 4.
Table 4. Summary of the interactions of selected compounds with LP, CC and Ile523
(COX-1).
12
(S, S) (S, R) (S, R)
-11.50 -7.40 -13.00 -13.60 -12.02 -9.30 -12.72 -11.90 -12.72 -13.04
12
13
5S
7S
9S
10S
11S
Ibu.
Cel.
Ala527
Arg120
Glu524
-0.73
---
---
---
-12.60 -9.54
--- ---
-2.43 -17.10 -1.60
--- -1.21 ---
-8.70 -15.95 -1.35
-3.81 1.86 ---
Ile523 -13.20 -17.40 -7.00 -19.64 -13.90 -27.40 -12.03 -16.50 -7.16 -15.80
-7.82
-10.10 -18.30 -5.13 -15.98 -18.00 -15.10 -9.20
-11.10 -4.95
-5.84
-7.92 -14.70 -11.33 -18.34
8.62
-6.97
-6.10
-5.50
-4.74
-4.56
-3.11
Leu531
Ser530
Tyr355
-9.10 -19.12 -12.71 -14.10 -21.74 -4.80 -10.80 -12.93
-16.50 -17.20 -9.60 -20.54 -16.90 -13.42 -20.40 -11.20 -10.40 -11.30
Val349
Ibu: ibuprofen; Cel: celecoxib
Similarly to COX-2, the selective binding to COX-1 relies on the interaction with
key residues of its active site. Key residues are similar in both isoforms, they have in
common the LP and CC. However, COX-1 lacks of a lipophilic pocket, which is the main
difference between isoforms and it is due to the presence of Ile523 & His513 instead of
Val523 and Arg513 [47]. The interaction with Ile523 is important because it controls the
access to the COX-1 active site; Ile523 must reach a conformation that allows the ligands to
accommodate favorably into the site [50].
In general, the selected derivatives 5 (S), 7 (S), 9 (S) - 11 (S), 12 (S, S), 12 (S, R) and
13 (S, R) bind into COX-1 active site mainly by forming steric interactions; they were more
prone to form steric clashes when binding to COX-1 than to COX-2. In contrast to COX-2,
the binding of 7 (S) and 12 (S, S) to COX-1 shows some important differences. In this
regard, compound 7 (S) accepts a HB from Tyr355 and Arg120 and binds facing its
ibuprofen to reach towards Ser530, whereas the fluoro-trans-cinnamic acid moiety interacts
with Ala527 and Val349; butyl chains interact with Ile523. The binding mode favors the
interaction with Ile523, which is higher in energy than Ibuprofen´s and Celecoxib´s.
Compound 12 (S, S) binds into COX-1 by accepting a HB from Ser530 and Arg120.
However, it clashes with Val349; its interactions with Ile523 are higher than celecoxib´s
and ibuprofen´s.
12

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Figure 10. Comparison of the binding modes of compounds 7 S (A) and 12 SS (B) to
ibuprofen (green). Legend: black arrows point the regions where steric clashes are
observed. The blue dashed lines represent the HB.
Docking results suggest that stannoxanes may bind to COX isoforms; thus, they
may be screened as COX inhibitors in vitro. The interaction energies of compounds 7 and
12 are suggestive of a theoretical selectivity towards COX-2, in part due to the differences
between COX isoforms’ active sites [51, 52]. Namely, (i) COX-2 active site is larger than
that of COX-1, which may allow it to “accept” larger inhibitors that may favorably
accommodate and interact with the lipophilic pocket (Val523). (ii) The active site of COX-
2 is more hydrophobic than COX-1, which may also favor the binding of hydrophobic
inhibitors, as is the case of Sn-derivatives. (iii) The COX-2 active site can use esters of
arachidonic acid as substrates [45, 53], which implies that the presence of an ester bond
within tin derivatives increase their selectivity and favor their binding to COX-2. The
reported anti-inflammatory activity of a variety of organotin(IV) derivatives is
straightforward [54, 55]. However, the results reported in this section should be framed in a
theoretical context and be validated experimentally through an in vitro model.
3. Conclusions
The organotin compounds discussed in this work displayed interesting behavior
regarding their coordination. Most of them (1-9) were hexacoordinated in chloroform.
However, molecules 1-4 and 7-9 could add a solvent’s molecule to their coordination
sphere when dissolved in DMSO, effectively bringing them to an heptacoordination. This
was concluded through the analysis and concordance of the NMR and FT-IR data, while
further supported by DFT calculations. In addition, the resulting energies from the docking
calculations suggested all compounds interact with COXs. Furthermore, all the systems
13

ACCEPTED MANUSCRIPT
were theoretically more selective towards COX-2 than the ibuprofen. Ligands with glycol
spacers and diphenyltin showed the best binding energies towards COX-2 due to forming
steric interactions in constriction channel and lipophilic pocket. The spacer group increases
the flexibility and favors the arrangement of the ligand in the active site.
4. Experimental
4.1. Materials and instruments
Hydrocinnamic acid, trans-cinnamic acid, 4-fluoro-trans-cinnamic acid, 4-trans-
chlorocinnamic acid, 4-bromo-trans-cinnamic acid, dimethylaminopyridine (DMAP),
dicyclohexylcarbodiimide (DCC), organotin(IV) monochlorides and dichlorides were
purchased from Sigma-Aldrich and were used without further purification. Ibuprofen was
supplied by the Alfadelta S. A. de C. V. as racemic mixture and was not further purified.
The NMR spectra of compounds were obtained in two deuterated solvents (CDCl3 and
1
DMSO-d6) and were analyzed with a Bruker 400 MHz NMR spectrometer for H
(400.13247 MHz), 13C (100.62282 MHz), 19F (376. 46071 MHz) and 119Sn (149.16624
MHz). Chemical shifts (δ) are reported in ppm and coupling constants in Hz. The infrared
spectra were recorded on a Varian Excalibur 3100 FT-IR spectrophotometer using KBr
pellets. Elemental analysis was performed on Truspec Micro elemental analyzers. Melting
points were obtained with a Melt-Temp II apparatus and were not corrected.
4.2. General procedure for the synthesis of stannoxanes (1-9) ibuprofen, 3-
phenylpropanoic acid and cinnamic acid derivatives
The nine stannoxanes were obtained by reacting two equivalents of the
corresponding carboxylic acid with dibutyltin dichloride in a mixture of boiling toluene and
triethylamine like base. This mixture was kept under reflux for 6 hours and then cooled to
room temperature and stirred vigorously for 12 hours (Scheme 1).
14

ACCEPTED MANUSCRIPT
O
O
O
O
Bu2SnCl2 / Et3N
+
R1
R
O
Sn
O
R1
OH
Toluene, 110°C
R
OH
1 = R1 and R
2 = R1 and R2
3 = R1 and R3
4 = R1 and R4
5 = R5 and R
6 = R5 and R1
7 = R5 and R2
8 = R5 and R3
9 = R5 and R4
R1 =
R =
R3 =
R2 =
Cl
F
R5 =
R4 =
Br
Scheme 1. Synthesis and sequence enumeration of stannoxanes derived from the
combination of carboxylic acids.
Dibutyl(3-phenylpropanoyl) oxystannyl cinnamate (1). In a dry flask, the hydrocinnamic
acid (246 mg, 1.638 mmol) and the trans-cinnamic acid (242 mg, 1.633 mmol) were
dissolved in 100 ml of dry toluene, next 0.874 ml of triethylamine (660 mg, 6.581 mmol)
was added, the mixture was stirred until its complete dissolution. On the reaction mixture at
80°C is added dropwise the dibutyltin dichloride (500 mg, 1.645 mmol) previously
dissolved in 50 ml of toluene. Then, the mixture was heated to 110 °C for 6 h, after that, the
heating was removed and kept for 12 h under continue stirring. The precipitated
triethylamine hydrochloride was eliminated by filtration and the toluene was evaporated
under reduced pressure. The final product was washed three times with CH2Cl2 and H2O to
remove any remaining triethylamine. The organic phase was treated with MgSO4 to remove
any residual water. Finally, the product was recovered by evaporation after removal of the
hydrated MgSO4 by filtration. Compound 1 was obtained as a yellow liquid. Yield: 0.863 g
(99%). Analyses (%): calcd for C26H34O4Sn, C 59.00, H 6.48, O 12.09, Sn 22.43; found, C
59.27, H 6.83. FT-IR (cm-1): ν1(O=C) 1639; ν2(O=C) 1580; νasym(COO) 1589; νsym(COO)
1499; ν(O-C) 1371; ν(Sn-C) 593; ν(Sn-O) 422. 1H NMR (CDCl3) : 7.81 (d, 3J = 16.0 Hz,
δ
1H, H7), 7.55 (m, 1H, H2), 7.55 (m, 1H, H6), 7.42 (m, 1H, H2’), 7.42 (m, 1H, H6’), 7.34
(d, 3J = 7.3 Hz, 1H, H3), 7.34 (d, 3J = 7.3 Hz, 1H, H5), 7.29 (m,1H, H4), 7.28 (d, 3J = 7.2
Hz, 1H, H3’), 7.28 (d, 3J = 7.2 Hz, 1H, H5’), 7.25 (m, 1H, H4’), 6.52 (d, 3J = 16.0 Hz, 1H,
15

