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.
Highlights
Heme metabolism is under the tight control of a family of phase II detoxifying enzymes known as heme oxygenase (HO).[1]
The detrimental role of heme oxygenase-1 (HO-1) has been demonstrated in leukemia, glioblastoma (GBM), prostate, lung, and colon cancers.[6−12] whereas HO-1 is generally found in the cytoplasm, a different subcellular localization was detected in cancerous tissues
The classical pharmacophore for HO-1 inhibition consists of (i) an iron(II)-binding group that coordinates Fe2+ in the HO-1 active site, (ii) a hydrophobic portion, and (iii) a central spacer connecting the two groups. This pharmacophore pattern has been investigated in the past years to derive a novel series of HO-1 inhibitors and will be further exploited.[16−18] cocrystallization studies performed with compound 3 highlighted the presence of an additional smaller secondary hydrophobic pocket in HO1 and heme oxygenase-2 (HO-2).21 This information allowed us to explain the 15
Summary
Heme metabolism is under the tight control of a family of phase II detoxifying enzymes known as heme oxygenase (HO).[1]. While HO-2 distribution remains unchanged regardless of the endogenous oxidative stress status, HO-1, whose expression is mainly under the control of the transcription factor, nuclear factor erythroid 2related factor 2 (Nrf2) is an inducible isoform implicated in counteracting inflammation and oxidative stress responses.[1,2] Metabolites produced upon heme breakdown, biliverdin, bilirubin, carbon monoxide, and Fe2+ further support HO-1 cytoprotective roles. The detrimental role of HO-1 has been demonstrated in leukemia, glioblastoma (GBM), prostate, lung, and colon cancers.[6−12] whereas HO-1 is generally found in the cytoplasm, a different subcellular localization was detected in cancerous tissues. Higher levels of nuclear HO-1 have been detected in malignant tissues than those in normal ones, which has been speculated to be strictly linked with cancer progression.[13,14] These aspects pushed for the search of selective HO-1 inhibitors. Structure−activity relationship (SAR) studies to identify new HO-1 inhibitors have been initially focused on metalloporphyrins (MPs), soon abandoned due to different side effects and subsequently on the nonporphyrin lead compound azalanstat (Figure 1).[15]
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