Making Bispirin: Synthesis, structure and activity against Helicobacter pylori of bismuth(iii) acetylsalicylate

Article abstract of DOI:10.1039/c3cc40645h

Reaction of Bi(O^tBu)₃ with aspirin (acetylsalicylic acid = aspH) in dry toluene results in the bismuth(iii) complex, [Bi(O ₂C(C₆H₄)OAc)₃]_∞ 1 (O₂C(C₆H₄)OAc = asp), minimum inhibitory concentration (MIC) against Helicobacter pylori ≥ 6.25 μg mL^-1, while the inclusion of a stoichiometric equivalent of KO^tBu leads to crystals of the bismuthate salt [KBi(O₂C(C₆H ₄)OAc)₄]_∞ 2. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc40645h

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Graphical Abstract
The bismuth(III) complexes of acetylsalicylate (aspirinate), [Bi(asp)3] and [KBi(asp)4],
are formed and crystallised without deacetylation or hydrolysis from treatment of
aspirin with Bi(OtBu)3 and Bi(OtBu)3/KOtBu respectively, with [Bi(asp)3], showing a
minimum inhibitory concentration of 6.25 ug/mL against H. pylori.
Activity against H. pylori:
6.25 µg mL-1 (9.4 µM)

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ARTICLE TYPE
Making Bispirin: Synthesis, structure and activity against Helicobacter
pylori of bismuth(III) acetylsalicylate
Philip C. Andrews,a Victoria L. Blair,a Richard L. Ferrero,b Peter C. Junkb and Ish Kumara
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Reaction of Bi(OtBu)3 with aspirin (acetylsalicylic acid =
to have potential in a wider range of biological and therapeutic
50 activities; for example, the organometallic cobalt(II) complex
[(μ4-η2)-(prop-2-ynyl)-2-acetoxybenzoate] dicobalthexacarbonyl
is cytotoxic towards tumorous cells,17 and bis-substituted
[Zn(asp)2] complexes are described as promising candidates for
treating type-2 diabetes and metabolic disorders.18 Other
55 examples for which crystal structures of the ‘active compounds’
are known are: [Cu2(asp)4(DMF)2]19 and [Zn(asp)(H2O)2]20 as
anticonvulsants; [Cu2(asp)4(DMSO)2] as an antioxidant;21 and
[Ag(asp)(PPh3)3]DMF as an anti-tumour agent.22
In this vein, we recently described the synthesis,
60 characterisation and activity against H. pylori of bismuth(III)
carboxylates derived from a series of common NSAIDs,23 as well
as the polynuclear oxido-cluster structure of bismuth
subsalicylate.24 However, the aspirin derivative remained elusive
due to facile deacetylation during deprotonation and
65 complexation, a common problem since bases frequently increase
the rate of hydrolysis and/or deacetylation. The only previous
report in this arena coming from a solution study on the 2:1
complex formed between acetylsalicylic acid and bismuth
nitrate.25
aspH) in dry toluene results in the bismuth(III) complex,
[Bi(O2C(C6H4)OAc)3]∞ 1 (O2C(C6H4)OAc = asp), minimum
inhibitory concentration (MIC) against Helicobacter pylori ≥
10 6.25 μg mL-1, while the inclusion of
a stoichiometric
equivalent of KOtBu leads to crystals of the bismuthate salt
[KBi(O2C(C6H4)OAc)4]∞ 2.
