Evaluation of novel aryloxyalkyl derivatives of imidazole and 1,2,4-triazole as heme oxygenase-1 (HO-1) inhibitors and their antitumor properties

Loredana Salerno; Valeria Pittalà; Giuseppe Romeo; Maria N Modica; Maria A Siracusa; Claudia Di Giacomo; Rosaria Acquaviva; Ignazio Barbagallo; Daniele Tibullo; Valeria Sorrenti

doi:10.1016/j.bmc.2013.06.040

Evaluation of novel aryloxyalkyl derivatives of imidazole and 1,2,4-triazole as heme oxygenase-1 (HO-1) inhibitors and their antitumor properties

Bioorg Med Chem. 2013 Sep 1;21(17):5145-53. doi: 10.1016/j.bmc.2013.06.040. Epub 2013 Jun 26.

Authors

Loredana Salerno¹, Valeria Pittalà, Giuseppe Romeo, Maria N Modica, Maria A Siracusa, Claudia Di Giacomo, Rosaria Acquaviva, Ignazio Barbagallo, Daniele Tibullo, Valeria Sorrenti

Affiliation

¹ Department of Drug Sciences, Section of Medicinal Chemistry, University of Catania, viale A. Doria 6, 95125 Catania, Italy. l.salerno@unict.it

PMID: 23867390
DOI: 10.1016/j.bmc.2013.06.040

Abstract

A novel series of aryloxyalkyl derivatives of imidazole and 1,2,4-triazole, 17-31, was designed and synthesized as inhibitors of heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2). Some of these compounds were found to be good inhibitors of HO-1, in particular those carrying an imidazole moiety as azolyl group and a 3-bromo or 4-iodophenyl as aryl moiety. The most potent compounds 6 and 30 were selected and studied for their antitumor properties in a model of LAMA-84 R cell line overexpressing HO-1 and resistant to imatinib mesylate (IM), a tyrosine-kinase inhibitor used in the treatment of multiple types of cancer, most notably Philadelphia Chromosome positive (Ph(+)) Chronic Myelogenous Leukemia (CML). Results show that both 6 and 30 sensitized LAMA-84 R cell line to antitumor properties of IM.

Keywords: 1,2,4-Triazole; Antitumor properties; HO-1inhibitors; Imatinib; Imidazole.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / toxicity
Brain / enzymology
Cell Cycle Checkpoints / drug effects
Cell Line
Cell Survival / drug effects
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / toxicity
Heme Oxygenase (Decyclizing) / antagonists & inhibitors
Heme Oxygenase (Decyclizing) / genetics
Heme Oxygenase (Decyclizing) / metabolism
Heme Oxygenase-1 / antagonists & inhibitors*
Heme Oxygenase-1 / genetics
Heme Oxygenase-1 / metabolism
Humans
Imidazoles / chemical synthesis
Imidazoles / chemistry*
Imidazoles / toxicity
Male
RNA, Messenger / metabolism
Rats
Rats, Sprague-Dawley
Spleen / enzymology
Triazoles / chemical synthesis
Triazoles / chemistry*
Triazoles / toxicity

Substances

Antineoplastic Agents
Enzyme Inhibitors
Imidazoles
RNA, Messenger
Triazoles
1,2,4-triazole
imidazole
Heme Oxygenase (Decyclizing)
Heme Oxygenase-1
heme oxygenase-2