title: Discovery of a new class of highly potent inhibitors of acid ceramidase: synthesis and structure-activity relationship (SAR).
abstract: Acid ceramidase (AC) is an intracellular cysteine amidase that catalyzes the hydrolysis of the lipid messenger ceramide. By regulating ceramide levels in cells, AC may contribute to the regulation of cancer cell proliferation and senescence and to the response to cancer therapy. We recently identified the antitumoral agent carmofur (4a) as the first nanomolar inhibitor of intracellular AC activity (rat AC, IC50 = 0.029 μM). In the present work, we expanded our initial structure-activity relationship (SAR) studies around 4a by synthesizing and testing a series of 2,4-dioxopyrimidine-1-carboxamides. Our investigations provided a first elucidation of the structural features of uracil derivatives that are critical for AC inhibition and led us to identify the first single-digit nanomolar inhibitors of this enzyme. The present results confirm that substituted 2,4-dioxopyrimidine-1-carboxamides are a novel class of potent inhibitors of AC. Selected compounds of this class may represent useful probes to further characterize the functional roles of AC.
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pizzirani
authors.forename: Chiara
authors.initials: C
authors.lastname: Pagliuca
authors.forename: Natalia
authors.initials: N
authors.lastname: Realini
authors.forename: Davide
authors.initials: D
authors.lastname: Branduardi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bottegoni
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Fabio
authors.initials: F
authors.lastname: Bertozzi
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors*; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011743:Pyrimidines; D055573:Acid Ceramidase