Acetylsalicylic acid (or Aspirin) is one of the worlds most
widely used drugs, providing anti-inflammatory, anti-pyretic and
2
15 analgesic action.1, In contrast to other common non-steroidal
anti-inflammatory drugs (NSAIDs) it acts irreversibly by
deactivating both COX-1 and COX-2 enzymes. In low doses (<
300 mg per day) it functions as an anti-platelet agent, preventing
heart attack and blood-clotting and thus lowering the risk of
20 adverse cardiovascular and brain-bleeding events.3,4 It has also
been demonstrated to reduce and delay incidences of various
types of cancer when taken on a regular basis.3-6 As with other
NSAIDs, the major drawback in the consistent ingestion of
aspirin is a greater risk of upper-gastrointestinal bleeding,
25 affecting 1 - 2 % of patients, though this can be higher is some
8
populations.7, The associated risk factors include; old age, a
70
Having explored various synthetic routes and reaction
conditions for the formation of bismuth aspirinate complexes, we
can now describe the formation, stability, solubility and crystal
history of peptic ulcer disease, co-administration of other
NSAIDs, antithrombotic drugs, and infection by Helicobacter
pylori.7 While there have been contradictory reports dealing with
30 the relationship of NSAIDs, H. pylori and peptic ulcer disease,7 it
is now generally accepted that H. pylori infection should be
treated to minimise the possibility of NSAID induced
structures of [Bi(asp)3]∞
1 and [KBi(asp)4]∞ 2, and the
bactericidal activity of 1 against three strains of H. pylori.
75
The protolysis reaction of aspirin with BiPh3 (3:1) under both
solvent-mediated and solvent-free conditions, our typical routes
into bismuth carboxylates, proved problematic providing a
mixture of complexes, including those formed through
deacetylation. The DSC for the solvent-free reaction shows an
10
gastrointestinal injury, ulceration and prolonged bleeding.9,
Attempts to minimise aspirin related gastrointestinal injury have
35 primarily focused on dose lowering and modified release
formulations. This appears to have little effect.8
80 exotherm (73.5 °C) immediately after the melting of BiPh3 (71.3
°C). The corresponding weight-loss in the TGA (17 %) is
indicative of the removal of two equivalents of benzene or three
equivalents of acetic acid. The pungent aroma of acetic acid from
the solvent-free reaction indicates that it is most likely a mixture
85 of both. Up to 250 °C the total weight-loss is ca. 46 %,
representing formation of tris-salicylato bismuth(III), [Bi(Sal)3],
through the loss of three equivalents each of benzene and acetic
acid. The 1H NMR spectrum of the solid recovered from the
solvent-mediated reaction conducted in dry toluene (to avoid
90 aspirin hydrolysis) at reflux showed a complex mixture of
products. Alongside residual aspirin (ca 15 %) and [Bi(asp)3] (ca
47%), was evidence of other bismuth complexes incorporating
Bismuth compounds; bismuth subsalicylate and potassium
bismuth citrate, are commonly used in triple and quadruple
therapies in the treatment and eradication of H. pylori infection.11-
13
40
They also have a positive effect on reducing bleeding and in
healing stomach ulcers. It is feasible that a single drug;
bismuth(III) acetylsalicylate [Bi(O2C(C6H4)OAc)3], could
provide simultaneously the desirable therapeutic and preventative
effects of aspirin while providing the gastrointestinal protection
45 of chemotherapeutic bismuth(III) carboxylates.
Metal complexes of aspirinate (acetylsalicylate) and its
derivatives can show improved anti-inflammatory action when
compared with the parent acids.14 - 16 They have also been shown
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anions of aspirinate, o-salicylate and acetate (ca 11 %). Most
1). The dimers polymerise through formation of longer
notable from the NMR data is a bis-phenyl complex (or 40 intermolecular Bi-O bonds belonging to the carbonyl function of
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complexes) of form [Ph2BiL]. These data are presented as
Supplementary Information (SI).
one of the acetoxy moieties on the aspirin ligand [Bi(1)-O(12)’,
2.833(2) Å] to give rise to a new three element 16-membered
‘Bi2O6C8’ ring. Thus, the polymer results from a series of
alternating conjoined 4-membered planar Bi2O2 and 16-
5
To overcome these problems Bi(OtBu)3, as a stronger and more
labile base, was employed under dry, inert conditions. The
stoichiometric 1:3 reaction of Bi(OtBu)3 with aspirin in dry 45 membered ‘Bi2O6C8’ rings (Figure S1) bringing the overall
toluene produced the desired tris-substituted bismuth(III)
complex [Bi(asp)3]∞ 1 in 70 % yield after stirring at room
coordination number of each bismuth centre to seven in the dimer
and increased to eight through polymerization.
