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

Autor:	Agata Grazia D’Amico, Giuseppe Romeo, Velia D'Agata, Loredana Salerno, Antonio Rescifina, Sebastiano Intagliata, Valeria Consoli, Valeria Pittalà, Giuseppe Floresta, Antonino N. Fallica, Valeria Sorrenti, Luca Vanella
Rok vydání:	2021
Předmět:	Cell In vitro Heme oxygenase Vascular endothelial growth factor chemistry.chemical_compound medicine.anatomical_structure DU145 chemistry Drug Discovery Cancer cell Cancer research medicine Molecular Medicine Pharmacophore Heme
Zdroj:	Journal of Medicinal Chemistry. 64:13373-13393
ISSN:	1520-4804 0022-2623
DOI:	10.1021/acs.jmedchem.1c00633
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9cf40ba282c95b3b81206731b7af06a6 https://doi.org/10.1021/acs.jmedchem.1c00633 Zobrazit plný text záznamu