Synthesis and evaluation of antioxidant phenolic diaryl hydrazones as potent antiangiogenic agents in atherosclerosis.
A series of bis-hydrazones derived from diaryl and diaryl ether hydroxybenzaldehyde frames 1 and 2 have been synthesized as potential antioxidant and antiangiogenic agents, two properties required to limit atherogenesis and cardiovascular events. These compounds were evaluated for their ability to neutralize free radical formation, to block endothelial cell-induced low-density lipoprotein oxidation (monitored by the formation of TBARS), an essential step in atherogenesis, and subsequent toxicity, to prevent angiogenesis evoked by low oxidized LDL concentration (monitored by the formation of capillary tubes on Matrigel) and to inhibit intracellular ROS increase involved in the angiogenic signaling. A structure/activity study has been carried out and finally allowed to select the phenolic diaryl ether hydralazine derivative 2a, sharing all these protective properties, as a promising hit for further development.
Université Paul Sabatier Toulouse III, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France; CNRS, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France.
Corinne
C
Vanucci-Bacqué
INSERM, UMR1048, I2MC, BP 84225, 31432 Toulouse Cedex 4, France.
Caroline
C
Camare
Université Paul Sabatier Toulouse III, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France; CNRS, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France.
Chantal
C
Carayon
INSERM, UMR1048, I2MC, BP 84225, 31432 Toulouse Cedex 4, France.
Corinne
C
Bernis
Université Paul Sabatier Toulouse III, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France; CNRS, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France. Electronic address: baltas@chimie.ups-tlse.fr.
Michel
M
Baltas
INSERM, UMR1048, I2MC, BP 84225, 31432 Toulouse Cedex 4, France. Electronic address: Anne.Negre-salvayre@inserm.fr.
Anne
A
Nègre-Salvayre
Université Paul Sabatier Toulouse III, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France; CNRS, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France. Electronic address: bedos@chimie.ups-tlse.fr.
Florence
F
Bedos-Belval
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002460:Cell Line; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D066244:Proton Magnetic Resonance Spectroscopy; D017382:Reactive Oxygen Species / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
D020533:Angiogenesis Inhibitors; D000975:Antioxidants; D006835:Hydrazones; D008077:Lipoproteins, LDL; D017382:Reactive Oxygen Species; C099252:oxidized low density lipoprotein
Angiogenesis; Antioxidant; Atherosclerosis; Biphenyl derivatives; Hydrazone; Polyphenol