10 temperature for 6 hr and subsequent washing with dry ethanol
(Scheme 1). Crystals suitable for single crystal X-ray diffraction
were obtained from the toluene or ethanol mother liquors after
approximately 1-2 days. Similarly, reacting a 1:1 stoichiometry
of Bi(OtBu)3 and KOtBu with four equivalents of aspirin gave the
15 heterometallic aspirinate polymer [KBi(asp)4]∞ 2 as a white solid
in a 71% yield. Crystals suitable for X-ray analysis were grown
from an acetone or ethanol solution over four days (Scheme 1).
50
55
Figure 2 Molecular structure of [KBi(asp)4]∞ 2 with thermal ellipsoids at
60 50% probability. Hydrogen atoms have been omitted for clarity.
Symmetry operator: ’ = (1-x, 1-y, 1-z). Selected bond lengths (Å) and
angles (°):Bi(1)-O(1), 2.572(3); Bi(1)-O(2), 2.300(2); Bi(1)-O(5),
2.664(2); Bi(1)-O(6), 2.348(2); Bi(1)-O(9), 2.407(3); Bi(1)-O(10),
2.799(3); Bi(1)-O(10)’, 2.711(3); Bi(1)-O(13), 2.243(2); Bi(1)-O(14),
65 2.800(3); K(1)-O(5), 2.713(2); K(1)-O(14), 2.744(3); K(1)-O(1)’,
2.798(3); K(1)-O(4)’, 2.845(3); K(1)-O(12)’, 2.704(3); Bi(1)-O(10)-
Bi(1)’, 102.69(9); K(1)-O(4)-K(1)’, 114.15(9).
Scheme 1 Synthesis of bismuth carboxylate complexes [Bi(asp)3]∞ 1 and
[KBi(asp)4]∞ 2.
20 Figures 1 and 2 show dimeric sections of complexes of the crystal
structures of 1 and 2. Corresponding figures S1 and S2 in the SI
show a longer section of their extended polymeric chain structure
of each.
Similar to 1, 2 adopts a polymeric structure in the solid state.
70 Crystallising in the triclinic space group P-1, it is composed of
centrosymmetric dimers containing two Bi(III) atoms, two K
atoms and eight aspirinate ligands. The central planar Bi2O2 ring
is similar to that in complex 1, were O atoms belonging to the
carboxylate moiety [Bi(1)-O(10), 2.799(3); Bi(1)-O(10)’,
75 2.711(2) Å] bridge the two Bi atoms via a tridentate coordinative
bonding mode. Three more carboxylate groups surround each Bi
centre in a chelating bidentate bonding mode [Bi(1)-O(1),
2.572(3); Bi(1)-O(2), 2.300(2); Bi(1)-O(5), 2.664(2); Bi(1)-O(6),
2.348(2); Bi(1)-O(13) 2.407(3), Bi(1)-O(14), 2.800(3) Å] with
80 the overall coordination number of each bismuth being nine
(Figure 2). Perpendicular to the central Bi2O2 ring a K atom lies
above and below the plane coordinated to five aspirinate ligands
in a range of bonding modes. One aspirinate ligand is bound
through both its carboxylate [K(1)-O(1)’, 2.798(3) Å] and
85 acetoxy functional groups [K(1)-O(4)’, 2.845(3) Å]; two are
bound via traditional bidentate carboxylate bonding modes [K(1)-
O(5), 2.713(2); K(1)-O(14), 2.744(3) Å]; and one via its acetoxy
moiety alone [K(1)-O(12)’, 2.704(3) Å] to give a formal five-
coordinate K atom. These [BiK(asp)4]2 dimers polymerise
90 through formation of longer K-O bonds [K(1)-O(4)’, 2.826(3) Å]
from a bridging acetoxy group, increasing the coordination
number of each K atom to six (Figure S2). The final polymeric
structural arrangement is best viewed as alternating adjoining 8-
Figure 1 Molecular structure of [Bi(asp)3]∞ 1 with thermal ellipsoids at
25 50% probability. Hydrogen atoms have been omitted for clarity.
