First identification of 4-hydroxy-nonenal (HNE) was made as autoxidation product of unsaturated fats and oils, erroneously described as 4-hydroxy-octenal.
Schauenstein, E.; Esterbauer, H.; Jang, G.; Taufer, M. Über die Wirkung von Aldehyden auf gesunde und maligne Zellen, 1. Mitt.: Hydroxy-octenal, ein neuer Fett-aldehyd. MONATSH. CHEM.; 1964; 95: 180-183. See slide 2 of POWERPOINT file History of HNE
Chemical Synthesis of HNE (1967)
HNE was prepared by reaction of di-ethoxy-propyne with hexanal
Esterbauer, H.; Weger, W. Über die Wirkungen von Aldehyden auf gesunde und maligne Zellen, 2. Mitt.: Synthese von homologen 4-Hydroxy-2-alkenalen, I. MONATSH. CHEM.; 1967; 98: 1884-1891.
Enantioselective Synthesis of HNE (1994)
A multistep procedure employed for the synthesis of the S enantiomer of HNE was based on the Esterbauer method (Esterbauer & Wegner, 1967) with creation of the C-4 stereocenter by stereoselective reduction of 1,1-diethoxynon-2-yn-4-one.
Bringmann, G., Gassen, M., Lardy, R. 4-Hydroxynon-2-enal, a cytotoxic lipid peroxidation product, and its C5- analog 4-hydroxypent-2-enal: Enantioselective synthesis and stereoanalysis. Tetrahedron, 50 (34), pp. 10245-10252 (1994)
Carcinostatic Effect of Hydroxyalkenals (1968)
HNE inhibited the growth of Ehrlich Ascites Tumor Cells (EATC)
Schauenstein, E.; Wünschmann, B.; Esterbauer, H. Über die weitgehend selektive Abtötung subcutan implantierter Ehrlich-Ascites-Tumorzellen in vivo durch 4-Hydroxy-enale, insbesondere 4-Hydroxy-pentenal. Z. KREBSFORSCH.; 1968; 71: 21-29.
Biological Targets of Hydroxyalkenals (1971)
Glyceraldehyde phosphate dehydrogenase (GAPDH) was the first protein, for which thiol groups were shown to be targets of HNE. The adduct formation with a catalytic thiol group was accompanied by loss of enzyme activity.
Schauenstein, E.; Taufer, M.; Esterbauer, H.; Kylianek, A; Seelich, T. Über die Reaktion von Protein-SH-Gruppen mit 4-Hydroxy-pentenal. MONATSH. CHEM.; 1971; 102: 517-529.
Growth Stimulating Effects of 4-Hydroxynonenal (1993)
Transient inhibition of the growth of Human Cervical Carcinoma Cells (HeLa) by physiological and by supraphysiological concentrations of HNE were followed by enhanced cell growth in vitro.
Zarkovic N.; Ilic Z.; Jurin M.; Scahur R.J.; Puhl H.; Esterbauer H. Stimulation of HeLa cell growth by physiological con¬centrations of 4-hydroxynonenal. CELL BIOCHEM FUNCTION; 1993; 11: 279-286.
Formation from nonenal (1993)
Two distinct pathways were described for the formation of HNE from nonenal in the presence of the 269,000-g particle fraction of seed homogenate of the broad bean (Vicia faba L.)
Gardner HW, Hamberg M. Oxygenation of (3Z)-nonenal to (2E)-4-hydroxy-2-nonenal in the broad bean (Vicia faba L.). J Biol Chem. 1993;268:6971–6977 (1993)
Formation from linoleic acid (2001)
Two distinct pathways were described for the formation of HNE from linoleic acid
Schneider, C., Tallman, K.A., Porter, N.A., et al. Two distinct pathways of formation of 4-hydroxynonenal. Mechanisms of nonenzymatic transformation of the 9- and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals. J Biol Chem 276(24) 20831-20838 (2001).
Antibodies against HNE-Protein Adducts (1993 & 1996)
Polyclonal antibodies against HNE-protein adducts were first raised in the lab. of Earl Stadtman
Uchida K, Szweda LI, Chae H-Z, Stadtman ER. Immunochemical Detection of 4-Hydroxynonenal protein adducts in Oxidized Hepatocytes Proc.Natl.Acad.Sci.USA 90, 8742-8746 (1993)
Monoclonal Antibodies against HNE-Protein Adducts (1995, 1996)
Monoclonal antibodies against HNE-protein adducts were raised by Shinya Toyokuni and Koji Uchida, and in the lab. of H. Esterbauer .
Toyokuni, S., Miyake, N., Hiai, H., Hagiwara, M., Kawakishi, S., Osawa, T., and Uchida K. The monoclonal antibody specific for the 4-hydroxy-2-nonenal histidine adduct. FEBS Lett. 359, 189-191 (1995)
Waeg G, Dimisity G, Esterbauer H. Monoclonal antibodies for detection of 4-hydroxynonenal modified proteins. Free Rad Res 25(2):149–159 (1996) Stereoselective analysis
Resolution of the HNE enantiomers was achieved by coupling of racemic HNE dimethylacetal with optically pure (–) sorbic acid iron tricarbonyl complex, subsequent chromatography and deacetalization.
de Montarby L, Mosset P, Gree R. Sorbic acid iron tricarbonyl complex as resolving agent. Chiral syntheses of 4-hydroxy nonenal and coriolic acid. Tetrahedron Lett 29: 3937–3940 (1988)
Milestones in the Early History of HNE
Prof. R. Jörg Schaur
rudolf.schaur@uni-graz.at
First identification of 4-hydroxy-nonenal (HNE) was made as autoxidation product of unsaturated fats and oils, erroneously described as 4-hydroxy-octenal.
