Oxidation of benzoin catalyzed by oxovanadium (IV) schiff base complexes

BACKGROUND: The oxidative transformation of benzoin to benzil has been accomplished by the use of a wide variety of reagents or catalysts and different reaction procedures. The conventional oxidizing agents yielded mainly benzaldehyde or/and benzoic acid and only a trace amount of benzil. The limits of practical utilization of these reagents involves the use of stoichiometric amounts of corrosive acids or toxic metallic reagents, which in turn produce undesirable waste materials and required high reaction temperatures. In recent years, vanadium complexes have attracted much attention for their potential utility as catalysts for various types of reactions. RESULTS: Active and selective catalytic systems of new unsymmetrical oxovanadium(IV) Schiff base complexes for the oxidation of benzoin is reported. The Schiff base ligands are derived between 2-aminoethanol and 2-hydroxy-1- naphthaldehyde (H2L1) or 3-ethoxy salicylaldehyde (H2L3); and 2-aminophenol and 3-ethoxysalicylaldehyde (H2L2) or 2-hydroxy-1-naphthaldehyde (H2L4). The unsymmetrical Schiff bases behave as tridentate dibasic ONO donor ligands. Reaction of these Schiff base ligands with oxovanadyl sulphate afforded the mononuclear oxovanadium(IV) complexes (VIVOLx.H2O), which are characterized by various physico-chemical techniques. The catalytic oxidation activities of these complexes for benzoin were evaluated using H2O2 as an oxidant. The best reaction conditions are obtained by considering the effect of solvent, reaction time and temperature. Under the optimized reaction conditions, VOL4 catalyst showed high conversion (>99%) with excellent selectivity to benzil (~100%) in a shorter reaction time compared to the other catalysts considered. CONCLUSION: Four tridentate ONO type Schiff base ligands were synthesized. Complexation of these ligands with vanadyl(IV) sulphate leads to the formation of new oxovanadium(IV) complexes of type VIVOL.H2O. Elemental analyses and spectral data of the free ligands and their oxovanadium(IV) complexes were found to be in good agreement with their structures, indicating high purity of all the compounds. Oxovanadium complexes were screened for the oxidation of benzoin to benzil using H2O2 as oxidant. The effect of time, solvent and temperature were optimized to obtain maximum yield. The catalytic activity results demonstrate that these catalytic systems are both highly active and selective for the oxidation of benzoin under mild reaction conditions.Web of Scienc

A simple method for the alkaline hydrolysis of esters

A very mild and rapid procedure for the efficient alkaline hydrolysis of esters in non-aqueous conditions has been developed, by the use of dichloromethane/methanol (9:1) as solvent. This method conveniently provides both carboxylic acids and alcohols from the corresponding esters and sodium hydroxide in a few minutes at room temperature. A plausible reaction mechanism is proposed. © 2007 Elsevier Ltd. All rights reserved

Synthesis of β,γ-unsaturated primary amides from α,β-unsaturated acids and investigation of the mechanism

α,β-Unsaturated acids, through their acid chlorides, react with tritylamine in the presence of triethylamine under mild conditions, to afford in high yield and high regioselectivity the corresponding β,γ- unsaturated tritylamides. Detritylation with TFA generates quantitatively β,γ-unsaturated primary amides. An investigation of this deconjugative isomerization was performed. © 2011 Elsevier Ltd

Factor-inhibiting HIF-1 (FIH-1) is required for human vascular endothelial cell survival