Symmetry operator: ’ = (-x, 1-y, 2-z). Selected bond lengths (Å) and
angles (°): Bi(1)-O(1), 2.748(3); Bi(1)-O(2), 2.274(2); Bi(1)-O(5),
2.260(2); Bi(1)-O(6), 2.666(2); Bi(1)-O(6)’, 2.786(2)
Bi(1)-O(9),
2.223(2); Bi(1)-O(10), 2.547(2); Bi(1)-O(12)’, 2.833(2); O(2)-Bi(1)-O(1),
30 54.79(7); O(9)-Bi(1)-O(10), 54.52(7); O(5)-Bi(1)-O(6), 52.33(6); O(6)-
Bi(1)-O(6)’, 68.37(7).
Complex 1 crystallises in the monoclinic space group P21/c, with
the asymmetric unit comprising one half of the centrosymmetric
dimer [Bi(asp)3]2. The dimer is composed of two [Bi(asp)3] units
35 joined through O atoms from unsymmetrical bridging carboxylate
moieties [Bi(1)-O(6) 2.666(2), Bi(1)-O(6)’, 2.786(2) Å] while the
remaining carboxylate ligands surrounding the Bi(III) centre in 1
adopt the more usual bidentate chelating bonding mode (Figure
2
|
Journal Name, [year], [vol], 00–00
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c
School of Pharmacy and Molecular Sciences, James Cook University,
Townsville, QLD 4811, Australia.
membered (KOBiO)2 and K2O2 ring systems.
60
65
70
† Electronic Supplementary Information (ESI) available: full
experimental and analytical details, including crystallographic data and
tables. See DOI: 10.1039/b000000x/
1. D. Ekinci, M. Şentürk and Ö. İ. Küfrevioğlu, Expert Opin. Ther.
Patents, 2011, 21, 1831.
2. Y. Luan, W. Xu, Mini Rev. Med. Chem., 2006, 6, 1375.
3. Wong, B. C.; Zhu, G. H.; Lam, S. K. Biomed. Pharmacother.,1999,
53, 315.
4. S. Pathi, I. Jutooru, G. Chadalapaka, V. Nair, S.-O. Lee and S. Safe,
PLoS One, 2012, 7, e48208.
5. P. M. Rothwell, J. F. Price, F. G. R. Fowkes, A. Zanchetti, M. C.
Roncaglioni, G. Tognoni, R. Lee, J. F. F. Belch, M. Wilson, Z. Mehta
and T. W. Meade, Lancet, 2012, 379, 1602.
View Article Online
Complexes 1 and 2 can best be compared to two other similar
26
bismuth carboxylate complexes, [Bi(O2C-C6H4-2-OEt)3]2 3 and
27
5
[Bi(O2C-C6H4-2-OMe)3]∞ 4. Both 3 and 4 share a common
planar Bi2O2 central motif with both 1 and 2 where the
carboxylate moiety bridges the two bismuth centers together via a
tri-dentate bonding mode. In 1, 3 and 4 the carboxylate bridges
are asymmetrically bound, with 1 having a an elongated ‘short
10 bond’ [2.666(2) and 2.786(2) Å in 1; 2.325(1) and 2.758(1) Å in
3; and 2.3302(2) and 2.804(3) Å in 4], while complex 2 adopts a
more symmetrically bonded arrangement [Bi(1)-O(10), 2.799(3);
Bi(1)-O(10)’, 2.711(2) Å]. Similar to both 1 and 2, 4 forms an
overall polymeric structure although all three complexes do not
15 share a common Bi-O polymeric growth pattern.