Schauenstein, E.; Esterbauer, H.; Jang, G.; Taufer, M. Über die Wirkung von Aldehyden auf gesunde und maligne Zellen, 1. Mitt.: Hydroxy-octenal, ein neuer Fett-aldehyd. MONATSH. CHEM.; 1964; 95: 180-183. See slide 2 of POWERPOINT file History of HNE
HNE was prepared by reaction of di-ethoxy-propyne with hexanal
Esterbauer, H.; Weger, W. Über die Wirkungen von Aldehyden auf gesunde und maligne Zellen, 2. Mitt.: Synthese von homologen 4-Hydroxy-2-alkenalen, I. MONATSH. CHEM.; 1967; 98: 1884-1891.
A multistep procedure employed for the synthesis of the S enantiomer of HNE was based on the Esterbauer method (Esterbauer & Wegner, 1967) with creation of the C-4 stereocenter by stereoselective reduction of 1,1-diethoxynon-2-yn-4-one.
Bringmann, G., Gassen, M., Lardy, R. 4-Hydroxynon-2-enal, a cytotoxic lipid peroxidation product, and its C5- analog 4-hydroxypent-2-enal: Enantioselective synthesis and stereoanalysis. Tetrahedron, 50 (34), pp. 10245-10252 (1994)
HNE inhibited the growth of Ehrlich Ascites Tumor Cells (EATC)
Schauenstein, E.; Wünschmann, B.; Esterbauer, H. Über die weitgehend selektive Abtötung subcutan implantierter Ehrlich-Ascites-Tumorzellen in vivo durch 4-Hydroxy-enale, insbesondere 4-Hydroxy-pentenal. Z. KREBSFORSCH.; 1968; 71: 21-29.
Glyceraldehyde phosphate dehydrogenase (GAPDH) was the first protein, for which thiol groups were shown to be targets of HNE. The adduct formation with a catalytic thiol group was accompanied by loss of enzyme activity.
Schauenstein, E.; Taufer, M.; Esterbauer, H.; Kylianek, A; Seelich, T. Über die Reaktion von Protein-SH-Gruppen mit 4-Hydroxy-pentenal.
MONATSH. CHEM.; 1971; 102: 517-529.
Transient inhibition of the growth of Human Cervical Carcinoma Cells (HeLa) by physiological and by supraphysiological concentrations of HNE were followed by enhanced cell growth in vitro.
Zarkovic N.; Ilic Z.; Jurin M.; Scahur R.J.; Puhl H.; Esterbauer H. Stimulation of HeLa cell growth by physiological con¬centrations of 4-hydroxynonenal. CELL BIOCHEM FUNCTION; 1993; 11: 279-286.
Two distinct pathways were described for the formation of HNE from nonenal in the presence of the 269,000-g particle fraction of seed homogenate of the broad bean (Vicia faba L.)
Gardner HW, Hamberg M. Oxygenation of (3Z)-nonenal to (2E)-4-hydroxy-2-nonenal in the broad bean (Vicia faba L.). J Biol Chem. 1993;268:6971–6977 (1993)
Two distinct pathways were described for the formation of HNE from linoleic acid
Schneider, C., Tallman, K.A., Porter, N.A., et al. Two distinct pathways of formation of 4-hydroxynonenal. Mechanisms of nonenzymatic transformation of the 9- and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals. J Biol Chem 276(24) 20831-20838 (2001).
Polyclonal antibodies against HNE-protein adducts were first raised in the lab. of Earl Stadtman
Uchida K, Szweda LI, Chae H-Z, Stadtman ER. Immunochemical Detection of 4-Hydroxynonenal protein adducts in Oxidized Hepatocytes
Proc.Natl.Acad.Sci.USA 90, 8742-8746 (1993)
Monoclonal antibodies against HNE-protein adducts were raised by Shinya Toyokuni and Koji Uchida, and in the lab. of H. Esterbauer .
Toyokuni, S., Miyake, N., Hiai, H., Hagiwara, M., Kawakishi, S., Osawa, T., and Uchida K. The monoclonal antibody specific for the 4-hydroxy-2-nonenal histidine adduct. FEBS Lett. 359, 189-191 (1995)
Waeg G, Dimisity G, Esterbauer H. Monoclonal antibodies for detection of 4-hydroxynonenal modified proteins. Free Rad Res 25(2):149–159 (1996)
Stereoselective analysis
Resolution of the HNE enantiomers was achieved by coupling of racemic HNE dimethylacetal with optically pure (–) sorbic acid iron tricarbonyl complex, subsequent chromatography and deacetalization.
de Montarby L, Mosset P, Gree R. Sorbic acid iron tricarbonyl complex as resolving agent. Chiral syntheses of 4-hydroxy nonenal and coriolic acid.
Tetrahedron Lett 29: 3937–3940 (1988)