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

ACS Med Chem Lett. 2015 Oct 5;6(11):1150-5. doi: 10.1021/acsmedchemlett.5b00298.

Andrijana Meščić ¹, Anja Harej ², Marko Klobučar ², Danijel Glavač ¹, Mario Cetina ³, Sandra Kraljević Pavelić ², Silvana Raić-Malić ¹

Affiliations

1 University of Zagreb , Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, Marulićev trg 20, HR-10000 Zagreb, Croatia.
2 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.
3 University of Zagreb , Faculty of Textile Technology, Department of Applied Chemistry, Prilaz baruna Filipovića 28a, HR-10000 Zagreb, Croatia.

PMID: 26617970 DOI: 10.1021/acsmedchemlett.5b00298

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.

Keywords

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

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