title: Discovery of New Acid Ceramidase-Targeted Acyclic 5-Alkynyl and 5-Heteroaryl Uracil Nucleosides.
abstract: 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.
authors.affiliation: University of Zagreb , Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev trg 20, HR-10000 Zagreb, Croatia.
authors.forename: Andrijana
authors.initials: A
authors.lastname: Meščić
authors.affiliation: University of Rijeka , Department of Biotechnology, Radmile Matejčić 2, HR-51000 Rijeka, Croatia ; University of Rijeka , Centre for high-throughput technologies, Radmile Matejčić 2, HR-51000 Rijeka, Croatia.
authors.forename: Anja
authors.initials: A
authors.lastname: Harej
authors.affiliation: University of Rijeka , Department of Biotechnology, Radmile Matejčić 2, HR-51000 Rijeka, Croatia ; University of Rijeka , Centre for high-throughput technologies, Radmile Matejčić 2, HR-51000 Rijeka, Croatia.
authors.forename: Marko
authors.initials: M
authors.lastname: Klobučar
authors.affiliation: University of Zagreb , Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev trg 20, HR-10000 Zagreb, Croatia.
authors.forename: Danijel
authors.initials: D
authors.lastname: Glavač
authors.affiliation: University of Zagreb , Faculty of Textile Technology, Department of Applied Chemistry, Prilaz baruna Filipovića 28a, HR-10000 Zagreb, Croatia.
authors.forename: Mario
authors.initials: M
authors.lastname: Cetina
authors.affiliation: University of Rijeka , Department of Biotechnology, Radmile Matejčić 2, HR-51000 Rijeka, Croatia ; University of Rijeka , Centre for high-throughput technologies, Radmile Matejčić 2, HR-51000 Rijeka, Croatia.
authors.forename: Sandra Kraljević
authors.initials: SK
authors.lastname: Pavelić
authors.affiliation: University of Zagreb , Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev trg 20, HR-10000 Zagreb, Croatia.
authors.forename: Silvana
authors.initials: S
authors.lastname: Raić-Malić
keywords: Nucleosides; acid ceramidase (ASAH1); apoptosis; breast cancer; pyrimidine; sphingolipid signaling