Discovery of a New Class of Highly Potent Inhibitors of Acid Ceramidase: Synthesis and Structure-Activity Relationship (SAR)
Discovery of a New Class of Highly Potent Inhibitors of Acid Ceramidase: Synthesis and Structure-Activity Relationship (SAR)
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DOI：
10.1021/jm301879g
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发表时间：
2013-05-09
影响因子：
7.3
通讯作者：
Bandiera, Tiziano
中科院分区：
文献类型：
--
作者：
Pizzirani, Daniela;Pagliuca, Chiara;Bandiera, Tiziano
酸性神经酰胺酶(AC)是一种胞内半胱氨酸酰胺酶，催化脂质信使神经酰胺的水解。通过调节细胞内神经酰胺水平，AC可能有助于调节癌细胞的增殖和衰老，以及对癌症治疗的反应。我们最近发现抗肿瘤药物卡莫氟(4a)是第一个抑制细胞内AC活性的纳摩尔抑制剂(大鼠AC，IC_(50)=0.029微米)。在本工作中，我们通过合成和测试一系列2，4-二氧基吡啶-1-甲酰胺，在4a左右扩展了我们的初步构效关系(SAR)研究。我们的研究首次阐明了尿嘧啶衍生物的结构特征，这些结构特征对AC抑制至关重要，并使我们鉴定出这种酶的第一个个位数的纳米分子抑制剂。这些结果证实了取代的2，4-二氧基嘧啶-1-甲酰胺类化合物是一类新的有效的AC抑制剂。这类选定的化合物可能代表有用的探针，以进一步表征AC的功能作用。
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 mu M). In the present work, we expanded our initial structure activity relationship (SAR) studies around 4a by synthesizing and testing a series of 2,4-dioxopyrimicline-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.