engleski

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

A series of novel N-acyclic uracil analogs with linear, branched, aromatic and cyclopropyl-alkynyl as well as heteroaryl moiety 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 showed 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 anti-breast cancer activities comparable to 5-FU. Selected compounds induced cell death, partially due to apoptosis, of MCF-7 breast cancer cells. Abrogation of ASAH1 expression of 9c and 9e indicated that these compounds could perturb acid ceramidase-mediated (ASAH1) 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.

Nucleosides ; pyrimidine ; apoptosis ; breast cancer ; acid ceramidase (ASAH1) ; sphingolipid signaling

nije evidentirano