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

Autori
Meščić, Andrijana ; Harej, Anja ; Klobučar, Marko ; Glavač, Danijel ; Cetina, Mario ; Kraljević Pavelić, Sandra ; Raić-Malić, Silvana

Izvornik
ACS Medicinal Chemistry Letters (1948-5875) 6 (2015), 11; 1150-1155

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

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

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Interdisciplinarne prirodne znanosti, Temeljne medicinske znanosti

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