Discovery of New Acid Ceramidase-Targeted Acyclic 5‑Alkynyl and 5‑Heteroaryl Uracil Nucleosides

A series of novel <i>N</i>-acyclic uracil analogs with linear, branched, aromatic, and cyclopropyl-alkynyl as well as heteroaryl moieties at C-5 were prepared using palladium catalyzed Sonogashira and Stille cross-coupling and evaluated against malignant tumor cell lines. C-5-Furan-2-yl uracil derivative <b>6</b> was shown to be more potent against MCF-7 than the reference drug 5-fluorouracil (5-FU), while C-5-alkynyl uracil derivatives <b>9c</b> and <b>9e</b> exhibited antibreast cancer activities comparable to 5-FU. Selected compounds induced cell death, partially due to apoptosis, of MCF-7 breast cancer cells. Abrogation of acid ceramidase (ASAH1) expression of <b>9c</b> and <b>9e</b> indicated that these compounds could perturb ASAH1-mediated sphingolipid signaling. The selective activity of <b>9c</b> and <b>9e</b> against breast cancer cells via the ASAH1-mediated signaling, as a molecular target, might have a great advantage for potential future therapeutic use.