Cinnamic Derivatives as Antiatherogenic Agents
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26 8123
(12) (a) Noguchi, N.; Iwaki, Y.; Takahashi, M.; Komuro, E.; Kato,
Y.; Tamura, K.; Cynshi, O.; Kodama, T.; Niki, E. 2,3-Dihydro-
5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran: Design and
Evaluation as a Novel Radical-Scavenging Antioxidant against
Lipid Peroxidation. Arch. Biochem. Biophys. 1997, 342, 236-
243. (b) Gey, K. F. Ten-year Retrospective on the Antioxidant
Hypothesis of Arteriosclerosis: Threshold Plasma Levels of
Antioxidant Micronutrients Related to Minimum Cardiovascular
Risk. J. Nutr. Biochem. 1995, 6, 206-236. (c) Buckley, M. M.;
Goa, K. L.; Price, A. H.; Brogden, R. N. Probucol. A Reappraisal
of its Pharmacological Properties and Therapeutic Use in
Hypercholesterolaemia. Drugs 1989, 37, 761-800.
Jeunesse, de l’Education Nationale et de la Recherche’
(grant to C.L.). Thanks are also due to the CNRS,
INSERM and the “Universite´ Paul Sabatier” for finan-
cial support.
Supporting Information Available: Spectroscopic and
analytical data for compounds 5b-e, 8b′, 8c′, 12b, 12c, and
12e. This material is available free of charge via the Internet
(13) Noguchi, N. Novel insights into the molecular mechanisms of
the antiatherosclerotic properties of antioxidants: the alterna-
tives to radical scavenging. Free Radic. Biol. Med. 2002, 33,
1480-1489.
(14) Witting, P.; Pettersson, K.; O¨ stlund-Lindqvist, A.-M.; Wester-
lund, C.; Wågberg, M.; Stocker, R. Dissociation of atherogenesis
from aortic accumulation of lipid hydro(pero)xides in Watanabe
heritable hyperlipidemic rabbits. J. Clin. Invest. 1999, 104, 213-
220.
(15) (a) Karten, B.; Boechzelt, H.; Mittelbach, M.; Sattler, W. Core
aldehydes: Formation occurrence and biological significance.
Recent Res. Devel. Lipids Res. 1999, 3, 23-41. (b) Esterbauer,
H.; Schaur, R. J.; Zollner, H. Chemistry and biochemistry of
4-hydroxynonenal, malonaldehyde and related aldehydes. Free
Radic. Biol. Med. 1991, 11, 81-128. (c) Itabe, H. Oxidized
phospholipids as a new landmark in atherosclerosis. Prog. Lipid
Res. 1998, 37, 181-207. (d) Brown, A. J.; Jessup, W. Oxysterols
and atherosclerosis. Atherosclerosis 1999, 142, 1-28. (e) Nogu-
chi, N.; Numano, R.; Kaneda, H.; Niki, E. Oxidation of lipids in
low-density lipoprotein particles. Free Rad. Res. 1998, 29, 43-
52.
References
(1) (a) Chisolm, G. M.; Steinberg, D. The Oxidative Modification
Hypothesis of Atherogenesis: an Overview. Free Radic. Biol.
Med. 2000, 28, 1815-1826. (b) Heineke, J. W. Oxidants and
Antioxidants in the Pathogenesis of Atherosclerosis: Implica-
tions for the Oxidized Low-Density Lipoprotein Hypothesis.
Atherosclerosis 1998, 141, 1-15. (c) Yokoyama, M. Oxidant
Stress and Atherosclerosis. Curr. Opin. Chem. Biol. 2004, 4,
110-115. (d) Harrison, D.; Griendling, K. K.; Landmesser, U.;
Hornig, B.; Drexler, H. Role of Oxidative Stress in Atheroscle-
rosis. Am. J. Cardiol. 2003, 91, 7A-11A.
(2) (a) Morel, D. W.; Hessler, J. R.; Chisolm, G. W. Low-Density
Lipoprotein Cytotoxicity Induced by Free Radical Peroxidation
of Lipid. J. Lipid Res. 1983, 24, 1070-1076. (b) Ne`gre-Salvayre,
A.; Vieira, O.; Escargueil-Blanc, I.; Salvayre, R. Oxidized LDL
and 4-Hydroxynonenal Modulate Tyrosine Kinase Receptor
Activity. Mol. Aspects Med. 2003, 24, 251-261.