ACCEPTED MANUSCRIPT
H8), 3.03 (t, 3J = 7.7 Hz, 2H, H7’), 2.82 (t, 3J = 7.8 Hz, 2H, H8’), 1.70 (m, 2H, H10), 1.70
(m, 2H, H12), 1.34 (sext, 3J = 7.2 Hz, 2H, H11), 0.94 (d, 3J = 7.3 Hz, 3H, H13). NMR 13C
(CDCl3) δ: 182.9 (C9’), 176.2 (C9), 146.3 (C7), 140.5 (C1’), 134.4 (C1), 130.3 (C4), 129.3
(C3),129.3 (C5), 128.9 (C3’), 128.9 (C5’), 128.3(C2),128.3 (C6), 128.1 (C2’), 128.1 (C6’),
126.2 (C4’), 117.7 (C8), 35.6 (C8’), 31.1 (C7’), 26.3 (J (C11-119Sn) = 95.5 Hz), 26.6 (J
(C12-119Sn) = 35.2 Hz), 25.2 (J (C10-119Sn) = 569.5 Hz; J (C10-117Sn) = 562.4), 13.6
(C13). 119Sn NMR (CDCl3)
δ: –146.9.
Dibutyl(((E,Z)-3-(4-fluorophenyl)acryloyl)oxy)stannyl cinnamate (2). Following the same
procedure that for compound 1, a mixture of 4-fluoro-trans-cinnamic acid (272 mg, 1.637
mmol), trans-cinnamic acid (242 mg, 1.633 mmol), 0.874 ml of triethylamine (660 mg,
6.581 mmol) and the dibutyltin dichloride (500 mg, 1.645 mmol) were reacted. The
residual solution was dried under low pressure to get compound 2 as a white solid. Yield:
0.887 g (98%). M.p. 70-72 °C. Analyses (%): calcd for C26H31FO4Sn, C 57.27, H 5.73, F
3.48, O 11.74, Sn 21.77; found, C 56.94, H 6.12. FT-IR (cm-1): ν1(O=C) 1683; ν2(O=C)
1
1639; νasym(COO) 1547; νsym(COO) 1491; ν(O-C) 1223; ν(Sn-C) 593; v(Sn-O) 470. H
NMR (CDCl3)
1H, H4), 7.56 (m, 1H, H3’), 7.56 (m, 1H, H5’), 7.41 (m, 1H, H2), 7.41 (m, 1H, H6), 7.11
δ
: 7.79 (d, 3J = 18.0 Hz, 1H, H7’), 7.79 (d, 3J = 16.2 Hz, 1H, H7), 7.57 (m,
3
3
3
(d, J = 8.6 Hz,1H, H2’), 7.11 (d, J = 8.6 Hz, 1H, H6’), 7.09 (d, J = 8.6 Hz, 1H, H3),
7.09 (d, 3J = 8.6 Hz, 1H, H5), 6.54 (d, 3J = 16.0 Hz, 1H, H8’), 6.45 (d, J = 16.0 Hz, 1H,
3
H8), 1.74 (m, 2H, H10), 1.74 (m, 2H, H12), 1.44 (sext, 3J = 8.0 Hz, 2H, H11), 0.95 (t, 3J =
7.3 Hz, 3H, H13). 13C NMR (CDCl3) : 176.3 (C9’), 176.1 (C9), 165.2 (J (C4’-19F) = 251.5
δ
Hz), 146.3 (C7’), 144.9 (C7), 134.4 (C4’), 130.7 (C1), 130.7 (C2’), 130.7 (C6’), 130.5
(C2), 130.5 (C6), 128.2 (C3), 128.8 (C4), 128.2 (C5), 117.5 (C8), 117.7 (C8’), 116.1 (C3’),
116.1 (C5’), 26.4 (J (C11-119Sn) = 97.6 Hz), 26.6 (J (C12-119Sn) = 34.5 Hz), 25.4 (J (C10-
119Sn) = 586.8 Hz; J (C10-117Sn) = 560.5 Hz), 13.6 (C13). 119Sn NMR (CDCl3)
δ: –147.4.
Dibutyl(((E,Z)-3-(4-chlorophenyl)acryloyl)oxy)stannyl cinnamate (3). Following the same
procedure that for compound 1, a mixture of 4-chloro-trans-cinnamic acid (299 mg, 1.64
mmol), trans-cinnamic acid (242 mg, 1.633 mmol), 0.874 ml of triethylamine (660 mg,
6.581 mmol) and dibutyltin dichloride (500 mg, 1.645 mmol) were reacted. The residual
solution was dried under low pressure to get compound 3 as a yellow crystalline solid.
Yield: 0.861 g (93%). M.p. 87-89 ºC. Analyses (%): calcd for C26H31ClO4Sn, C 55.60, H
5.56, Cl 6.31, O 11.39, Sn 21.13; found, C 55.95, H 5.73. FT-IR (cm-1): ν(O=C) 1637; νasym
(COO) 1534; νsym (COO) 1449; ν(O-C) 1356; ν(Sn-C) 589; ν(Sn-O) 465. 1H NMR (CDCl3)
δ
: 7.90 (d, 3J = 16.0 Hz, 1H, H7), 7.75 (d, 3J = 16.0 Hz, 1H, H7’), 7.57 (m, 1H, H2’), 7.57
(m, 1H, H6’), 7.41 (m, 1H, H2), 7.41 (m, 1H, H6), 7.40 (d, 3J = 8.4 Hz, 1H, H3’), 7.40 (d,
3J = 8.4 Hz, 1H, H5’), 7.37 (d, J = 8.5 Hz, 1H, H3), 7.37(d, J = 8.5 Hz, 1H, H5), 7.28
(m, 1H, H4), 6.52 (d, 3J = 15.7 Hz, 1H, H8’), 6.48 (d, 3J = 15.4 Hz, 1H, H8), 1.74 (sext, 3J
= 7.5 Hz, 2H, H11), 1.44 (m, 2H, H10), 1.44 (m, 2H, H12), 0.95 (t, 3J = 7.4 Hz, 3H, H13).
3
3
13C NMR (CDCl3)
δ
: 176.3 (C9), 175.9 (C9’). 146.3 (C7’), 144.7 (C7), 136.3 (C4’), 134.4
16

ACCEPTED MANUSCRIPT
(C1), 132.9 (C1’), 130.4 (C4), 129.3 (C2’), 129.3 (C6’), 129.2 (C2), 129.2 (C6), 128.9
(C3’), 1sta28.9 (C5’), 128.1 (C3), 128.1 (C5), 118.5 (C8’), 117.8 (C8), 26.7 (J (C12-119Sn)
= 35.2 Hz), 26.4 (J (C11-119Sn) = 98.6 Hz ), 25.8 (J (C10-119Sn) = 585.6 Hz; J (C10-117Sn)
= 561.5 Hz), 13.6 (C13). 119Sn NMR (CDCl3)
δ: –147.8.
(((E,Z)-3-(4-bromophenyl)acryloyl)oxy)dibutylstannyl cinnamate (4). Following the same
procedure that for compound 1, a mixture of 4-bromo-trans-cinnamic acid (372 mg, 1.638
mmol), trans-cinnamic acid (242 mg, 1.633 mmol), 0.874 ml of triethylamine (660 mg,
6.581 mmol) and dibutyltin dichloride (500 mg, 1.645 mmol) were reacted. The residual
solution was dried under low pressure to get compound 4 as a yellow crystalline solid.
Yield: 0.886 g (88%). M.p. 74-76 ºC. Analyses (%): calcd for C26H31BrO4Sn-H2O, C 50.03,
H 5.33, Br 12.80, O 12.82, Sn 19.02; found, C 49.95, H, 5.53. FT-IR (cm-1): ν1(O=C) 1685;
ν2(O=C) 1626; νasym(COO) 1535; νsym(COO) 1451; ν(O-C) 1334; ν(Sn-C) 593; ν(Sn-O)
445. 1H RMN (CDCl3) : 7.81 (d, 3J = 16.7 Hz, 1H, H7’), 7.71 (d, 3J = 15.9 Hz, 1H, H7),
δ
7.56 (m, 1H, H2’), 7.56 (m, 1H, H6’), 7.53 (m, 1H, H2), 7.53 (m, 1H, H6), 7.42 (m, 1H,
H3), 7.42 (m, 1H, H5), 7.41 (m, 1H, H3’), 7.41 (m, 1H, H5’), 7.28 (m, 1H, H4), 6.54 (d, 3J
3
= 8.9 Hz, 1H, H8’), 6.50 (d, J = 8.9 Hz, 1H, H8), 1.74 (m, 1H, H10), 1.74 (m, 1H, H12),
3
3
1.44 (sext, J = 7.2 Hz, 2H, H11), 0.95 (t, J = 7.4 Hz, H1, H13). 13C RMN (CDCl3)
δ:
176.3 (C9’),176.0 (C9), 146.3 (C7’), 144.7 (C7), 134.4 (C4’), 134.3 (C1), 132.1 (C1’),
130.4 (C4), 129.5 (C2’), 129.5 (C6’),128.9 (C2), 128.9 (C6), 128.2 (C3’), 128.2 (C5’),
124.6 (C3), 124.6 (C5), 117.7 (C8), 117.7 (C8’), 26.9 (J (C12-119Sn) = 35.2 Hz ), 26.5 (J
(C11-119Sn) = 99.6 Hz ), 25.8 (J (C10-119Sn) = 584.6 Hz; J (C10-117Sn) = 559.4 Hz), 13.6
(C13). 119Sn RMN (CDCl3)
δ: –149.6.
Dibutyl((2-(4-isobutylphenyl)propanoyl)oxy)stannyl 3-phenylpropanoate (5). Following the
same procedure that for compound 1, a mixture of hydrocinnamic acid (246 mg, 1.638
mmol), ibuprofen (338 mg, 1.638 mmol), 0.874 ml of triethylamine (660 mg, 6.581 mmol)
and dibutyltin dichloride (500 mg, 1.645 mmol) were reacted. Compound 5 was obtained as
a yellow liquid. Yield: 0.920 g (95%). Analyses (%): calcd for C26H31BrO4Sn, C 58.59, H
7.61, O 12.59, Sn 18.68; found, C 58.77, H 8.04. FT-IR (cm-1): ν1(O=C) 1639; ν2(O=C)
1
1565; νasym(COO) 1512; νsym (COO) 1383; ν(O-C) 1376; ν(Sn-C) 594; ν(Sn-O) 435. H
3
3
NMR (CDCl3) δ: 7.26 (d, J = 8.0 Hz, 1H, H2’), 7.26 (d, J = 8.0 Hz, 1H, H6’), 7.24 (m,
3
3
3
H4’), 7.23 (d, J = 8.0 Hz, 1H, H2), 7.23 (d, J = 8.0 Hz, 1H, H6), 7.19 (d, J = 8.0 Hz,
1H, H3’), 7.19 (d, J = 8.0 Hz, 1H, H5’), 7.11 (d, J = 8.0 Hz, 1H, H3), 7.11 (d, 3J = 8.0
3
3
Hz, 1H, H5), 3.79 (q, 3J = 7.0 Hz, 1H, H7), 3.00 (t, 3J = 8.0 Hz, 2H, H7’), 2.72 (t, 3J = 8.0
3
Hz, 2H, H8’), 2.45 (d, J = 7.5 Hz, 3H, H9), 1.86 (m, 1H, H10), 1.64 (m, 2H, H13), 1.55
(d, J = 7.2 Hz, 3H, H8), 1.54 (m, H14), 1.53 (d, J = 6.6 Hz, 3H, H11), 1.27 (sext, J =
7.7 Hz, 2H, H15), 0.85 (m, 2H, H16). 13C NMR (CDCl3)
: 186.0 (C9’), 185.0 (C12), 140.5
3
3
3
δ
(C1), 140.4 (C1’), 137.9 (C4), 129.2 (C2), 128.4 (C2’), 128.4 (C6’), 128.3 (C3’), 128.3
(C5’), 127.1 (C3), 127.1 (C5), 129.2 (C6), 126.2 (C4’), 45.1 (C10), 45.0 (C7), 35.6 (C8’),
17

