ORGANIC
LETTERS
2004
Vol. 6, No. 21
3767-3770
Caged trans-4-Hydroxy-2-nonenal
Robert G. Brinson and Paul B. Jones*
Department of Chemistry, Wake Forest UniVersity,
Winston-Salem, North Carolina 27109
Received August 2, 2004
ABSTRACT
A caged 4-hydroxy-2-nonenal (4-HNE) has been prepared and its photochemistry investigated. Upon photolysis, 1 releases 4-HNE in up to
100% yield. From these photolyses, 4-HNE could be isolated in up to 91% yield. 4-HNE is produced under either aerobic or anaerobic conditions.
The caging strategy does not require prior preparation of 4-HNE and, therefore, represents a three-step synthetic route to the bioactive enal
in 48% overall yield.
The use of photolabile protecting groups to “cage” bioactive
molecules that can then be released photochemically is of
great interest in the chemical and biological communities.1
An advantage of this technology is the temporal and spatial
control it allows in the distribution of bioactivity. Caged
molecules have been used extensively in the investigation
of biochemical pathways and mechanisms, such as calcium
uptake or the behavior of neurotransmitters.2
A number of R,â-unsaturated aldehydes, such as trans-
4-hydroxy-2-nonenal (4-HNE), display biological activity
with significance to human health.5 The biochemistry of such
molecules is under intensive investigation.6 Given the interest
in biologically active aldehydes and the need to develop new
oxygen independent PDT strategies, development of a
photoactivatable 4-HNE was pursued; preliminary results are
reported below.
Blankespoor has investigated the photochemistry of
1-alkoxyanthraquinones.7 Hydrogen abstraction, followed by
single electron transfer (SET), produces a zwitterion, 3, that
is rapidly trapped by solvent (Scheme 1). Upon oxidation, a
Similar chemistry has potential uses in photodynamic
therapy (PDT). Traditional PDT relies on the generation of
singlet oxygen via a photosensitization involving porphyrins.3
Due to dependence on oxygen, this technique has limited
use in hypoxic tissues or in cases where the therapy itself
generates a hypoxic condition.4 A photoactive agent that acts
independently of oxygen would be an important advance in
the development of PDT strategies.
(5) (a) d’Ippolito, G.; Romano, G.; Caruso, T.; Spinella, A.; Cimino,
G.; Fontana, A. Org. Lett. 2003, 5, 885-887. (b) Pan, J.; Chung, F. Chem.
Res. Toxicol. 2002, 15, 367-372. (c) Ghilarducci, D. P.’ Tjeerdema, R. S.
ReV. EnViron. Contam. Toxicol. 1995, 144, 95-146. (d) Schneider, C.;
Tallman, K. A.; Porter, N. A.; Brash, A. R. J. Biol. Chem. 2001, 276,
20831-20838. (e) Esterbauer, H.; Schaur, R.; Zollner, H. Free Radical
Biol. Med. 1991, 11, 81-128.
(6) (a) Grafstrom, R. Mutat. Res. 1990, 237, 175-184. (b) Witz, G. Free
Rad. Biol. 1989, 7, 333-349. (c) Eder, E.; Scheckenbach, S.; Deininger,
C.; Hoffman, C. Toxicol. Lett. 1993, 67, 87-103. (d) Feron, V. J.; Til, H.
P.; Devrijer, F.; Woutersen, R. A.; Cassee, F. R.; Vanbladeren, P. J. Mutat.
Res. 1991, 259, 363-385.
(7) (a) Blankespoor, R. L.; De Jong, R. L.; Dykstra, R.; Hamstra, D. A.;
Rozema, D. B.; VanMeurs, D. P.; Vink, P. J. Am. Chem. Soc. 1991, 113,
3507-3513. (b) Blankespoor, R. L.; Smart, R. P.; Batts, E. D.; Kiste, A.
A.; Lew, R. E.; Vasnder Vilet, M. E. J. Org. Chem. 1995, 60, 6852-6859.
(c) Smart, R. P.; Peelen, T. J.; Blankespoor, R. L.; Ward, D. L. J. Am.
Chem. Soc. 1997, 119, 461-465. (d) Blankespoor, R. L.; DeVries, T.;
Hansen, E.; Kallemeyn, J. M.; Klooster, A. M.; Mulder, J. A.; Smart, R.
P.; Vander Griend, D. A. J. Org. Chem. 2002, 67, 2677-2681.
(1) (a) Bochet, C. G. J. Chem. Soc., Perkins Trans. 1 2002, 125-142.
(b) Dorman, G.; Prestwich, G. D. Trends Biotechnol. 2000, 18, 64-77. (c)
Hess, G. P.; Grewer, C. Methods Enzymol. 1998, 291, 443-473.
(2) (a) Jayaraman, V.; Thiran, S.; Hess, G. P. Biochemistry 1999, 38,
11372-11378. (b) Li, G.; Oswald, R. E.; Niu, L. Biochemistry 2003, 42,
12367-12375. (c) Ghosh, M.; Ichetovkin, I.; Song, X.; Condeelis, J. S.;
Lawrence, D. S. J. Am. Chem. Soc. 2002, 124, 2440-2441.
(3) Dougherty, T. J.; Gomer, C. H.; Henderson, B. W.; Jori, G.; Kessel,
D.; Korbelik, M.; Moan, J.; Peng, Q. J. Natl. Cancer Inst. 1998, 90, 889-
905.
(4) (a) Huang, Z.; Chen, Q.; Shakil, A.; Beckers, J.; Shapiro, H.; Hetzel,
F. W. Photochem. Photobiol. 2003, 78, 496-502. (b) Henderson, B. W.;
Fingar, V. H. Cancer Res. 1987, 47, 3110-3114. (c) Fuchs, J.; Thiele, J.
Free Rad. Biol. Med. 1998, 24, 835-847.
10.1021/ol048478l CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/16/2004