6. P. S. Gardiner and F. F. Gilmer, Mini-Rev. Med. Chem., 2003, 3, 461.
75 7. A. Shiotani, N. Manabe, T. Kamada, Y. Fujimura, T. Sakakibara and
K. Haruma, J. Gastroenterol. Hepatol., 2012, 27 (S3), 8.
8. S. Derry and Y. K. Loke, BMJ, 2000, 321, 1183.
9. P. Malfertheiner, F. K. L. Chan and K. E. L. McColl, Lancet, 2009,
374, 1449.
80 10. F. L. Lanza, F. K. L. Chan and E. M. M. Quigley, on behalf of
American College of Gastroeneterologists; Guidelines for Prevention
of NSAID-Related Ulcer Complications, Am. J. Gastroenterol., 2009,
104, 728.
1
The H and 13C NMR spectra of both 1 and 2 (in D6-DMSO)
show a downfield shift for the H and C resonances in comparison
to the NMR spectrum of aspirin in its free acid form.
Disappearance of the CO2H proton supports the formation of tris-
20 substituted complexes, as established in the solid-state structures
of 1 and 2. Both 1 and 2 display similar aromatic proton signal
resonances with the biggest difference being the greater
downfield shift of the CH3 group; 2.17 ppm in 1 and 2.34 ppm in
2. Both complexes show no signs of immediate decomposition or
25 deacetylation in solution, even on the addition of a few drops of
D2O. However, both complexes decompose quickly in weakly
acidic media, a behaviour similar to other bismuth(III)-NSAID
complexes,23 and decompose slowly in polar and non-polar media
over several weeks, forming salicylic acid and bismuth oxido-
30 salicylate.
11. G. Treiber, P. Malfertheiner and U. Klotz, Expert Opin.
85
90
Pharmacother., 2007, 8, 329.
12. S. Marchi, F. Costa, M. Bellini, C. Belcari, M. G. Mumolo, R.
Tornar, R. Spisni, E. Torel and G. Maltinti, Eur. J. Gastroenterol.
Hepatol., 2001, 13, 547.
13. J. Houghton, J. G. Fox and T. C. Wang, J. Gastroenterol. Hepatol.,
2002, 17, 495.
14. J. R. J. Sorenson, Prog. Med. Chem., 1978, 15, 211.
15. J. E. Weder, C. T. Dillon, T. W. Hambley, B. J. Kennedy, P. A. Lay,
J. R. Biffin, H. L. Regtop, and N. M. Davies, Coord. Chem. Rev.,
2002, 232, 95.
95 16. Z. H. Chohan, M. S. Iqbal, H. S. Iqbal, A. Scozzafava and C. T.
Supuran, J. Enzyme Inhib. Med. Chem., 2002, 17, 87.
In the infrared spectra of 1 and 2 the acidic OH absorption is
absent and the C=O absorption band of the ester group is
observed at 1754 cm-1 for 1 and 1767 cm-1 for 2 (versus 1670-
17. G. Rubner, K. Bensdorf, A. Wellner, B. Kircher, S. Bergemann, I. Ott
and R. Gust, J. Med. Chem., 2010, 53, 6889.
18. Y. Yoshikawa, Y. Adachi, H. Yasui, M. Hattori and H. Sakurai,
1700 cm-1 in aspirin). The value of Δν (ν CO2 (asymm) - ν CO2
-
-
35 (symm)) in both 1 and 2 is less than 200 cm-1 indicating a bidentate
chelating mode of the ligand consistent with the solid state
structural analysis.28
100
Chem. Pharm. Bull. 2011, 59, 972.