ACCEPTED MANUSCRIPT
31.4 (C7’), 30.2 (C8), 26.2 (C14), 25.6 (C15), 25.0 (C13), 22.3 (C9), 18.7 (C11), 13.5
(C16). 119Sn NMR (CDCl3)
δ: –145.9.
Dibutyl((2-(4-isobutylphenyl)propanoyl)oxy)stannyl cinnamate (6). Following the same
procedure that for compound 1, a mixture of ibuprofen (338 mg, 1.638 mmol), trans-
cinnamic acid (242 mg, 1.633 mmol), 0.874 ml of triethylamine (660 mg, 6.581 mmol) and
dibutyltin dichloride (500 mg, 1.645 mmol) were reacted. Compound 6 was obtained as a
yellow liquid. Yield: 0.930 g (96%). Analyses (%): calcd for C30H42O4Sn, C 61.56, H 7.23,
O 10.93, Sn 20.28; found, C 61.47, H 7.64. FT-IR (cm-1): ν1(O=C) 1639; ν2(O=C) 1639;
1
ν
asym(COO) 1514; νsym(COO) 1372; ν(O-C) 1365; ν(Sn-C) 593; ν(Sn-O) 448. H NMR
(CDCl3) δ
: 7.78 (d, 3J = 16.0 Hz, 1H, H7’), 7.55 (m, 1H, H2’), 7.55 (m, 1H, H6’), 7.42 (m,
1H, H4’), 7.41 (m, 1H, H3’), 7.41 (m, 1H, H5’), 7.29 (d, 3J = 8.0 Hz, 1H, H2), 7.29 (d, 3J
= 8.0 Hz, 1H, H6), 7.11 (d, 3J = 8.1 Hz, 1H, H3), 7.11 (d, 3J = 8.1 Hz, 1H, H5), 6.52 (d, 3J
= 16.0 Hz, 1H, H8’), 3.81 (q, J = 7.1 Hz, 1H, H7), 2.46 (d, J = 7.2 Hz, 2H, H9), 1.86
(hept, 3J = 6.7 Hz, 1H, H10), 1.68 (m, 2H, H14), 1.61 (m, 2H, H13), 1.49 (d, 3J = 7.2 Hz,
3H, H8), 1.33 (sext, J = 7.4 Hz, 2H, H15), 0.91 (d, J = 6.6 Hz, 3H, H11), 0.85 (t, J =
7.3 Hz, 1H, H16). 13C NMR (CDCl3)
: 184.7 (C12), 176.1 (C9’), 146.3 (C7’), 140.5 (C4),
3
3
3
3
3
δ
137.9 (C1), 134.4 (C1’), 130.4 (C4’), 129.2 (C2), 129.2 (C6), 128.9 (C2’), 128.9 (C6’),
128.4 (C3’), 128.4 (C5’),127.2 (C3), 127.2 (C5), 117.7 (C8’), 45.1 (C9), 45.0 (C7), 30.1
(C10), 26.5 (J (C13-119Sn) = 583.6 Hz; J (C13-117Sn) = 557.5 Hz), 26.2 (J (C14-117Sn) =
97.6 Hz), 25.1 (J (C15-117Sn) = 36.2 Hz), 22.3 (C11), 18.7 (C8), 13.5 (C16). 119Sn NMR
(CDCl3) δ: –150.1.
(E,Z)-dibutyl((2-(4-isobutylphenyl)propanoyl)oxy)stannyl 3-(4-fluorophenyl)acrylate (7).
Following the same procedure that for compound 1, a mixture of ibuprofen (338 mg, 1.638
mmol), 4-fluoro-trans-cinnamic acid (272 mg, 1.633 mmol) 0.874 ml of triethylamine (660
mg, 6.581 mmol) and dibutyltin dichloride (500 mg, 1.645 mmol) were reacted. The
residual solution was dried under low pressure to get compound 7 as a white solid. Yield:
0.976 g (98%). M.p. 46-48 ºC. Analyses (%): calcd for C30H41FO4Sn, C 59.72, H 6.85, F
3.15, O 10.61, Sn 19.68; found, C 60.33, H 6.81. FT-IR (cm-1): ν1(O=C) 1626; ν2(O=C)
1
1565; νasym(COO) 1508; νsym(COO) 1387; ν(O-C) 1340; ν(Sn-C) 626; ν(Sn-O) 468. H
3
NMR (CDCl3)
δ
: 7.74 (d, 3J = 16.0 Hz, 1H, H7’), 7.53 (d, J = 5.6 Hz, 1H, H2’), 7.53 (d,
3J = 5.6 Hz, 1H, H6’), 7.28 (d, 3J = 5.8 Hz, 1H, H3’), 7.28 (d, 3J = 5.8 Hz, 1H, H5’), 7.11
(d, 3J = 7.8 Hz, 1H, H2), 7.11 (d, 3J = 7.8 Hz, 1H, H6), 7.09 (d, 3J = 7.8 Hz, 1H, H3), 7.09
(d, J = 7.8 Hz, 1H, H5), 6.43 (d, 3J = 16.8 Hz, 1H, H8’), 3.80 (q, J = 7.0 Hz, 1H, H7),
3
3
2.45 (d, 3J = 7.0 Hz, 2H, H9), 1.86 (hept, J = 6.6 Hz, 1H, H10), 1.75 (m, 2H, H13), 1.65
3
(m, 2H, H14), 1.53 (d, 3J = 7.1 Hz, 3H, H8), 1.33 (sext,3J = 7.3 Hz, 1H, H15), 0.90 (d, 3J
= 6.6 Hz, 3H, H11), 0.86 (t, J = 7.2 Hz, 3H, H16). 13C NMR (CDCl3)
δ
: 185.0 (C12),
3
176.0 (C9’), 162.2 (J (C4’-19F) = 251.6 Hz ), 144.9 (C7’), 140.4 (C4), 137.9 (C1), 130.6
(C1’), 130.0 (C3’), 130.0 (C5’), 129.0 (C2), 129.0 (C6), 127.1 (C3), 127.1 (C5), 117.5
(C8’), 115.9 (C2’), 115.9 (C6’), 45.1 (C9), 45.0 (C7), 30.1 (C10), 26.2 (J (C13-119Sn) =
18

