HO-2 is a constitutive isoform and has been characterized generally in testis and the brain, where this isoform is more abundant.

(1) HOs include heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2) isoforms. Heme metabolism is under the tight control of a family of phase II detoxifying enzymes known as heme oxygenase (HO). The obtained data suggest that 7l can reduce cell invasivity acting through modulation of HO-1 expression. 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 selected compounds showed the best activity toward U87MG cells. 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. In many tumors, overexpression of HO-1 correlates with poor prognosis and chemoresistance, suggesting the inhibition of HO-1 as a possible antitumor strategy. Specifically, an amide linker in the central spacer and an imidazole were fixed, and the hydrophobic moiety required by the pharmacophore was largely modified. Herein, we report the design, synthesis, molecular modeling, and biological evaluation of novel HO-1 inhibitors. Heme oxygenase-1 (HO-1) promotes heme catabolism exercising cytoprotective roles in normal and cancer cells.

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