(3) De Nigris, F.; Lerman, A.; Ignarro, L. J.; Williams-Ignarro, S.;
Sica, V.; Baker, A. H.; Lerman, L. O.; Geng, Y. J.; Napoli, C.
Oxidation-Sensitive Mechanisms, Vascular Apoptosis and Ath-
erosclerosis. Trends Mol. Med. 2003, 9, 351-359.
(4) Escargueil-Blanc, I.; Salvayre, R.; Vacaresse, N.; Jurgens, G.;
Darblade, B.; Arnal, J. F.; Parthasarathy, S.; Ne`gre-Salvayre,
A. A Midly Oxidised LDL Induces Activation of Platelet-Derived
Growth Factor Beta-Receptor Pathway. Circulation 2001, 104,
1814-1821.
(5) (a) Hiltunen, M. O.; Tuomisto, T. T.; Niemi, M.; Bra¨sen, J. H.;
Rissanen, T. T.; To¨ro¨nen, P.; Vajanto, I.; Yla¨-Herttuala, S.
Changes in Gene Expression in Atherosclerotic Plaques Ana-
lyzed Using DNA Array. Atherosclerosis 2002, 165, 23-32. (b)
McCormick, S. M.; Eskin, S. G.; McIntire, L. V.; Teng, C. L.;
Lu, C. M.; Russell, C. G.; Chittur, K. K. DNA Microarray Reveals
Changes in Gene Expression of Shear Stressed Human Umbili-
cal Vein Endothelial Cells. Proc. Natl. Acad. Sci. 2001, 98, 8955-
8960.
(6) Salvayre, R.; Auge, N.; Benoist, H.; Ne`gre-Salvayre, A. Oxidized
Low-density lipoprotein-induced apoptosis. Biochim. Biophys.
Acta 2002, 1585, 213-221.
(7) Rosenfeld, M. E.; Palinski, W.; Yla¨-Herttuala, S.; Butler, S.;
Witztum, J. L. Distribution of oxidation specific lipid-protein
adducts and apolipoprotein-B in atherosclerotic lesions of vary-
ing severity from WHHL rabbits. Arteriosclerosis 1990, 10, 336-
349.
(16) Freudenberg, K.; Neish, A. In Constitution and Biosynthesis of
Lignin; Freudenberg, K.; Neish, A., Eds.; Springer-Verlag: New
York, 1968; pp 47-116.
(17) (a) Lee, S.; Han, J.-M.; Kim, H.; Kim, E.; Jeong, T.-S.; Lee, W.
S.; Cho, K.-H. Synthesis of cinnamic acid derivatives and their
inhibitory effects on LDL-oxidation, acyl-CoA: cholesterol acyl-
transferase-1 and -2 activity, and decrease of HDL-particle size.
Bioorg. Med. Chem. Lett. 2004, 14, 4677-4681. (b) Ahn, H.-Y.;
Hadizadeh, K. R.; Seul, C.; Yun, Y.-P.; Vetter, H.; Sachinidis,
A. Epigallocathechin-3 Gallate Selectively Inhibits the PDGF-
BB-induced Intracellular Signaling Transduction Pathway in
Vascular Smooth Muscle Cells and Inhibits Transformation of
sis-transfected NIH 3T3 Fibroblasts and Human Glioblastoma
Cells (A172). Mol. Biol. Cell. 1999, 10, 1093-1104. (c) Szewczuk,
L. M.; Penning, T. M. Mechanism-Based Inactivation of COX-1
by Red Wine m-Hydroquinones: A Structure-Activity Relation-
ship Study. J. Nat. Prod. 2004, 67, 1777-1782. (d) Rajan, P.;
Vedernikova, I.; Cos, P.; Vanden Berghe, D.; Augustyns, K.;
Haemers, A. Synthesis and evaluation of caffeic acid amides as
antioxidants. Bioorg. Med. Chem. Lett. 2001, 11, 215-217.
(18) Lee, W. S.; Baek, Y.-I.; Kim, J.-R.; Cho, K.-H.; Sok, D.-E.; Jeong,
T.-S. Antioxidant activities of a new lignan and a neolignan from
Saururus chinensis. Bioorg. Med. Chem. Lett. 2004, 14, 5623-
5628.
(8) (a) Heineke, J. W.; Rosen, H.; Chait, A. Iron and copper promote
modification of low-density lipoprotein by human arterial smooth
muscle cells in culture. J. Clin. Invest. 1984, 74, 1890-1894.