ACCEPTED MANUSCRIPT
584.6 Hz; J (C13-117Sn) = 559.5 Hz), 26.0 (J (C14-119Sn) = 98.6 Hz C14), 25.1 (J (C15-
119Sn) = 36.2 Hz C15), 22.3 (C11), 18.7 (C8), 13.5 (C16). 119Sn NMR (CDCl3)
δ: –149.5.
(E,Z)-dibutyl((2-(4-isobutylphenyl)propanoyl)oxy)stannyl 3-(4-chlorophenyl)acrylate (8).
Following the same procedure that for compound 1, a mixture of ibuprofen (338 mg, 1.638
mmol), 4-chloro-trans-cinnamic acid (299 mg, 1.653 mmol), 0.874 ml of triethylamine
(660 mg, 6.581 mmol) and dibutyltin dichloride (500 mg, 1.645 mmol) was reacted. The
residual solution was dried under low pressure to get compound 8 as a yellow crystalline
solid. Yield: 0.990 g (98%). M.p. 83-85 ºC. Analyses (%): calcd for (C30H41ClO4Sn)2-H2O,
C 57.30, H 6.73, Cl 5.72, O 10.33, Sn 19.15; found, C 57.08, H 6.75. FT-IR (cm-1):
ν1(O=C) 1687; ν2(O=C) 1627; νasym(COO) 1510; νsym(COO) 1386; ν(O-C) 1334; ν(Sn-C)
1
3
637; ν(Sn-O) 452. H NMR (CDCl3) δ
: 7.69 (d, 3J = 16.3 Hz, 1H, H7’), 7.53 (d, J = 7.9
Hz, 1H, H2’), 7.53 (d, 3J = 7.9 Hz, 1H, H6’), 7.39 (d, 3J = 7.9 Hz, 1H, H3’), 7.39 (d, 3J =
7.9 Hz, 1H, H5’), 7.27 (d, 3J = 7.6 Hz, 1H, H2), 7.27 (d, J = 7.6 Hz, 1H, H6), 7.09 (d, 3J
3
= 7.4 Hz, 1H, H3), 7.09 (d, 3J = 7.4 Hz, 1H, H5), 6.48 (d, 3J = 15.9 Hz, 1H,H8’), 3.79 (q,
3J = 6.8 Hz, 1H, H7), 2.44 (d, J = 6.9 Hz, 2H, H9), 1.86 (hept, J = 6.8 Hz, 1H, H10),
3
3
3
3
1.71 (m, 1H, H13), 1.65 (m, 1H, H14), 1.53 (d, J = 7.8 Hz, 3H,H8), 1.31 (sext, J = 7.5
Hz, 2H, H15), 0.88 (d, J = 6.4 Hz, 3H, H11), 0.84 (t, J = 7.3 Hz, 3H, H16). C NMR
(CDCl3) : 185.0 (C12), 175.9 (C9’), 144.7 (C7’), 140.4 (C4), 132.1 (C2’), 137.9 (C1),
3
3
13
δ
133.3 (C4’), 132.1 (C6’) 129.5 (C3), 129.5 (C5), 129.2 (C2), 129.2 (C6), 127.1 (C3’),
127.1 (C5’), 124.6 (C1’), 118.5 (C8’), 45.1 (C9), 45.0 (C7), 30.1 (C10), 26.3 (J (C13-119Sn)
= 568.5 Hz; J (C13-117Sn) = 555.5 Hz), 26.2 (J (C14-119Sn) = 97.6 Hz), 25.1 (J (C15-119Sn)
= 37.2 Hz), 22.3 (C11), 18.7 (C8), 13.5 (C16). 119Sn NMR (CDCl3)
δ: –149.4.
(E,Z)-dibutyl((2-(4-isobutylphenyl)propanoyl)oxy)stannyl 3-(4-bromophenyl)acrylate (9).
Following the same procedure that for compound 1, a mixture of ibuprofen (338 mg, 1.638
mmol), 4-bromocinnamic acid (372 mg, 1.638 mmol), 0.874 ml of triethylamine (660 mg,
6.581 mmol) and dibutyltin dichloride (500 mg, 1.645 mmol) were reacted. The residual
solution was dried under low pressure to get compound 9 as a yellow crystalline solid.
Yield: 1.006 g (97%). M.p. 60-62 ºC. Analyses (%): calcd for (C30H41ClO4Sn)2-H2O, C
54.24, H 6.22, Br 12.03, O 9.63, Sn 17.87; found, C 5.74, H 9.90. FT-IR (cm-1): ν1(O=C)
1626; ν2(O=C) 1566; νasym(COO) 1513; νsym(COO) 1384; ν(O-C) 1338; ν(Sn-C) 583; ν(Sn-
1
3
3
O) 433. H NMR (CDCl3)
δ: 7.71 (d, J = 16.0 Hz, 1H, H7’), 7.46 (d, J = 8.4 Hz, 1H,
H3’), 7.46 (d, 3J = 8.4 Hz, 1H, H5’), 7.36 (d, 3J = 8.4 Hz, 1H, H6’), 7.36 (d, 3J = 8.4 Hz,
3
3
3
1H, H2’), 7.26 (d, J = 8.0 Hz, 1H, H2), 7.26 (d, J = 8.0 Hz, 1H, H6), 7.09 (d, J = 8.4
Hz, 1H, H3), 7.09 (d, 3J = 8.4 Hz, 1H, H5), 6.47 (d, J = 16.0 Hz, 1H, H8’), 3.79 (q, J =
3
3
7.1 Hz, 1H, H7), 2.46 (d, 3J = 7.2 Hz, 2H, H9), 1.84 (hept, 3J = 6.7 Hz, 1H, H10), 1.72 (m,
3
3
2H, H13), 1.64 (m, 1H, H14), 1.53 (d, J = 7.2 Hz, 3H, H8), 1.32 (sext, J = 7.3 Hz, 2H,
H15), 0.88 (d, 3J = 6.6 Hz, 3H, H11), 0.85 (t, 3J = 7.3 Hz, 3H, H16). 13C NMR (CDCl3)
δ
:
184.9 (C12), 175.8 (C9’) 140.4 (C4), 144.7 (C7’), 137.9 (C1), 132.9 (C1’), 129.5 (C3’),
129.5 (C5’), 129.3 (C2), 129.2 (C6), 129.2 (C2’), 129.2 (C4’), 129.2 (C6’), 127.1 (C3),
19

ACCEPTED MANUSCRIPT
127.1 (C5), 118.3 (C8’), 45.1 (C9), 45.0 (C7), 30.1 (C10), 26.3 (J (C13-119Sn) = 571.5 Hz;
J (C13-117Sn) = 558.2 Hz), 26.2 (J (C14-119Sn) = 96.5 Hz), 25.1 (J (C15-119Sn) = 36.2 Hz),
22.3 (C11), 18.7 (C8), 13.5 (C16). 119Sn NMR (CDCl3)
δ: –149.3.
4.3. General procedure for the synthesis of stannoxanes ibuprofen derivatives using glycol
spacers (10-13)
As a first step for the synthesis of compounds, the coupling between ibuprofen and the
diols (i.e., the spacer group) was performed (Scheme 2: I, II). After purification, the free
alcohol in this structure acts as nucleophile against organotin(IV) halides to form the
stannoxanes 10-13 (Scheme 2).
O
O
DCC/DMAP(10%)
Ph2SnCl2
o
+
HO
OH
n
+
O
OH
n
OH
CH2Cl2:THF
Bu3SnCl
1h 0°C & 6h 25°C
I
II
(n = 2)
(n = 3)
Et3N
Toluene
110°C
8h
8
7
10
11
12
13
(R1, R2, R3 = Bu; n = 2)
(R1, R2, R3 = Bu; n = 3)
(R1, R3 = Ph; R2 = I)
(R1, R3 = Ph; R2 = II)
2
5
1
O
3
11
R1
12
10
4
6
O
O
Sn R2
R3
n
9
13-14, I
13-15, II
Scheme 2. Synthesis and sequence enumeration of stannoxanes ibuprofen derivatives with
spacers groups.
2-hydroxyethyl 2-(4-isobutylphenyl)propanoate (I) and 3-hydroxypropyl 2-(4-
isobutylphenyl)propanoate (II). In a dry flask, the ibuprofen (1000 mg, 4.85 mmol),
dimethylaminopyridine (60 mg, 0.48 mmol) and ethylene or propylene glycol (14.56
mmol) were added in dry tetrahydrofuran (THF) and dichloromethane (DCM) (1:1), this
mixture was stirred and the dicyclohexylcarbodiimide (1000 mg, 4.84 mmol) was added
dropwise over 30 min in anhydrous dichloromethane solution, the reaction mixture was
stirred at 0 °C for 2 h and then kept overnight at room temperature. The dicyclohexylurea
(DCU) was separated by filtration and washed with HCl (0.05 N, 30 ml), 5% potassium
bicarbonate and water, respectively, the mixture was dried over anhydrous MgSO4, the
solvent was evaporated and the products I and II were obtained as yellow liquids with
yields of 92% and 90%, respectively [56].
2-((tributylstannyl)oxy)ethyl 2-(4-isobutylphenyl)propanoate (10). For stannoxanes 10-15,
the same procedure was used. For compound 10, in a flask ball was added the hydroxy ester
20

