title: Benzylidenemalononitrile compounds as activators of cell resistance to oxidative stress and modulators of multiple signaling pathways. A structure-activity relationship study.
abstract: Benzylidenemalononitrile (BMN) tyrphostins are well known as potent tyrosine kinase inhibitors. Moreover, in recent years it has been recognized that members of the tyrphostin family possess additional biological activities independent of their ability to inhibit protein tyrosine kinases. In this study, we examined the relationship between the structure of 49 BMNs and related compounds, and their capacity to induce heme oxygenase 1 (HO-1) gene expression in U937 human monocytic cells, to activate upstream signaling pathways and to protect cells against menadione-induced oxidative stress. It was found that the electron-withdrawing (NO(2), CN, halogen) groups in BMN molecules and double meta-MeO substituents increased the HO-1 gene induction, while the electron-donating groups in ortho/para position (OH, MeO and N-morpholino) significantly decreased it. The magnitude of activation of c-Jun, Nrf2, p38 MAPK, and p70S6K correlated with specific substitution patterns in the BMN structure. BMN-dependent maximal up-regulation of HO-1 required parallel increase in Nrf2 and phospho-c-Jun cellular levels. Liquid chromatography mass spectrometry (LC-MS) analysis revealed that BMNs can generate conjugates with one or two glutathione equivalent(s). This study supports the hypothesis that BMNs induce the expression of protective genes by alkylating sensitive cysteine residues of regulatory factors.
authors.affiliation: Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherche de Gif, Gif-sur-Yvette, France.
authors.forename: Kyril
authors.initials: K
authors.lastname: Turpaev
authors.forename: Mikhail
authors.initials: M
authors.lastname: Ermolenko
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Drapier
mesh_terms: D001597:Benzylidene Compounds / Q000378:metabolism / Q000494:pharmacology*; D002853:Chromatography, Liquid; D005978:Glutathione / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship; D020032:Tyrphostins / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D001597:Benzylidene Compounds; D009570:Nitriles; D012333:RNA, Messenger; D020032:Tyrphostins; C069028:AG 127; D051547:Heme Oxygenase-1; D005978:Glutathione