Polymethacrylate-Based Nitric Oxide Donors
A R T I C L E S
umdiolate functional groups and demonstrate that such materials
release NO for extended time periods.
polymerizing appropriate monomers (containing secondary
amines) on such surfaces to create thin films of covalently linked
polymers that could then be reacted with NO, in situ, to form
the desired NO releasing diazeniumdiolates.
Diazeniumdiolates are widely known as useful NO donor
molecules.15-17 They are the product of the addition of two
molecules of nitric oxide with an amine, usually a secondary
amine structure. In the presence of water, diazeniumdiolates
decompose releasing two moles of NO(g). There have been
several efforts reported to date on the preparation of different
NO release polymeric systems using N-diazeniumdiolate
chemistry.3,5-7,9,10,16,18,19 Some of these have consisted of
polymeric films containing physically suspended small diaz-
eniumdiolate molecules. For example, Kaul et al. incorporated
spermine diazeniumdiolates within a biodegradable copolymer
of polylactic and polyglycolic acid.19 Mowery et al. as well as
Annich et al. employed (N-methyl-N-[6-(N-methylammonio-
hexyl)amino]diazen)-1-ium-1,2-diolate (MAHMA-NO) doped
within PVC and silicone rubber films to create more thombo-
resistance NO release materials.3,6 Others have developed
methods to link the diazeniumdiolate NO donors covalently to
the polymer backbone. Among these, diazeniumdiolated pip-
erazine modified PVC and heparin, poly(ethyleneimine),6 modi-
fied proteins,20 poly(butanediol spermate),12 dipropylenetriamine
grafted on polysaccharide,9 and amine modified silicone rub-
bers7,21 have all been reported.
Unfortunately, there is no straightforward route to the
synthesis of acrylic polymers containing the required secondary
amine sites necessary to generate N-diazeniumdiolate moieties.
This is primarily because of the Michael addition reaction that
takes place between amines and the unsaturated bonds of
acrylates. Monomers with both amine and acrylic bonds would
be unstable and could react with each other. Moreover, during
polymerization, a competitive Michael reaction would occur
leading to a reduction in the amount of secondary amine sites
within the resulting polymeric material.
There are two possible solutions to this problem. One is the
modification of existing acrylic polymers (e.g., poly(glicydyl
methacrylate), poly(acrylic acid), etc.) by grafting residues that
contain secondary amine sites to pendant side chains. A second
approach involves the synthesis of modified monomers contain-
ing protected amine sites. It is this latter approach that is
described herein, using boc-protected amine sites before intro-
duction of methacrylic groups to create the new monomers and
subsequent deprotection of these amine sites after polymeriza-
tion. In this work, we present the synthesis of new methacrylic
monomers possessing pendant secondary amine sites and their
application for preparation of novel NO releasing polymethacryl-
ates
Acrylate-based polymers are potentially more attractive
materials to prepare NO release coatings that can be covalently
linked to metal surfaces or prepared in uniform microbead form
and then incorporated, in controlled amounts, within other
polymeric materials to create a wide variety of NO release films.
The latter approach has been demonstrated recently by doping
NO releasing fumed silica particles at varying wt % into silicone
rubber and polyurethanes to create polymers with enhanced
blood compatibility.22 In principle, NO release acrylic coatings
for metallic stents, and other blood-contacting metal surfaces
(e.g., heat exchangers used in extracorporeal systems), could
be achieved by first treating the metal surface with a silane agent
possessing a pendant acrylate or methacrylate group, and then
Experimental Section
Materials. All reagents were purchased from Aldrich Chemical,
Fisher, or Acros Organics. Methyl methacrylate was distilled before
use and stored in the refrigerator. Tetrahydrofuran was distilled prior
to use over potassium benzophenone ketyl. Compounds 1a-c,23 2d,24
and 3d,f25 were synthesized according to previously described proce-
dures.
Instrumentation. 1H NMR spectra of the monomers and polymers
were obtained on a Varian 300 or 400 MHz spectrometer in CDCl3 or
CD3OD. Nitric oxide release was monitored with a Sievers NOATM
280 nitric oxide analyzer. UV-vis spectra were recorded using a
Beckman DU 640B spectrophotometer. Molecular weights were
determined using size exclusion chromatography with Waters HT-4,
HT-3, and HT-2 columns and a dichloromethane mobile phase. Glass-
transition temperatures were measured with a Perkin-Elmer DSC 7.
Synthesis of Monomer Compounds. Synthesis of 2a,b,c,e Mono-
mer Precursors. To a vigorously stirred solution of 0.1 mol of amine
alcohol in 60 mL of dry THF, 0.105 mol of di-tert-butyl dicarbonate
was added dropwise at 10 °C. The reaction mixture was stirred
overnight. The solvent was removed in vacuo. The residue was
redissolved in dichloromethane and washed with water and brine. The
solution was dried with sodium sulfate and the dichloromethane was
removed in vacuo. Liquid products where then kept on a vacuum pump
overnight to remove any residual solvent, while the resulting solids
were recrystallized and dried. The products and their purity were
(15) (a) Keefer, L. K.; Hrabie, J. A. Chem. ReV. 2002. (b) Keefer, L. K.; Flippen-
Anderson, J. L.; George, C.; Shanklin, A. P.; Dunams, T. M.; Christodoulou,
D.; Saavedra, J. E.; Sagan, E. S.; Bohle, D. S. Nitric Oxide Biol. Ch. 2001,
5, 377-394. (c) Davies, K. M.; Wink, D. A.; Saavedra, J. E.; Keefer, L.
K. J. Am. Chem. Soc. 2001, 123, 5473-5481. (d) Bohle, D. S.; Imonigie,
J. A. J. Org. Chem. 2000, 65 (18), 5685-5692. (e) Keefer, L. K.; Hrabie,
J. A.; Arnold, E. V.; Citro, M. L.; George, C.; Keefer, L. K. J. Org. Chem.
2000, 65 (18), 5745-5751. (f) Nims, R. W.; Davies, K. M.; Wink, D. A.
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O.; Eyman, D. P. J. Am. Chem. Soc. 1961, 4337.
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1
confirmed by H NMR.
Indroduction of Polymerizable Group: Synthesis of 3a,b,c,e. A
solution containing 0.2 mol of the protected amine alcohol and 0.22
mol of triethylamine was prepared in dry THF at -10 °C under
nitrogen. The solution was then stirred vigorously and 0.22 mol of
(meth)acryloil chloride was added dropwise maintaining the temperature
(21) (a) Zhang, H.; Osterholzer, K.; Annich, G. M.; Merz, S. I.; Miskulin, J.;
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H.; Meyerhoff, M. E. Presented at the 218th National Meeting of the
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at the 222nd National Meeting of the American Chemical Society, 2001;
Paper MACR-8. (b) Frost, M. C.; Zhang, H.; Meyerhoff, M. E. Presented
at the 221st National Meeting of the American Chemical Society, 2001;
Paper PMSE-345. (c) Zhang, H.; Batchelor, M. M.; Meyerhoff, M. E.
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