ACCEPTED MANUSCRIPT
(I) (1000 mg, 3.99 mmol), triethylamine (0.56 ml, 3.99 mmol) in dry toluene, then,
tributyltin chloride (1.07 ml, 3.99 mmol) was slowly added and the reaction was allowed 8h
at 110 °C. Then the solvent was evaporated at low pressure, the hydrochloride
triethylamine (Et3N: HCl) was precipitated and filtered in cold pentane, at once the solvent
was evaporated under reduced pressure. Compound 10 was obtained as a yellow liquid.
Yield: 1.68 g (78%). Analyses (%): calcd for C27H48O3Sn-(H2O)3, C 54.65, H 9.17, O
16.18, Sn 20.00; found, C 54.26, H 9.65. FT-IR (cm-1): ν(O=C) 1737; ν(O-C) 1163; ν(Sn-
C) 507; ν(Sn-O) 466. 1H NMR (CDCl3)
δ
: 7.14 (d, 3J = 8.0 Hz, 1H, H2), 7.14 (d, 3J = 8.0
3
3
Hz, 1H, H6), 7.01 (d, J = 8.0 Hz, 1H, H3), 7.01 (d, J = 8.0 Hz, 1H, H5), 4.12 (w, 2H,
H13), 3.67 (w, 1H, H7), 3.67 (w, 2H, H14), 2.38 (d, 3J = 7.2 Hz, 2H, H9), 1.78 (hept, d, 3J
= 7.2 Hz, 1H, H10), 1.55 (w, 2H, H15), 1.43 (d, 3J = 7.2 Hz, 3H, H8),1.28 (sext, 3J = 7.6
Hz, 2H, H17), 1.23 (sext, 3J = 7.6 Hz, 2H, H16), 0.85 (t, 3J = 7.2 Hz, 3H, H18), 0.81 (d, 3J
= 6.8 Hz, 3H, H11). 13C NMR (CDCl3)
δ: 175.1 (12), 140.7 (4), 137.7 (1), 129.4 (2), 129.4
(6), 127.2 (3), 127.2 (5), 66.3 (13), 62.3 (14), 45.1 (7), 45.1 (9), 30.2 (10), 27.9 (J (C17-
119Sn) = 22.1 Hz), 26.9 (J (C16-119Sn) = 63.4 Hz), 22.4 (11), 19.2 (8), 17.6 (J (C15-119Sn) =
336.1 Hz; J (C15-117Sn) = 332.0 Hz), 13.6 (18). 119Sn NMR (CDCl3)
δ: + 156.4.
3-((tributylstannyl)oxy)propyl 2-(4-isobutylphenyl)propanoate (11). Following the same
procedure that for compound 10, a mixture of compound II (1000 mg, 3.78 mmol),
triethylamine (0.53 ml, 3.78 mmol) and tributyltin chloride (1.02 ml, 3.78 mmol) was
reacted. Compound 11 was obtained as a yellow liquid. Yield: 1.72 g (82%). Analyses (%):
calcd for C28H50O3Sn-(H2O)2, C 57.06, H 9.23, O 13.57, Sn 20.14; found, C 56.28, H 9.42.
FT-IR (cm-1): ν(O=C) 1734; ν(O-C) 1166; ν(Sn-C) 536; ν(Sn-O) 462. 1H NMR (CDCl3)
δ:
7.21 (d, 3J = 8.0 Hz, 1H, H2), 7.21 (d, 3J = 8.0 Hz, 1H, H6), 7.12 (d, 3J = 8.0 Hz, 1H, H3),
7.12 (d, 3J = 8.0 Hz, 1H, H5), 4.25 (oct, 3J = 6.0 Hz, 2H, H13), 3.73 (q, 3J = 7.2 Hz, 1H,
H7), 3.55 (t, 3J = 6.8 Hz, 2H, H15), 2.47 (d, 3J = 7.2 Hz, 2H, H9), 1.86 (hept, 3J = 6.8 Hz,
1H, H10), 1.83 (sext, 3J = 6.4 Hz, 2H, H14), 1.68 (m, 3J = 7.2 Hz, 2H, H16), 1.52 (d, 3J =
3
7.2 Hz, 3H, H8), 1.41 (m, 3J = 7.2 Hz, 2H, H17), 1.33 (m, J = 7.6 Hz, 2H, H18), 0.94 (t,
3
13
3J = 7.2 Hz, 3H, H19), 0.91 (d, J = 6.8 Hz, 3H, H11). C NMR (CDCl3)
δ: 175.2 (12),
140.5 (4), 137.7 (1), 129.9 (2), 129.9 (6), 126.3 (3), 126.3 (5), 61.7 (13), 58.8 (15), 45.1 (7),
45.1 (9), 31.7 (14), 30.1 (10), 27.8 (J (C18-119Sn) = 22.1 Hz), 26.8 (J (C17-119Sn) = 64.4
Hz), 22.3 (11), 18.4 (8), 18.3 (J (C16-119Sn) = 337.1 Hz; J (C16-117Sn) = 332.0 Hz), 13.6
(19). 119Sn NMR (CDCl3)
δ: + 156.2.
((diphenylstannanediyl)bis(oxy)) bis(ethane-2,1-diyl)bis(2-(4-isobutylphenyl) propanoate)
(12)). Following the same procedure that for compound 10, a mixture of compound I (1000
mg, 3.99 mmol), triethylamine (0.56 ml, 3.99 mmol) and diphenyltin dichloride (0.68 mg,
1.99 mmol) was reacted. Compound 12 was obtained as a yellow liquid. Yield: 2.56 g
(83%). Analyses (%): calcd for C42H52O6Sn-CHCl3, C 57.97, H 6.00, O 10.77, Sn 13.32;
found, C 58.95, H 6.32. FT-IR (cm-1): ν(O=C) 1735; ν(O-C) 1162; ν(Sn-C) 517; ν(Sn-O)
1
462. H NMR (CDCl3)
δ
: 7.68 (w, 1H, H16), 7.46 (W, 1H, H17), 7.46 (w, 1H, H18), 7.16
21

ACCEPTED MANUSCRIPT
(d, 3J = 8.0 Hz, 1H, H2), 7.16 (d, 3J = 8.0 Hz, 1H, H6), 7.02 (d, 3J = 8.0 Hz, 1H, H3), 7.02
(d, 3J = 8.0 Hz, 1H, H5), 4.19 (w, 2H, H13), 3.75 (w, 1H, H7), 3.75 (w, 1H, H14), 2.45 (d,
3
3
3J = 7.2 Hz, 2H, H9), 1.86 (hept, J = 6.8 Hz, 1H, H10), 1.41 (d, J = 6.8 Hz, 3H, H8),
0.88 (d, 3J = 6.8 Hz, 3H, H11). 13C NMR (CDCl3)
δ: 175.1 (12), 141.1 (4), 137.4 (1), 137.4
(J (C15-119Sn) = 619.8 Hz), 136.2 (J (C17-119Sn) = 48.2 Hz), 130.5 (J (C18-119Sn) = 14.1
Hz), 129.8 (2), 129.8 (6), 129.2 (J (C16-119Sn) = 58.3 Hz), 127.0 (3), 127.0 (5), 66.3 (13),
61.2 (14), 45.2 (7), 45.0 (9), 30.2 (10), 22.3 (11), 18.4 (8). 119Sn NMR (CDCl3)
δ: -46.6.
((diphenylstannanediyl)bis(oxy))bis(propane-3,1-diyl) bis(2-(4-isobutylphenyl)propanoate)
(13). Following the same procedure that for compound 10, a mixture of compound II (1000
mg, 3.78 mmol), triethylamine (0.53 ml, 3.78 mmol) and diphenyltin dichloride (0.65 mg,
1.89 mmol) was reacted. Compound 13 was obtained as a yellow liquid. Yield: 2.60 g
(86%). Analyses (%): calcd for C44H56O6Sn-CHCl3, C 58.81, H 6.25, O 10.45, Sn 12.92;
found, C 58.36, H 6.47. FT-IR (cm-1): ν(O=C) 1732; ν(O-C) 1165; ν(Sn-C) 514; ν(Sn-O)
1
455. H RMN (CDCl3)
δ
: 7.67 (w, 1H, H17), 7.46 (w, 1H, H18), 7.46 (w, 1H, H19), 7.21
(d, 3J = 8.0 Hz, 1H, H2), 7.21 (d, 3J = 8.0 Hz, 1H, H6), 7.18 (d, 3J = 8.0 Hz, 1H, H3), 7.18
3
3
3
(d, J = 8.0 Hz, 1H, H5), 4.22 (m, 2H, H13), 3.69 (q, J = 7.2 Hz, 1H, H7), 3.53 (t, J =
7.2 Hz, 1H, H15), 2.45 (d, 3J = 7.2 Hz, 2H, H9), 1.85 (hept, 3J = 6.8 Hz, 1H, H10), 1.49 (d,
3J = 7.2 Hz, 3H, H8), 0.88 (d, J = 6.7 Hz, 3H, H11). 13C RMN (CDCl3)
δ
:175.3 (12),
3
140.6 (4), 137.9 (1), 137.4 (J (C16-119Sn) = 631.9 Hz), 136.1 (J (C18-119Sn) = 49.3 Hz),
130.5 (J (C19-119Sn) = 14.1 Hz), 130.3 (9) 129.5 (2), 129.5 (6), 129.2 (J (C17-119Sn) = 63.4
Hz) 127.0 (3), 127.0 (5), 61.7 (13), 59.1 (15), 45.2 (7), 45.1 (9), 31.9 (14), 30.2 (10), 22.4
(11), 18.3 (8). 119Sn RMN (CDCl3)
δ: -46.23.
3.4. Compounds (1a-13a) were analyzing directly in the NMR tube by adding DMSO-d6,
and were not isolated
(1a). 1H NMR (DMSO-d6)
δ: 7.67 (w, 1H, H7), 7.57 (w,1H, H4), 7.53 (m, 1H, H4’), 7.40
(w, 1H, H2), 7.40 (w, 1H, H6), 7.25 (w, 1H, H2’), 7.25 (w, 1H, H6’), 7.25 (w, 1H, H3’),
3
7.25 (w, 1H, H5’), 7.17 (w, 1H, H3), 7.17 (w, 1H, H5), 6.55 (d, J = 16.0 Hz, 1H, H8),
2.83 (t, 3J = 7.0 Hz, 2H, H7’), 2.83 (t, 3J = 7.0 Hz, 2H, H8’), 1.44 (w, 2H, H10), 1.35 (w,
3
3
2H, H12), 1.25 (sext, J = 7.2 Hz, 2H,H11), 0.80 (d, J = 7.2 Hz, 3H, H13). 13C NMR
(DMSO-d6) δ: 180.0 (C9’), 173.0 (C9), 143.6 (C7), 141.6 (C1’), 135.1 (C1), 130.3 (C4),
129.3 (C2’), 129.3 (C6’), 128.6 (C2),128.6 (C6), 128.6 (C3),128.6 (C5), 128.4 (C3’), 128.4
(C5’), 126.3 (C4’), 117.8 (C8), 37.1 (C8’), 36.3 (C7’), 29.9 (J (C10-119Sn) = 855.2 Hz; J
(C10-117Sn) = 827.1 Hz), 27.2 (J (C12-119Sn) = 50.3 Hz), 26.2 (J (C11-119Sn) = 138.8 Hz),
13.9 (C13). 119Sn NMR (DMSO-d6)
δ: –204.6.
(2a). 1H RMN (DMSO-d6)
δ
: 7.76 (w, 1H, H2’), 7.76 (w, 1H, H6’), 7.68 (w, 1H, H3’), 7.68
(w, 1H, H5’), 7.56 (d, 3J = 16.0 Hz, 1H, H7’), 7.56 (d, 3J = 16.0 Hz, 1H, H7), 7.39 (w, 1H,
3
3
H4), 7.39 (w, 1H, H2), 7.39 (w, 1H, H6), 7.23 (d, J = 8.7 Hz, 1H, H3), 7.23 (d, J = 87
Hz, 1H, H5), 6.58 (d, 3J = 16.0 Hz, 1H, H8’), 6.54 (d, 3J = 16.0 Hz, 1H, H8), 1.56 (w, 2H,
22

