EME OXYGENASE (HO) is a microsomal enzyme catalyzing the first, rate-limiting step in degradation of heme. Three distinct mammalian HO isoforms (HO-1, HO-2, and HO- 3) have been identified. Expression of HO-1 is usually increased in tumors, compared with surrounding healthy tissues (1). Thus, pharmacologic inhibition of HO-1 has been suggested as a new therapeutic option (2). Programs in various laboratories were concerned with the design of HO inhibitors that are not based on the porphyrin nucleus and has the objective of obtaining more selective HO inhibitors. To this purpose we assayed a number of imidazole-based compounds previously synthetized by our research group as inhibitors of nitric oxide synthase. These compounds maintained the two key-features required for the binding to HO-1 (i.e. the N-3 imidazole nitrogen and a hydrophobic moiety), consequently they may constitute a collection of imidazole-based compounds useful to select potential inhibitors of this enzyme. To assay enzyme inhibition, HO-1 obtained from rat spleen as the microsomal fraction and full-length recombinant HO-1, were used. The data obtained using this series of imidazole derivatives revealed general inhibitory activity for HO-1. The most active of tested compounds was 1-[4-(3-Bromophenoxy)butyl]-1H-imidazole (A) and its binding to heme-conjugated recombinant HO-1 was additionally examined by spectral analysis. Our results revealed that the concentration of compound A that was required to cause changes in the heme spectrum was in the order of 50-fold (100 M) higher than that found to inhibit rat HO activity in vitro and are not consistent with compound A forming a complex with heme at low micromolar concentrations. However, results obtained with heme bound to HO-1, revealed that when heme is bound to HO-1 compound A was able to form a complex with heme also at low micromolar concentrations and this might be in agreement with its selectivity versus HO-1 rather than other heme enzymes such as NOS or Cit P450. These compounds might become very useful tools in elucidating the physiological roles of HO-1 and carbon monoxide in mammalian and other biological systems and might have useful therapeutic applications

Imidazole Derivatives as Heme Oxygenase-1 Inhibitors

SORRENTI, Valeria;DI GIACOMO, Claudia;GUCCIONE, Salvatore;ACQUAVIVA, ROSARIA;PITTALA', Valeria;SALERNO, Loredana
2012

Abstract

EME OXYGENASE (HO) is a microsomal enzyme catalyzing the first, rate-limiting step in degradation of heme. Three distinct mammalian HO isoforms (HO-1, HO-2, and HO- 3) have been identified. Expression of HO-1 is usually increased in tumors, compared with surrounding healthy tissues (1). Thus, pharmacologic inhibition of HO-1 has been suggested as a new therapeutic option (2). Programs in various laboratories were concerned with the design of HO inhibitors that are not based on the porphyrin nucleus and has the objective of obtaining more selective HO inhibitors. To this purpose we assayed a number of imidazole-based compounds previously synthetized by our research group as inhibitors of nitric oxide synthase. These compounds maintained the two key-features required for the binding to HO-1 (i.e. the N-3 imidazole nitrogen and a hydrophobic moiety), consequently they may constitute a collection of imidazole-based compounds useful to select potential inhibitors of this enzyme. To assay enzyme inhibition, HO-1 obtained from rat spleen as the microsomal fraction and full-length recombinant HO-1, were used. The data obtained using this series of imidazole derivatives revealed general inhibitory activity for HO-1. The most active of tested compounds was 1-[4-(3-Bromophenoxy)butyl]-1H-imidazole (A) and its binding to heme-conjugated recombinant HO-1 was additionally examined by spectral analysis. Our results revealed that the concentration of compound A that was required to cause changes in the heme spectrum was in the order of 50-fold (100 M) higher than that found to inhibit rat HO activity in vitro and are not consistent with compound A forming a complex with heme at low micromolar concentrations. However, results obtained with heme bound to HO-1, revealed that when heme is bound to HO-1 compound A was able to form a complex with heme also at low micromolar concentrations and this might be in agreement with its selectivity versus HO-1 rather than other heme enzymes such as NOS or Cit P450. These compounds might become very useful tools in elucidating the physiological roles of HO-1 and carbon monoxide in mammalian and other biological systems and might have useful therapeutic applications
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/109264
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