(b) Morel, D. W.; DiCorleto, P. E.; Chisolm, G. M. Endothelial
and smooth muscle cells alter low-density lipoprotein in vitro
by free radical oxidation. Arteriosclerosis 1984, 4, 357-364. (c)
Steinbrecher, U. P.; Parthasarathy, S.; Leake, D. S.; Witztum,
J. L.; Steinberg, D. Modification of low-density lipoprotein by
endothelial cells involves lipid peroxidation and degradation of
low-density lipoprotein phospholipids. Proc. Natl. Acad. Sci.
U.S.A. 1984, 81, 3883-3887.
(19) (a) McKie, J. H.; Jaouhari, R.; Douglas, K. T.; Goffner, D.;
Feuillet, C.; Grima-Pettenati, J.; Boudet, A. M.; Baltas, M.;
Gorrichon, L. A molecular model for cinnamyl alcohol dehydro-
genase, a plant aromatic alcohol dehydrogenase involved in
lignification. Biochim. Biophys. Acta 1993, 1202, 61-69. (b)
Lauvergeat, V.; Kennedy, K.; Feuillet, C.; McKie, J. H.; Gorri-
chon, L.; Baltas, M.; Boudet, A. M.; Grima-Pettenati, J.; Douglas,
K. T. Site-Directed Mutagenesis of a Serine Residue in Cinnamyl
Alcohol Dehydrogenase, a Plant NADPH-Dependent Dehydro-
genase, Affects the Specificity for the Coenzyme. Biochemistry
1995, 34, 12426-12434.
(9) (a) Berliner, J. A.; Heineke, J. W. The role of oxidized lipoproteins
in atherogenesis. Free Radic. Biol. Med. 1996, 20, 707-727. (b)
Lynch, S. M.; Frei, B. Antioxidants as Anti-atherogens: Animal
Studies. In Natural antioxidants in human health and disease;
Frei, B., Eds.; Academic Press: Orlando, 1994. (c) Steinberg, D.
Clinical Trials of Antioxidants in Atherosclerosis: are we Doing
the Right Thing? Lancet 1995, 346, 36-38. (d) Diaz, M. N.; Frei,
B.; Vita, J. A.; Keaney, J. F. Antioxidants and Atherosclerotic
Heart Disease. New Eng. J. Med. 1997, 337, 408-416.
(10) Noguchi, N.; Niki, E. Phenolic Antioxidants: A Rationale for
Design and Evaluation of Novel Antioxidant Drug for Athero-
sclerosis. Free Radic. Biol. Med. 2000, 28, 1538-1546.
(11) (a) Yokoyama, W. H. Plasma LDL cholesterol lowering by plant
phytosterols in a hamster model. Trends Food Sci. Technol.
2004, 15, 528-531. (b) Ho, C. T. Phenolic compounds in food:
an overview. In Phenolic compounds in food and their effects on
health: Vol. II Antioxidants and cancer prevention; Huang, M.
T.; Ho, C. T.; Lee, C. Y., Eds.; ACS Symposium Series, American
Chemical Society: Washington, DC, 1992; pp 2-7.
(20) Duran, E.; Duran, H.; Cazaux, L.; Gorrichon, L.; Tisnes, P.;
Sarni, F. Synthe`se de Parahydroxythiocinnamates de S-phe´nyle
Pre´curseurs d’Esters de S-CoA. Bull. Soc. Chim. Fr. 1987, 1,
143-148.
(21) Kennedy, K.; Baltas, M.; Douglas, K. T.; Duran, H.; Embrey, K.
J.; Giraudon, J. G.; McKie, J. H.; Grima-Pettenati, J.; Gorrichon,
L. Rational inhibitor design, synthesis ans NMR spectroscopic
study by transferred nuclear overhauser spectroscopy of novel
inhibitors of cinnamyl alcohol dehydrogenase, a critical enzyme
in lignification. J. Enzymol. Inhib. 1999, 14, 217-237.
(22) (a) Coulter, C. V.; Kelso, G. F.; Lin, T.-K.; Smith, R. A. J.;
Murphy, M. P. Mitochondrially targeted antioxidants and thiol
reagents. Free Radic. Biol. Med. 2000, 28, 1547-1554. (b)
Dietzmann, J.; Thiel, U.; Ansorge, S.; Neumann, K. H.; Tager,
M. Thiol-inducing and immunoregulatoy effects of flavonoids in
peripheral blood mononuclear cells from patients with end-stage
diabetic nephropathy. Free Radic. Biol. Med. 2002, 33, 1347-
1354.