ACCEPTED MANUSCRIPT
H10), 1.45 (w, 2H, H12), 1.28 (sext, 3J = 7.2 Hz, 2H, H11), 0.95 (t, 3J = 7.3 Hz, 3H, H13).
δ
13C RMN (DMSO-d6) : 173.8 (C9’), 173.8 (C9), 163.4 (J (C4’-19F) = 248.0 Hz), 143.5
(C7), 142.2 (C7’), 135.0 (C1), 131.7 (C1’), 130.8 (C4), 130.7 (C2’), 130.7 (C6’), 129.3
(C2), 129.3 (C6), 128.5 (C3), 128.5 (C5), 121.4 (C8), 121.2 (C8’), 116.3 (C3’), 116.3
(C5’), 30.0 (J (C10-119Sn) = 835.1 Hz; J (C10-117Sn) = 820.0 Hz), 27.3 (J (C12-119Sn) =
62.3 Hz), 26.2 (J (C11-119Sn) = 137.8 Hz), 13.6 (C13). 119Sn RMN (DMSO-d6)
δ
: –193.4.
3
3
(3a). 1H NMR (DMSO-d6)
δ: 7.73 (d, J = 8.1 Hz, 1H, H2’), 7.73 (d, J = 8.1 Hz, 1H,
H6’), 7.67 (w, 1H, H3’), 7.67 (w, 1H, H5’), 7.60 (d, 3J = 15.8 Hz, 1H, H7’), 7.55 (d, J =
15.8 Hz, 1H, H7), 7.43 (d, 3J = 8.6 Hz, 1H, H2), 7.43 (d, 3J = 8.6 Hz, 1H, H6), 7.39 (d, 3J
= 8.5 Hz, 1H, H3), 7.39 (d, 3J = 8.5 Hz, 1H, H5), 7.39 (w, 1H, H4), 6.61 (d, 3J = 15.8 Hz,
3
1H, H8’), 6.57 (d, 3J = 15.8 Hz, 1H, H8), 1.53 (w, 2H, H10), 1.43 (w, 2H, H12), 1.27 (sext,
3J = 7.0 Hz, 2H, H11), 0.95 (t, J = 7.4 Hz, 3H, H13). 13C NMR (DMSO-d6)
δ
: 174.1
3
(C9’), 173.3 (C9), 143.6 (C7), 142.2 (C7’), 135.0 (C4’), 134.9 (C1’), 130.4 (C4), 130.4
(C1), 130.1 (C3’), 130.2 (C5’), 129.3 (C3), 129.3 (C5), 128.1 (C2’), 128.1 ( C6’), 128.1
(C2), 128.1 (C6), 120.9 (C8’), 120.9 (C8), 30.0 (J (C10-119Sn) = 851.2 Hz; J (C10-117Sn) =
814.0 Hz), 27.2 (J (C12-119Sn) = 57.3 Hz), 26.1 (J (C11-119Sn) = 137.8 Hz ), 14.0 (C13).
119Sn NMR (DMSO-d6)
δ
: –205.8.
1
3
3
(4a). H NMR (DMSO-d6)
δ
: 7.67 (d, J = 16.0 Hz, 1H, H7), 7.66 (d, J = 16.0 Hz, 1H,
H7’), 7.63 (m, 1H, H2’), 7.63 (m, 1H, H6’), 7.60 (m, 1H, H2), 7.60 (m, 1H, H6), 7.58 (m,
1H, H3’), 7.58 (m, 1H, H5’), 7.53 (m, 1H, H3), 7.53 (m, 1H, H5), 7.40 (m, 1H, H4), 6.59
(d, 3J = 8.4 Hz, 1H, H8’), 6.55 (d, 3J = 8.5 Hz, 1H, H8), 1.58 (m, 1H, H10), 1.43 (m, 1H,
H12), 1.24 (sext, 3J = 7.1 Hz, 2H, H11), 0.81 (t, 3J = 7.2 Hz, H1, H13). 13C NMR (DMSO-
d6) δ: 172.6 (C9’),172.6 (C9), 143.4 (C7), 141.9 (C7’), 135.0 (C4’), 134.4 (C1’), 132.3
(C4), 130.3 (C1), 130.4 (C2’), 130.4 (C6’), 129.3 (C3’), 129.3 (C5’), 129.3 (C3), 129.3
(C5), 128.4 (C2), 128.4 (C6),122.3 (C8’), 121.3 (C8), 29.3 (J (C10-119Sn) = 855.2 Hz; J
(C10-117Sn) = 854.2 Hz), 27.2 (J (C12-119Sn) = 72.4 Hz ), 26.2 (J (C11-119Sn) = 139.8 Hz ),
13.9 (C13). 119Sn NMR (DMSO-d6)
δ
: –198.4.
(5a). 1H NMR (DMSO-d6)
δ: 7.23 (w, 1H, H2’), 7.23 (w, 1H, H6’), 7.25 (w, 1H, H4), 7.20
3
3
(d, J = 7.9 Hz, 1H, H2), 7.23 (d, J = 7.9 Hz, 1H, H6), 7.21 (w, 1H, H3’), 7.21 (w, 1H,
H5’), 7.01 (d, 3J = 7.8 Hz, 1H, H3), 7.01 (d, 3J = 78 Hz, 1H, H5), 3.58 (q, 3J = 7.0 Hz, 1H,
H7), 2.84 (d, 3J = 7.5 Hz, 2H, H7’), 2.50 (d, J = 7.5. Hz, 2H, H8’), 2.39 (d, J = 7.1 Hz,
3
3
2H, H9), 1.86 (hept, 3J = 6.6 Hz, 1H, H10), 1.64 (H13), 1.54 (H14), 1.34 (d, J = 7.1 Hz,
3
2H, H8), 1.30 (w, 2H, H13), 1.22 (w, 2H, H14), 1.13 (sext, 3J = 7.1 Hz, 2H, H15) 0.84 (d,
3J = 6.8 Hz, 3H, H11), 0.72 (t, J = 7.9 Hz, 3H, H16). 13C NMR (DMSO-d6)
δ
: 181.6
3
(C12), 179.4 (C9’), 141.6 (C4), 139.6 (C1’), 139.6 (C1), 129.2 (C2), 129.2 (C6), 128.9
(C3), 128.9 (C4’), 128.9 (C5), 126.5 (C3’), 126.5 (C5’), 126.3 (C2’), 126.3 (C6’), 45.1
(C9), 45.0 (C7), 36.2 (C8’), 31.4 (C7’), 30.3 (J (C13-119Sn) = 867.3 Hz; J (C13-117Sn) =
847.2 Hz), 30.1 (C10), 27.8 (J (C15-119Sn) = 41.6 Hz), 26.1 (J (C14-119Sn) = 142.8 Hz),
22.6 (C11), 19.4 (C8), 14.0 (C16). 119Sn NMR (DMSO-d6)
δ: –167.4.
23