Factor-inhibiting hypoxia-inducible factor (HIF)-1 (FIH-1) is an asparaginyl β-hydroxylase enzyme that was initially found to hydroxylate the HIF-α, preventing its transcriptional activity and leading to adaptive responses to hypoxia. More recently, other substrates, such as neurogenic locus notch homolog (Notch), have been found to be alternative FIH targets, but the biologic relevance of this regulation was never investigated. Given the key function of Notch in angiogenesis, we here investigate the role of FIH/Notch signaling in endothelial cells. We report that FIH-1 silencing in HUVECs results in reduced growth and increased apoptosis. The knockdown of FIH is associated with increased Notch2 activity, leading to enhanced expression of the Notch target hairy/enhancer-of-split related with YRPW motif protein 1 (Hey-1). Consistent with recent findings showing that Notch2 suppresses survivin (a key inhibitor of apoptosis), FIH targeting in HUVECs leads to selective repression of survivin in endothelial cells, thus promoting cell apoptosis and growth arrest. Our data support the concept that FIH-1 may interact with Notch2 and repress its activity, thereby playing a critical role in controlling the survival of vascular endothelial cells. These findings might pave the way toward novel, antiangiogenic strategies in disorders that are characterized by excessive vascular growth, such as cancer and rheumatoid arthritis.—Kiriakidis, S., Henze, A.-T., Kruszynska-Ziaja, I., Skobridis, K., Theodorou, V., Paleolog, E. M., Mazzone, M. Factor-inhibiting HIF-1 (FIH-1) is required for human vascular endothelial cell survival. FIH-1 was first identified in a yeast 2-hybrid screen for proteins that potentially interacted with the C-terminus of HIF-1α (1). In parallel studies, FIH-1 was shown to regulate transactivation of HIF-α by hydroxylation of an asparagine (Asn) residue in the HIF-α C-terminal transactivation domain (2, 3). HIF-α is a transcription factor that coordinates cellular responses in situations of reduced availability of oxygen (hypoxia), and activation of HIF-α signaling leads to extensive changes in gene expression to allow adaption of cells and tissues to reduced oxygenation (4, 5). The role of FIH-1 in HIF-α hydroxylation underlies the importance of this enzyme in angiogenesis, which plays a key function in many diseases, including cancer and rheumatoid arthritis (RA) (6, 7). The HIF complex consists of a constitutively expressed β subunit and an oxygen-responsive α subunit. Hydroxylation by FIH-1 of specific Asn residues in HIF-α (Asn803 in HIF-1α and Asn851 in HIF-2α) prevents recruitment of coactivators p300/cAMP response element-binding protein (CBP) and thereby, HIF-mediated gene transcription (1, 2). In contrast, prolyl hydroxylase domain (PHD) enzymes (PHD1–3) modify HIF-α by hydroxylation of specific proline residues in HIF-α (8), enabling capture by an E3 ubiquitin ligase complex whose recognition component is the von Hippel Lindau protein, leading to proteasomal destruction of HIF-α (9, 10). FIH-1 and PHD1–3 belong to a superfamily of 2-oxoglutarate and iron-dependent dioxygenases, which require molecular oxygen as a cosubstrate, explaining how these enzymes act as the oxygen sensors (11, 12). An important characteristic of FIH-1 is that unlike the PHD enzymes, FIH-1 is active even at relatively low oxygen levels (13–15). Whereas the role of FIH-1 in regard to HIF-α has been well characterized, increasing evidence suggests that HIF-α is not the only target for FIH-1, highlighting the importance of Asn hydroxylation as a means of posttranslational modification of intracellular proteins. A number of proteins have been identified as FIH-1 substrates, including members of the IκB family of proteins (16) and the intracellular domain (ICD) of the Notch transmembrane receptor (17). The discovery of alternative substrates for FIH-1 led to identification of the ankyrin repeat domain (ARD) as the common amino acid motif containing the Asn residues targeted by FIH-1. Hydroxylation of ARD at specific Asn residues within the p105 NF-κB precursor, the inhibitory proteins IκBα and IκBε, as well as in Notch proteins has been demonstrated (18). Recently, FIH-1 has been shown to regulate the survival of tumor cells via HIF-α-dependent and -independent mechanisms (19, 20). In the present study, we have investigated the role of FIH-1 in vascular endothelial cells by use of RNA interference (RNAi) approaches to determine whether FIH-1 also regulates the survival of endothelial cells. We observed that RNAi-mediated inhibition of FIH-1 resulted in reduced endothelial cell growth and increased apoptosis as a result of a decrease in expression levels of the key protective molecule survivin. As discussed, Notch proteins are a potential target for Asn hydroxylation by FIH-1 (18). Notch plays a pivotal role in vascular development and is required for arterial cell specification (21), as well as for tip and stalk cell specification during angiogenesis (22, 23). We demonstrated the use of a coimmunoprecipitation approach that FIH-1 is able to bind Notch2 in endothelial cells. Taken together, our findings suggest that FIH-1-driven modification of Asn within the ARD of Notch could play a role in endothelial cell function and thereby, in angiogenesis-dependent diseases, such as cancer and RA. </p

Factor-inhibiting HIF-1 (FIH-1) is required for human vascular endothelial cell survival

