HO-1 overexpression has been reported in several cases/types of human malignancies. Unfortunately, poor clinical outcomes are reported in most of these cases, and the inhibition of HO-1 is considered a valuable and proven anticancer approach. To identify novel hit compounds suitable as HO-1 inhibitors, we report here a fragment-based approach where ligand joining experiments were used. The two most important parts of the classical structure of the HO-1 inhibitors were used as a starting point, and 1000 novel compounds were generated and then virtually evaluated by structure and ligand-based approaches. The joining experiments led us to a novel series of indole-based compounds. A synthetic pathway for eight selected molecules was designed, and the compounds were synthesized. The biological activity revealed that some molecules reach the micromolar activity, whereas molecule 4d inhibits the HO-1 with an IC50 of 1.03 µM. This study suggested that our joining approach was successful, and a novel hit compound was generated. These results are ongoing for further development.

From far west to east: Joining the molecular architecture of imidazole-like ligands in ho-1 complexes

Floresta G.;Fallica A. N.;Patamia V.;Sorrenti V.;Rescifina A.;Pittala V.
2021

Abstract

HO-1 overexpression has been reported in several cases/types of human malignancies. Unfortunately, poor clinical outcomes are reported in most of these cases, and the inhibition of HO-1 is considered a valuable and proven anticancer approach. To identify novel hit compounds suitable as HO-1 inhibitors, we report here a fragment-based approach where ligand joining experiments were used. The two most important parts of the classical structure of the HO-1 inhibitors were used as a starting point, and 1000 novel compounds were generated and then virtually evaluated by structure and ligand-based approaches. The joining experiments led us to a novel series of indole-based compounds. A synthetic pathway for eight selected molecules was designed, and the compounds were synthesized. The biological activity revealed that some molecules reach the micromolar activity, whereas molecule 4d inhibits the HO-1 with an IC50 of 1.03 µM. This study suggested that our joining approach was successful, and a novel hit compound was generated. These results are ongoing for further development.
Fragment growing
Fragment-based ligand design
Heme oxygenase
HO-1 inhibitors
Imidazole
Ligand joining
Structure-based drug design
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/519637
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