ACCEPTED MANUSCRIPT
(6a). 1H NMR (DMSO-d6)
δ
: 7.64 (d, 3J = 16.0 Hz, 1H, H7’), 7.45 (m, 1H, H4’), 7.40 (m,
3
1H, H2’), 7.40 (m, 1H, H6’), 7.38 (m, 1H, H3’), 7.38 (m, 1H, H5’), 7.21 (d, J = 8.0 Hz,
1H, H2), 7.21 (d, 3J = 8.0 Hz, 1H, H6), 7.05 (d, 3J = 7.9 Hz, 1H, H3), 7.05 (d, 3J = 7.9 Hz,
1H, H5), 6.52 (d, 3J = 16.0 Hz, 1H, H8’), 3.52 (q, J = 7.4 Hz, 1H, H7), 2.39 (d, J = 7.1
3
3
Hz, 2H, H9), 1.85 (hept, 3J = 6.6 Hz, 1H, H10), 1.44 (d, 3J = 7.9 Hz, 3H, H8), 1.33 (m, 2H,
3
3
H13), 1.30 (m, 2H, H14), 1.17 (sext, J = 7.5 Hz, 2H, H15), 0.84 (d, J = 6.9 Hz, 3H,
3
13
H11), 0.75 (t, J = 7.1 Hz, 1H, H16). C NMR (DMSO-d6) δ: 181.0 (C12), 172.5 (C9’),
143.8 (C7’), 139.7 (C4), 135.0 (C1), 134.9 (C1’), 130.4 (C4’), 129.3 (C2), 129.3 (C6),
129.2 (C3’), 129.2 (C5’), 128.5 (C2’), 128.5 (C6’),127.6 (C3), 127.6 (C5), 120.6 (C8’),
44.7 (C9), 43.3 (C7), 29.9 (C10), 30.3 (J (C13-119Sn) = 856.3 Hz; J (C13-117Sn) = 839.1
Hz), 27.3 (J (C15-117Sn), 26.2 (J (C14-117Sn) = 144.8 Hz), = 34.1 Hz), 22.6 (C11),
19.3(C8), 14.0 (C16). 119Sn NMR (DMSO-d6)
δ: –172.1.
1
3
3
(7a). H NMR (DMSO-d6)
δ: 7.71 (d, J = 8.6 Hz, 1H, H2’), 7.71 (d, J = 8.6 Hz, 1H,
H6’), 7.54 (d, 3J = 16.0 Hz, 1H, H7’), 7.45 (d, 3J = 8.5 Hz, 1H, H3’), 7.45 (d, 3J = 8.5 Hz,
3
3
3
1H, H5’), 7.21 (d, J = 7.8 Hz, 1H, H2), 7.21 (d, J = 7.8 Hz, 1H, H6), 7.02 (d, J = 8.1
Hz, 1H, H3), 7.02 (d, 3J = 8.1 Hz, 1H, H5), 6.56 (d, J = 16.0 Hz, 1H, H8’), 3.59 (q, J =
3
3
7.1 Hz, 1H, H7), 2.38 (d, 3J = 7.1 Hz, 2H, H9), 1.78 (hept, 3J = 6.6 Hz, 1H, H10), 1.45 (m,
2H, H13), 1.38 (m, 2H, H14), 1.35 (d, J = 7.1 Hz, 3H, H8), 1.21(sext,3J = 7.2 Hz, 1H,
3
H15), 0.83 (d, 3J = 6.6 Hz, 3H, H11), 0.78 (t, 3J = 7.3 Hz, 3H, H16). 13C NMR (DMSO-d6)
δ
: 172.3 (C12), 172.3 (C9’), 164.4 (J (C4’-19F) = 248.0 Hz), 144.4 (C7’), 139.7 (C4), 135.9
(C1), 131.6 (C1’), 130.8 (C2’), 130.8 (C6’), 130.2 (C2), 130.2 (C6), 127.6 (C3), 127.6
(C5), 120.7 (C8’), 116.3 (C3’), 116.3 (C5’), 45.4 (C9), 44.7 (C7), 31.3 (C10), 30.2 (J (C13-
119Sn) = 857.3 Hz; J (C13-117Sn) = 813.0 Hz), 27.4 (J (C14-119Sn) = 140.8 Hz C14), 26.2 (J
(C15-119Sn) = 35.1 Hz C15), 22.6 (C11), 19.4 (C8), 14.0 (C16). 119Sn NMR (DMSO-d6)
–149.5.
δ:
3
3
(8a). 1H NMR (DMSO-d6)
δ: 7.64 (d, J = 8.6 Hz, 1H, H2’), 7.64 (d, J = 8.6 Hz, 1H,
H6’), 7.59 (d, 3J = 8.6 Hz, 1H, H3’), 7.59 (d, 3J = 8.6 Hz, 1H, H5’), 7.52 (d, 3J = 16.0 Hz,
3
3
3
1H, H7’), 7.21 (d, J = 8.0 Hz, 1H, H2), 7.21 (d, J = 8.0 Hz, 1H, H6), 7.01 (d, J = 8.0
Hz, 1H, H3), 7.01 (d, 3J = 8.0 Hz, 1H, H5), 6.58 (d, J = 16.0 Hz, 1H, H8’), 3.60 (q, J =
3
3
7.1 Hz, 1H, H7), 2.44 (d, 3J = 7.1 Hz, 2H, H9), 1.78 (hept, 3J = 6.8 Hz, 1H, H10), 1.43 (m,
3
3
1H, H13), 1.43 (m, 1H, H14), 1.53 (d, J = 7.1 Hz, 3H, H8), 1.31 (sext, J = 7.1 Hz, 2H,
H15), 0.82 (d, 3J = 6.6 Hz, 3H, H11), 0.77 (t, 3J = 7.3 Hz, 3H, H16). 13C NMR (DMSO-d6)
δ
: 172.7 (C12), 172.7 (C9’), 142.2 (C7’), 142.2 (C4’), 139.7 (C4), 134.4 (C1), 132.2 (C2’),
132.2 (C6’) 127.6 (C3), 127.6 (C5), 130.4 (C2), 130.4 (C6), 129.2 (C3’), 129.2 (C5’),
134.4 (C1’), 116.3 (C8’), 44.7 (C9), 45.4 (C7), 30.1 (C10), 30.3 (J (C13-119Sn) = 850.2 Hz;
J (C13-117Sn) = 825.1 Hz), 26.1 (J (C14-119Sn) = 139.8 Hz), 27.5 (J (C15-119Sn) = 38.2
Hz), 22.6 (C11), 20.0 (C8), 14.0 (C16). 119Sn NMR (DMSO-d6)
δ: –149.4.
1
3
3
(9a). H NMR (DMSO-d6) δ: 7.71 (d, J = 16.0 Hz, 1H, H7’), 7.46 (d, J = 8.4 Hz, 1H,
H2’), 7.46 (d, 3J = 8.4 Hz, 1H, H6’), 7.36 (d, 3J = 8.4 Hz, 1H, H2’), 7.36 (d, 3J = 8.4 Hz,
24

