Discovery of a New Class of Highly Potent Inhibitors of Acid Ceramidase: Synthesis and Structure–Activity Relationship (SAR)

Daniela Pizzirani,Chiara Pagliuca,Rita Scarpelli,Tiziano Bandiera,Giovanni Bottegoni,Fabio Bertozzi,Daniele Piomelli,Marco Mor,Davide Branduardi,Natalia Realini

doi:10.1021/jm301879g

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.

Highlights

Sphingosine-containing lipids are essential structural components of cell membranes that serve important signaling functions in cell migration, cell recognition, and inflammation, as well as in the control of cell growth and differentiation.[1]
We have identified and characterized 2,4-dioxopyrimidine-1carboxamides as a novel class of potent small-molecule Acid ceramidase (AC) inhibitors
A systematic structure−activity relationship (SAR) study around the uracil scaffold allowed a first elucidation of critical structural features associated with AC inhibition

Summary

Introduction

Sphingosine-containing lipids are essential structural components of cell membranes that serve important signaling functions in cell migration, cell recognition, and inflammation, as well as in the control of cell growth and differentiation.[1]. By regulating the intracellular levels of ceramides, AC may influence the survival, growth, and death of tumor cells.[5] Consistent with this view, cells that express abnormally high levels of AC are more resistant than normal cells to pharmacological induction of programmed cell death.[6] several types of cancer (including prostate, head and neck, colon and melanoma) overexpress AC, which is suggestive of a role for this enzyme in the resistance to radiotherapy and chemotherapy.[7]

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