Development of new inhibitors for N-acylethanolamine-hydrolyzing acid amidase as promising tool against bladder cancer

• Published in: Bioorganic & medicinal chemistry Vol. 25; no. 3; pp. 1242 - 1249
• Main Authors: Vago, Riccardo, Bettiga, Arianna, Salonia, Andrea, Ciuffreda, Pierangela, Ottria, Roberta
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.02.2017; Elsevier
• Subjects: Amidohydrolases - antagonists & inhibitors; Amidohydrolases - metabolism; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry & Molecular Biology; Bladder cancer; Cell Death - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Endocannabinoid; Enzyme inhibition; Ethanolamines - chemical synthesis; Ethanolamines - chemistry; Ethanolamines - pharmacology; Humans; Life Sciences & Biomedicine; Molecular Structure; N-acylethanolamine-hydrolyzing acid amidase; Pharmacology & Pharmacy; Physical Sciences; Recombinant Proteins - metabolism; Science & Technology; Structure-Activity Relationship; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Enzyme inhibition; Endocannabinoid; N-acylethanolamine-hydrolyzing acid amidase; Bladder cancer; PROSTATE-CANCER; ANANDAMIDE; AGENTS; CELL-LINES; CANNABINOIDS; HYDROLASE
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.12.042

[Display omitted] •New eight palmitamine derivatives were synthesized as NAAA inhibitors.•Compounds inhibition activity was evaluated by a fluorimetric analysis on human NAAA.•Fluorimetric screening allowed to select three promising compounds.•New NAAA inhibitors can induce bladder cancer cell death and reduce cell migration.•Effects on bladder cancer cells are due to a selective inhibition of NAAA. The endocannabinoid system is a signaling system involved in a wide range of biological effects. Literature strongly suggests the endocannabinoid system role in the pathogenesis of cancer and that its pharmacological activation produces therapeutic benefits. Last research promotes the endocannabinoid system modulation by inhibition of endocannabinoids hydrolytic enzymes instead of direct activation of endocannabinoid receptors to avoid detrimental effects on cognition and motor control. Here we report the identification of N-acylethanolamine-hydrolyzing acid amidase (NAAA) inhibitors able to reduce cell proliferation and migration and cause cell death on different bladder cancer cell lines. These molecules were designed, synthesized and characterized and active compounds were selected by a fluorescence high-throughput screening method set-up on human recombinant NAAA that also allows to characterize the mechanism of inhibition. Together our results suggest an important role for NAAA in cell migration and in inducing tumor cell death promoting this enzyme as pharmacological target against bladder cancer.