ACCEPTED MANUSCRIPT
1H, H6’), 7.26 (d, 3J = 8.0 Hz, 1H, H3’), 7.26 (d, 3J = 8.0 Hz, 1H, H5’), 7.09 (d, 3J = 8.4
3
3
Hz, 1H, H3), 7.09 (d, 3J = 8.4 Hz, 1H, H5), 6.47 (d, J = 16.0 Hz, 1H, H8’), 3.79 (q, J =
7.1 Hz, 1H, H7), 2.46 (d, 3J = 7.2 Hz, 2H, H9), 1.84 (hept, 3J = 6.7 Hz, 1H, H10), 1.72 (m,
2H, H13), 1.64 (m, 1H, H14), 1.53 (d, J = 7.2 Hz, 3H, H8), 1.32 (sext, J = 7.3 Hz, 2H,
H15), 0.88 (d, 3J = 6.6 Hz, 3H, H11), 0.85 (t, 3J = 7.3 Hz, 3H, H16). 13C NMR (DMSO-d6)
3
3
δ
: 184.9 (C12), 175.8 (C9’) 140.4 (C4), 144.7 (C7’), 137.9 (C1), 132.9 (C4’), 129.5 (C3’),
129.5 (C5’), 129.3 (C2), 129.2 (C6), 129.2 (C2’), 129.2 (C1’), 129.2 (C6’), 127.1 (C3),
127.1 (C5), 118.3 (C8’), 45.1 (C9), 45.0 (C7), 30.1 (C10), 26.3 (J (C13-119Sn) = 571.5 Hz;
J (C13-117Sn) = 558.2 Hz), 26.2 (J (C14-119Sn) = 96.5 Hz), 25.1 (J (C15-119Sn) = 36.2 Hz),
22.3 (C11), 18.7 (C8), 13.5 (C16). 119Sn NMR (DMSO-d6)
δ: –149.3.
(10a). 1H NMR (DMSO-d6)
δ
: 7.13 (d, 3J = 8.0 Hz, 1H, H2), 7.13 (d, 3J = 8.0 Hz, 1H, H6),
3
7.01 (d, J = 8.0 Hz, 1H, H3), 7.01 (d, 3J = 8.0 Hz, 1H, H5), 4.12 (m, 2H, H13), 3.64 (w,
1H, H7), 3.64 (w, 2H, H14), 2.38 (d, 3J = 7.2 Hz, 2H, H9), 1.77 (hept, d, 3J = 6.8 Hz, 1H,
H10), 1.57 (w, 2H, H15), 1.41 (d, J = 7.2 Hz, 3H, H8),1.29 (sext, 3J = 7.6 Hz, 2H, H17),
3
1.22 (sext, 3J = 8.0 Hz, 2H, H16), 0.85 (t, 3J = 7.6 Hz, 3H, H18), 0.81 (d, 3J = 6.8 Hz, 3H,
H11). 13C NMR (DMSO-d6)
δ: 175.0 (12), 140.7 (4), 137.7 (1), 129.5 (2), 129.5 (6), 127.1
(3), 127.1 (5), 66.2 (13), 60.8 (14), 45.0 (7), 45.0 (9), 30.1 (10), 27.8 (J (C17-119Sn) = 23.1
Hz), 26.8 (J (C16-119Sn) = 64.3 Hz), 22.3 (11), 19.4 (8), 17.7 (J (C15-119Sn) = 343.2 Hz; J
(C15-117Sn) = 327.0 Hz), 13.5 (18). 119Sn NMR (DMSO-d6)
δ: + 148.9.
(11a). 1H NMR (DMSO-d6) : 7.16 (d, 3J = 8.0 Hz, 1H, H2), 7.16 (d, 3J = 8.0 Hz, 1H, H6),
δ
7.05 (d, 3J = 8.0 Hz, 1H, H3), 7.05 (d, 3J = 8.0 Hz, 1H, H5), 4.18 (w, 2H, H13), 3.65 (q, 3J
3
= 6.0 Hz, 1H, H7), 3.49 (w, 2H, H15), 2.40 (d, J = 7.2 Hz, 2H, H9), 1.74 (w, 1H, H10),
3
1.74 (w, 2H, H14), 1.60 (m, 2H, H16), 1.45 (d, J = 7.2 Hz, 3H, H8), 1.33 (m, 2H, H18),
3
3
1.29 (m, 3J = 7.2 Hz, 2H, H17), 0.90 (t, J = 7.6 Hz, 3H, H19), 0.84 (d, J = 6.6 Hz, 3H,
H11). 13C NMR (DMSO-d6)
δ: 175.0 (12), 140.5 (4), 137.7 (1), 129.3 (2), 129.3 (6), 127.1
(3), 127.1 (5), 61.7 (13), 58.8 (15), 4501 (7), 45.0 (9), 31.7 (14), 30.1 (10), 27.8 (J (C18-
119Sn) = 23.1 Hz), 26.8 (J (C17-119Sn) = 64.4 Hz), 22.3 (11), 18.4 (8), 17.9 (J (C16-119Sn) =
339.1 Hz), 13.1 (19). 119Sn NMR (DMSO-d6)
δ: + 143.8.
1
(12a). H NMR (DMSO-d6)
δ
: 7.72 (w, 1H, H16), 7.49 (w, 1H, H17), 7.49 (w, 1H, H18),
7.22 (d, 3J = 8.0 Hz, 1H, H2), 7.22 (d, 3J = 8.0 Hz, 1H, H6), 7.10 (d, 3J = 8.0 Hz, 1H, H3),
3
7.10 (d, J = 8.0 Hz, 1H, H5), 4.23 (m, 2H, H13), 3.79 (w, 1H, H7), 3.79 (w, 1H, H14),
2.44 (d, 3J = 7.2 Hz, 2H, H9), 1.88 (hetp, 3J = 6.8 Hz, 1H, H10), 1.49 (d, 3J = 7.2 Hz, 3H,
H8), 0.91 (d, 3J = 6.4 Hz, 3H, H11). 13C NMR (DMSO-d6)
δ: 175.1 (12), 140.7 (4), 137.7
(1), 137.5 (J (C15-119Sn) = 619.8 Hz), 136.1 (J (C17-119Sn) = 42.3 Hz), 130.5 (C18), 129.3
(2), 129.3 (6), 129.1 (J (C16-119Sn) = 62.4 Hz), 127.1 (3), 127.1 (5), 66.3 (13), 61.2 (14),
45.1 (7), 45.0 (9), 30.2 (10), 22.4 (11), 18.4 (8). 119Sn NMR (DMSO-d6)
δ: -63.7.
1
(13a). H NMR (DMSO-d6)
δ
: 7.75 (w, 1H, H17), 7.46 (w, 1H, H18), 7.46 (w, 1H, H19),
7.21 (d, 3J = 8.4 Hz, 1H, H2), 7.21 (d, 3J = 8.4 Hz, 1H, H6), 7.09 (d, 3J = 8.0 Hz, 1H, H3),
25

ACCEPTED MANUSCRIPT
3
3
3
7.09 (d, J = 8.0 Hz, 1H, H5), 4.23 (t, J = 6.4 Hz, 2H, H13), 3.72 (q, J = 7.2 Hz, 1H,
H7), 3.52 (t, 3J = 6.0 Hz, 1H, H15), 2.47 (d, 3J = 7.2 Hz, 2H, H9), 1.85 (hept, 3J = 6.8 Hz,
1H, H10), 1.51 (d, J = 7.2 Hz, 3H, H8), 0.91 (d, J = 6.8 Hz, 3H, H11). 13C NMR
3
3
(DMSO-d6) δ
:175.1 (12), 140.6 (4), 137.7 (1), 138.8 (C16), 136.2 (J (C18-119Sn) = 49.3
Hz), 130.1 (J (C19-119Sn) = 13.1 Hz), 130.3 (2), 130.3 (6), 129.1 (J (C17-119Sn) = 63.4 Hz)
127.0 (3), 127.0 (5), 61.7 (13), 59.0 (15), 45.1 (7), 45.0 (9), 32.7 (14), 30.5 (10), 22.4 (11),
18.4 (8). 119Sn NMR (DMSO-d6)
δ: -73.6.
4.5. Computational details
Full structure optimizations, without symmetry constraints, were performed with the
hybrid exchange–correlation functional, B3LYP [57-60]. To confirm the optimized minima
on the potential energy surface, a frequency analysis was performed. All electrons were
treated explicitly using the triple zeta valence plus polarization (def2-TZVP) [61, 62] basis
set for all atoms as they are implemented in the Gaussian 09 code [63].
4.5.1 Molecular docking
Molecular dockings were carried out on Molegro Virtual Docker (MVD) 6 [64],
employing the crystal structure (retrieved from the Protein Data Bank) of COX-1 [PDB:
1EQG] [65] and COX-2 [PDB: 4PH9] [66], complex with ibuprofen. Both, rigid and
flexible docking approaches were performed. The potential binding sites (defined as
cavities) of both: COX-1 and COX-2 were detected by the expanded Van der Waals
spheres method.
The cavities found for COX-1 (61.44 Å3) and COX-2 (56.32Å3), where all the binding
calculations were performed, corresponded to the active site of each isoform. All water
molecules were removed from the crystal.
For the flexible approach, a total of 47 residues were set as flexible for COX-2 and 46
for COX-1. Partial charges were set according to MVD´s 6.0 internal charge scheme. All
the residues bearing four or more free rotating bonds were assigned as a zero strength
factor. For those whose number of free rotating bonds was less than four, a one strength
factor was set. The search function MolDock SE (Simplex Evolution) was employed for
COX-1 and MolDock Optimizer for COX-2, both functions used genetic algorithm
technique for searching the best binding site of a given enzyme. The scoring function
Moldock Score [GRID] was used to calculate the binding energy. A value of 2000
minimization steps for each flexible residue and the ligand, and 2000 steps of global
minimization per run were set. For the scoring function, the GRID partition was of 0.2 Å
26

ACCEPTED MANUSCRIPT
and the search sphere was fixed with a 10 Å radius. For the energetic analysis of the ligand:
the electrostatic internal interactions, the internal H-bond and the sp2-sp2 torsions were
used. For the MolDock SE function a total of 15 runs with a maximum of 1500 iterations
using a population of 50 individuals per run were set. For Moldock SE optimizer the same
number of runs was set with a maximum of 2000 iterations and a population of 100
individuals per run.
Rather than looking for overall binding energies, the interactions with residues that are
considered key to selectively binding to each isoform were analyzed and compared among
stannoxanes and reference compounds following the reported method [48, 67].
The method was validated by reproducing the experimental binding mode of the
reference inhibitor, with a root mean square deviation (RMSD) value of 0.38 Å for COX-1
and 0.56 Å for COX-2 (see supporting information).
Acknowledgements
Maria Romero-Chávez is grateful for the scholarship 289752 from CONACYT-México and
Partial funding support by grant #130381 and grant #226165 provided by CONACYT are
also acknowledged.
D.J.P gratefully acknowledges The National Council for Science and Technology
(CONACYT, México) for the Postdoctoral Fellowship (287012), granted under the
program “Estancias Posdoctorales en el Extranjero”.
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