19. B. Voissat, J.-C. Daran, G. Savouret, G. Morgant, F. T. Greenaway,
N.-H. Dung, V. A. Pham-Tran, J. R. J. Sorenson, J. Inorg. Biochem.,
2003, 96, 375.
An assessment of the antibacterial activity of 1 and aspirin in its
free acid form was carried out against three laboratory strains of
40 H. pylori: B128, 251 and 26695, using compound concentrations
ranging from 25 to 6.25 μg mL-1. The Minimum Inhibitory
Concentration (MIC) of each was determined by the Agar
20. P. Lemoine, B. Viossat, N.-H. Dung, A. Tomas, G. Morgant, F. T.
Greenaway and J. R. J. Sorenson, J. Inorg. Biochem., 2004, 98, 1734.
21. T. Fujimori, S. Yamada, H. Yasui, H. Sakurai, Y. In and T. Ishada, J.
Biol. Inorg. Chem., 2005, 10, 831.
22. M. Poyraz, C. N. Banti, N. Kourkoumelis, V. Dokorou, M. J. Manos,
M. Simčič, S. Golič-Grdadolnik, T. Mavromoustakos, A. D.
Giannoulis, J. J. Verginadis, K. Charalabopoulos and S. K.
Hadjikakou, Inorg. Chim. Acta, 2011, 375, 114.
23. P. C. Andrews, R. L. Ferrero, P. C. Junk, I. Kumar, Q. Luu, K.
Nguyen and J. W. Taylor, Dalton Trans., 2010, 39, 2861.
24. P. C. Andrews, G. B. Deacon, P. C. Junk and M. Maguire, Angew.
Chem. Int. Ed, 2006, 45, 5638.
25. R. K. Baslas, R. Zamani R, A. A. Nomani, Experientia, 1979, 35,
455.
105
Diffusion method.29 The activity of the complex was found to be 110
6.25 μg mL-1, which is typical of carboxylato-based Bi-NSAID
45 complexes.23 Below this confluent growth of the bacteria was
observed. In comparison, we found aspirin to be inactive (> 25 μg
mL-1), supporting a previous report of its activity (MIC50) against
115
H. pylori to be 256 μg mL-1.30 This indicates that the bismuth
complex shows far greater bactericidal activity and is at least
50 comparable, if not better than, standard bismuth-based treatments
26. P. C. Andrews, G. B. Deacon, W. R. Jackson, M. Maguire, N. M.
Scott, B. W. Skelton and A. H. White, J. Chem. Soc., Dalton Trans.,
2002, 4634.
for H. pylori infection.23 The anti-inflammatory and anti-
120
ulcerative activity of 1 and 2 is the focus of ongoing research.
27. P. C. Andrews, G. B. Deacon, P. C. Junk, I. Kumar and M.
Silberstein, Dalton Trans., 2006, 4852.
28. G. B. Deacon and R. J. Phillips, Coord. Chem. Rev., 1980, 33, 227.
29. J. Viala, F. G. Boneca, A. Cardona, S. E. Girardin, A. P. Moran, R.
Athman, S. Mémet, M. R. Huerre, A. J. Coyle, P. S. DiStefano, P. J.
Sansonetti, A. Labigne, J. Bertin, D. J. Philpott and R. L. Ferrero,
Nat. Immunol., 2004, 5, 1166.
Notes and references
a
125
School of Chemistry, Monash University, Clayton, Melbourne, VIC
3800, Australia.
55
b Monash Institute of Medical Research, Centre for Innate Immunity and
Infectious Diseases Monash University, Clayton, Melbourne, VIC
3168, Australia.
30. W. H. Wang, W. M. Wong, D. Dailidiene, D. E. Berg, Q. Gu, K. C.
Lai, S. K. Lam, and B. C. Y. Wong, Gut, 2003, 52, 490.
This journal is © The Royal Society of Chemistry [year]
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