A focus on Heme Oxygenase-1 (HO-1) inhibitors

The aim of this review is to highlight the advances in the field of heme oxygenase-1 (HO-1) inhibitors over thepast years, particularly from a medicinal chemistry point of view; progresses made in the field strongly helped to clarifyphysiological roles of the heme oxygenase (HO) system. HO is a family of ubiquitously expressed enzymes which regulatethe regiospecific catabolism of heme leading to the formation of equimolar amounts of carbon monoxide (CO), ferrousiron (Fe++), and biliverdin. HO exists in two distinct, catalytically active isoforms: HO-1 and HO-2. HO-1 is an inducible32-kDa protein, while HO-2 is a constitutively synthesized 36-kDa protein and generally is unresponsive to any ofthe inducers of HO-1. A third isoform, HO-3, is still an elusive protein. The HO system, along with its catabolism products,is involved in a variety of crucial physiological functions, including cytoprotection, inflammation, anti-oxidative effects,apoptosis, neuro-modulation, immune-modulation, angiogenesis, and vascular regulation. The use of selective HOinhibitors is a very important tool to clarify the role of the HO system and the mechanisms underlying its physiological effectsand pathological involvement; due to the inducible nature of HO-1, selective inhibition of HO-1 isoform is generallypreferable. Notably, HO-1 inhibitors may be also beneficial in therapeutic applications and have been mainly studied fortreatment of hyperbilirubinemia and certain types of cancer. Historically, the first molecules used as non selective HO-1inhibitors were metalloporphyrins (Mps). The subsequent development of the imidazole-dioxolane derivatives affordedthe first generation of non-porphyrin based, isozyme selective HO-1 inhibitors.