Heme Oxygenase (HO) is a microsomal enzyme catalyzing the regioselective, oxidative cleavage of heme iron, yielding equimolar quantities of carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin, the last of which is further reduced to bilirubin by biliverdin reductase. Three distinct mammalian HO isoforms (HO-1, HO-2, and HO-3) have been identified so far. HO-1, the inducible 32-kDa isoform, is predominantly expressed in the liver and spleen and can be induced by a variety of stimuli such as heat shock, heavy metals, and reactive oxygen species. HO-2 is a constitutively expressed 36-kDa protein, present in high levels in the brain, testes, or endothelial cells. HO-3 was postulated as a 33-kDa protein expressed in different organs, very similar to HO-2, but with much lower catalytic activity (1). Despite the variety of cellular regulatory actions of the HO system, in particular of the constitutive isoform HO-2, expression of HO-1 is usually increased in tumors, compared with surrounding healthy tissues. It has been reported that the growth of a number of tumors is dependent on HO-1 activity supporting the idea that HO-1 may be a potential target in antitumor therapy (2). Starting from azalanstat, a number of azole-based compounds have been described in literature as HO-1 inhibitors (3). Recently our group has demonstrated that 1-[4-(3-bromophenoxy)butyl]-1H-imidazole, a compound previously developed as neuronal nitric oxide synthase (nNOS) inhibitor, is endowed with good inhibitory properties against HO-1 (Ki = 2.1 M) (4). In this work, a series of aryloxyalkyl-imidazoles and -1,2,4-triazoles possessing the following general structure, was designed and synthesized in order to evaluate their ability to inhibit HO-1 and HO-2 obtained from the microsomal fractions of rat spleen and rat brain, respectively.

Evaluation of Novel Imidazole- and 1,2,4 Triazole-based Compounds as Heme Oxygenase-1 (HO-1) Inhibitors.

SALERNO, Loredana;PITTALA', Valeria;ROMEO, Giuseppe;SIRACUSA, Maria Angela;ACQUAVIVA, ROSARIA;SORRENTI, Valeria
2012

Abstract

Heme Oxygenase (HO) is a microsomal enzyme catalyzing the regioselective, oxidative cleavage of heme iron, yielding equimolar quantities of carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin, the last of which is further reduced to bilirubin by biliverdin reductase. Three distinct mammalian HO isoforms (HO-1, HO-2, and HO-3) have been identified so far. HO-1, the inducible 32-kDa isoform, is predominantly expressed in the liver and spleen and can be induced by a variety of stimuli such as heat shock, heavy metals, and reactive oxygen species. HO-2 is a constitutively expressed 36-kDa protein, present in high levels in the brain, testes, or endothelial cells. HO-3 was postulated as a 33-kDa protein expressed in different organs, very similar to HO-2, but with much lower catalytic activity (1). Despite the variety of cellular regulatory actions of the HO system, in particular of the constitutive isoform HO-2, expression of HO-1 is usually increased in tumors, compared with surrounding healthy tissues. It has been reported that the growth of a number of tumors is dependent on HO-1 activity supporting the idea that HO-1 may be a potential target in antitumor therapy (2). Starting from azalanstat, a number of azole-based compounds have been described in literature as HO-1 inhibitors (3). Recently our group has demonstrated that 1-[4-(3-bromophenoxy)butyl]-1H-imidazole, a compound previously developed as neuronal nitric oxide synthase (nNOS) inhibitor, is endowed with good inhibitory properties against HO-1 (Ki = 2.1 M) (4). In this work, a series of aryloxyalkyl-imidazoles and -1,2,4-triazoles possessing the following general structure, was designed and synthesized in order to evaluate their ability to inhibit HO-1 and HO-2 obtained from the microsomal fractions of rat spleen and rat brain, respectively.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/110197
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