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

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posted on 2015-11-12, 00:00 authored by Andrijana Meščić, Anja Harej, Marko Klobučar, Danijel Glavač, Mario Cetina, Sandra Kraljević Pavelić, Silvana Raić-Malić
A series of novel N-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 6 was shown to be more potent against MCF-7 than the reference drug 5-fluorouracil (5-FU), while C-5-alkynyl uracil derivatives 9c and 9e 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 9c and 9e indicated that these compounds could perturb ASAH1-mediated sphingolipid signaling. The selective activity of 9c and 9e against breast cancer cells via the ASAH1-mediated signaling, as a molecular target, might have a great advantage for potential future therapeutic use.

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