Factor-inhibiting hypoxia-inducible factor (HIF)-1 (FIH-1) is an asparaginyl β-hydroxylase enzyme that was initially found to hydroxylate the HIF-α, preventing its transcriptional activity and leading to adaptive responses to hypoxia. More recently, other substrates, such as neurogenic locus notch homolog (Notch), have been found to be alternative FIH targets, but the biologic relevance of this regulation was never investigated. Given the key function of Notch in angiogenesis, we here investigate the role of FIH/Notch signaling in endothelial cells. We report that FIH-1 silencing in HUVECs results in reduced growth and increased apoptosis. The knockdown of FIH is associated with increased Notch2 activity, leading to enhanced expression of the Notch target hairy/enhancer-of-split related with YRPW motif protein 1 (Hey-1). Consistent with recent findings showing that Notch2 suppresses survivin (a key inhibitor of apoptosis), FIH targeting in HUVECs leads to selective repression of survivin in endothelial cells, thus promoting cell apoptosis and growth arrest. Our data support the concept that FIH-1 may interact with Notch2 and repress its activity, thereby playing a critical role in controlling the survival of vascular endothelial cells. These findings might pave the way toward novel, antiangiogenic strategies in disorders that are characterized by excessive vascular growth, such as cancer and rheumatoid arthritis.—Kiriakidis, S., Henze, A.-T., Kruszynska-Ziaja, I., Skobridis, K., Theodorou, V., Paleolog, E. M., Mazzone, M. Factor-inhibiting HIF-1 (FIH-1) is required for human vascular endothelial cell survival. FIH-1 was first identified in a yeast 2-hybrid screen for proteins that potentially interacted with the C-terminus of HIF-1α (1). In parallel studies, FIH-1 was shown to regulate transactivation of HIF-α by hydroxylation of an asparagine (Asn) residue in the HIF-α C-terminal transactivation domain (2, 3). HIF-α is a transcription factor that coordinates cellular responses in situations of reduced availability of oxygen (hypoxia), and activation of HIF-α signaling leads to extensive changes in gene expression to allow adaption of cells and tissues to reduced oxygenation (4, 5). The role of FIH-1 in HIF-α hydroxylation underlies the importance of this enzyme in angiogenesis, which plays a key function in many diseases, including cancer and rheumatoid arthritis (RA) (6, 7). The HIF complex consists of a constitutively expressed β subunit and an oxygen-responsive α subunit. Hydroxylation by FIH-1 of specific Asn residues in HIF-α (Asn803 in HIF-1α and Asn851 in HIF-2α) prevents recruitment of coactivators p300/cAMP response element-binding protein (CBP) and thereby, HIF-mediated gene transcription (1, 2). In contrast, prolyl hydroxylase domain (PHD) enzymes (PHD1–3) modify HIF-α by hydroxylation of specific proline residues in HIF-α (8), enabling capture by an E3 ubiquitin ligase complex whose recognition component is the von Hippel Lindau protein, leading to proteasomal destruction of HIF-α (9, 10). FIH-1 and PHD1–3 belong to a superfamily of 2-oxoglutarate and iron-dependent dioxygenases, which require molecular oxygen as a cosubstrate, explaining how these enzymes act as the oxygen sensors (11, 12). An important characteristic of FIH-1 is that unlike the PHD enzymes, FIH-1 is active even at relatively low oxygen levels (13–15). Whereas the role of FIH-1 in regard to HIF-α has been well characterized, increasing evidence suggests that HIF-α is not the only target for FIH-1, highlighting the importance of Asn hydroxylation as a means of posttranslational modification of intracellular proteins. A number of proteins have been identified as FIH-1 substrates, including members of the IκB family of proteins (16) and the intracellular domain (ICD) of the Notch transmembrane receptor (17). The discovery of alternative substrates for FIH-1 led to identification of the ankyrin repeat domain (ARD) as the common amino acid motif containing the Asn residues targeted by FIH-1. Hydroxylation of ARD at specific Asn residues within the p105 NF-κB precursor, the inhibitory proteins IκBα and IκBε, as well as in Notch proteins has been demonstrated (18). Recently, FIH-1 has been shown to regulate the survival of tumor cells via HIF-α-dependent and -independent mechanisms (19, 20). In the present study, we have investigated the role of FIH-1 in vascular endothelial cells by use of RNA interference (RNAi) approaches to determine whether FIH-1 also regulates the survival of endothelial cells. We observed that RNAi-mediated inhibition of FIH-1 resulted in reduced endothelial cell growth and increased apoptosis as a result of a decrease in expression levels of the key protective molecule survivin. As discussed, Notch proteins are a potential target for Asn hydroxylation by FIH-1 (18). Notch plays a pivotal role in vascular development and is required for arterial cell specification (21), as well as for tip and stalk cell specification during angiogenesis (22, 23). We demonstrated the use of a coimmunoprecipitation approach that FIH-1 is able to bind Notch2 in endothelial cells. Taken together, our findings suggest that FIH-1-driven modification of Asn within the ARD of Notch could play a role in endothelial cell function and thereby, in angiogenesis-dependent diseases, such as cancer and RA. </p

Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors.

Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr-Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity, which is an important consideration for rational drug design. Herein we report a new series of imatinib derivatives that in general have greater activity against the family of PDGF receptors and poorer activity against Abl, as a result of modifications of the phenyl and N-methylpiperazine rings. These new compounds provide a platform for further drug development against the therapeutically important PDGF receptor family and they also provide insight into the engineering of drugs with altered biological activity