Modulation of heme oxygenase-1 activity by novel synthetic compounds for pharmacological applications

In the past few years, heme oxygenase (HO) has been regarded as a potential pharmacological target, especially the inducible isoform, heme oxygenase-1 (HO-1). HO catalyzes the rate-limiting step of endogenous heme degradation, releasing carbon monoxide (CO), free iron (Fe2+), and biliverdin (BV), then reduced to bilirubin (BR). HO-1 also acts as a signaling molecule that mediates the activation of oxidant-responsive transcription factors in the nucleus. Mounting evidence underlines that HO-1 exerts antioxidant, anti-apoptotic, and anti-inflammatory effects. However, HO-1 overexpression may be detrimental, especially in cancer cells where the enzyme can sustain tumor aggressiveness and resistance to therapies. Therefore, HO-1 inhibition has been proposed as a stand-alone or adjuvant anticancer therapy, and a library of imidazole-based HO-1 inhibitors has been synthesized. On these grounds, the first part of this thesis focuses on the development of novel arylethanolimidazoles, designed through modifications of previously reported potent and selective HO-1 inhibitors. Molecular docking studies were performed to investigate their interactions with the enzyme, and the most active molecule was tested for its potential cytotoxic activity in hormone-sensitive and hormone-resistant breast cancer cell lines (MCF-7 and MDA-MB-231). The second part of this thesis concerns the design, synthesis, and biological evaluation of hybrid compounds as multitargeted anticancer agents. To this extent, an HO-1 inhibitory portion was coupled with different molecules endowed with antitumor activity. Since sigma receptors (sigmaRs) ligands showed potential antiproliferative effects in human cancers, the coadministration of sigmaR ligands and HO-1 inhibitors was evaluated in cancer cell lines that overexpress both proteins. Based on the promising results achieved, the synthesis, characterization, and in vitro cytotoxicity of a small series of HO-1/sigmaRs hybrids was performed. Secondly, two already approved anticancer drugs were chosen as coupling counterparts in new HO-1 hybrids: 5-fluorouracil (5-FU) and nilotinib (NIL). Particularly, 5-FU was combined with 1-(3-bromophenyl)-2-(1H-imidazol-1-yl)ethanol, a potent HO-1 inhibitor, to develop a novel 5-FU mutual prodrug. Finally, NIL was used as the structural backbone for new TK/HO-1 hybrid inhibitors to target chronic myeloid leukemia (CML). Their cytotoxic effects were studied on NIL-resistant and sensitive K562 cells. Docking studies explained the different interactions with BCR-ABL and HO-1 proteins. The last stage of this thesis was the design and synthesis of imatinib(IM)-based hybrids. According to recent findings, IM and HO-1 inducers could be potential antiviral agents against SARS-CoV-2. Therefore, the newly synthesized compounds bear an IM-like phenylamino-pyrimidine portion and an α,β-unsaturated carbonyl structure endowed with HO-1 inducer activity.