Discovery of Novel Acetamide-Based Heme Oxygenase-1 Inhibitors with Potent In Vitro Antiproliferative Activity

Abstract

Heme oxygenase-1 (HO-1) promotes heme catabolism exercising cytoprotective roles in normal and cancer cells. Herein, we report the design, synthesis, molecular modeling, and biological evaluation of novel HO-1 inhibitors. Specifically, an amide linker in the central spacer and an imidazole were fixed, and the hydrophobic moiety required by the pharmacophore was largely modified. In many tumors, overexpression of HO-1 correlates with poor prognosis and chemoresistance, suggesting the inhibition of HO-1 as a possible antitumor strategy. Accordingly, compounds 7i and 7l – p emerged for their potency against HO-1 and were investigated for their anticancer activity against prostate (DU145), lung (A549), and glioblastoma (U87MG, A172) cancer cells. The selected compounds showed the best activity toward U87MG cells. Compound 7l was further investigated for its in-cell enzymatic HO-1 activity, expression levels, and effects on cell invasion and vascular endothelial growth factor (VEGF) extracellular release. The obtained data suggest that 7l can reduce cell invasivity acting through modulation of HO-1 expression.

Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells

“…Taken together, these results highlight the role of HO as one of the many factors that are able to sustain ferroptosis. Thus, it is worth remarking on the difference between the two pharmacological strategies used by us and other research groups [ 29 , 37 , 53 ], exploiting either the induction or inhibition of the HO system in order to understand their effectiveness in different cellular and animal models. Low basal HO-1 levels appear to be critical to predict cells’ sensitivity to ferroptosis, suggesting its potential targeting as a novel therapeutic approach for BC.…”

“…In particular, HO-1 overexpression is generally observed in several malignant human neoplastic diseases, serving as a cytoprotective factor in the early stages of tumorigenesis, but eventually promoting malignant cells’ growth, proliferation and invasion [ 25 , 26 , 27 , 28 ]. On the basis of these observations, HO-1 inhibition has been widely exploited as a valid therapeutic strategy for cancer treatment [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. However, recent findings seem to propose a different approach for pharmacological modulation of HO-1 in cancer therapy, displaying a reduction in cancerous cell proliferation following enzyme induction [ 36 , 37 ].…”

The Promise of Nanotechnology in Personalized Medicine

“…However, this type of cancer is particularly aggressive, and poor chances of survival have often been reported. Therefore, new anticancer strategies based on the discovery of novel small molecules or nanomedicine approaches are urgently needed [ 50 ]. Kumthekar et al developed a RNA interference-based spherical nucleic acids (SNAs), made of a gold nanoparticle conjugated with siRNA oligonucleotides targeting the highly expressed GBM oncogene Bcl2Like12 (Bcl2L12).…”

Novel Tyrosine Kinase Inhibitors to Target Chronic Myeloid Leukemia

“…Therefore, HO-1 inhibition may be considered for more effective anticancer treatments, specifically to reduce drug resistance [ 17 , 18 ]. To this end, so far, we have developed a large library of selective HO-1 inhibitors belonging to the class of imidazole-based derivatives [ 11 , 18 , 19 , 20 , 21 , 22 ].…”