{"id":{"repo_id":"catania","oai_identifier":"oai:www.iris.unict.it:20.500.11769/581371"},"canonical_url":"https://search.dev.ndltd.org/etd/catania/oai:www.iris.unict.it:20.500.11769/581371","repository":{"repo_id":"catania","name":"Università degli Studi di Catania","base_url":"https://www.iris.unict.it/oai/request"},"display":{"title":"Modulation of heme oxygenase-1 activity by novel synthetic compounds for pharmacological applications","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["CIAFFAGLIONE, VALERIA"],"institution":"Università degli studi di Catania","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["SORTINO, Salvatore"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-03-29","date_published":"2022-03-29","updated_at":"2026-07-24T01:35:13Z","subjects":["heme oxygenase, imidazole, HO-1 inhibitors, structure-activity relationships, anticancer agents, hybrid compounds, mutual prodrugs, HO-1 inducers"],"languages":["ita"],"rights":["info:eu-repo/semantics/openAccess","license:PUBBLICO - Pubblico con Copyright","license uri:iris.PUB02"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/20.500.11769/581371","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Ciaffaglione, Valeria","SORTINO, Salvatore"]},{"key":"dc:creator","label":"Author","values":["CIAFFAGLIONE, VALERIA"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2022-03-29"]},{"key":"dc:publisher","label":"Institution","values":["Università degli studi di Catania","place:Catania"]},{"key":"dc:type","label":"Dc Type","values":["info:eu-repo/semantics/doctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["heme oxygenase, imidazole, HO-1 inhibitors, structure-activity relationships, anticancer agents, hybrid compounds, mutual prodrugs, HO-1 inducers"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["ita"]},{"key":"dc:rights","label":"Dc Rights","values":["info:eu-repo/semantics/openAccess","license:PUBBLICO - Pubblico con Copyright","license uri:iris.PUB02"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/20.500.11769/581371"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["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."]},{"key":"dc:title","label":"Title","values":["Modulation of heme oxygenase-1 activity by novel synthetic compounds for pharmacological applications"]}]}],"canonical_facts":{"dc:contributor":["Ciaffaglione, Valeria","SORTINO, Salvatore"],"dc:creator":["CIAFFAGLIONE, VALERIA"],"dc:date":["2022-03-29"],"dc:description":["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."],"dc:identifier":["https://hdl.handle.net/20.500.11769/581371"],"dc:language":["ita"],"dc:publisher":["Università degli studi di Catania","place:Catania"],"dc:rights":["info:eu-repo/semantics/openAccess","license:PUBBLICO - Pubblico con Copyright","license uri:iris.PUB02"],"dc:subject":["heme oxygenase, imidazole, HO-1 inhibitors, structure-activity relationships, anticancer agents, hybrid compounds, mutual prodrugs, HO-1 inducers"],"dc:title":["Modulation of heme oxygenase-1 activity by novel synthetic compounds for pharmacological applications"],"dc:type":["info:eu-repo/semantics/doctoralThesis"]},"updated_at":"2026-07-24T01:35:13Z"}