Naslov
Novel pyrimidine-2,4-dione–1,2,3-triazole and furo[2,3-d]pyrimidine-2-one–1,2,3-triazole hybrids as potential anti-cancer agents: Synthesis, computational and X-ray analysis and biological evaluation

Autori
Gregorić, Tomislav ; Sedić, Mirela ; Grbčić, Petra ; Tomljenović Paravić, Andrea ; Kraljević Pavelić, Sandra ; Cetina, Mario ; Vianello, Robert ; Raić-Malić, Silvana

Izvornik
European journal of medicinal chemistry (0223-5234) 125 (2017); 1247-1267

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

Ključne riječi
Furo[2, 3-d]pyrimidine-2-one ; 5-endo-trig cyclization ; Computational chemistry ; X-ray analysis ; Sphingolipid signaling ; Wee-1 kinase

Sažetak
Regioselective 1, 4-disubstituted 1, 2, 3-triazole tethered pyrimidine-2, 4-dione derivatives (5-23) were successfully prepared by the copper(I)- catalyzed click chemistry. While known palladium/copper cocatalyzed method based on Sonogashira cross-coupling followed by the intramolecular 5-endo-dig ring closure generated novel 6-alkylfuro[2, 3-d]pyrimidine-2-one-1, 2, 3- triazole hybrids (24b-37b), a small library of their 5-alkylethynyl analogs (24a-37a) was synthesized and described for the first time by tandem terminal alkyne dimerization and subsequent 5-endo-trig cyclization, which was additionally corroborated with computational and X-ray crystal structure analyses. The nature of substituents on alkynes and thereof homocoupled 1, 3-diynes predominantly influenced the ratio of the formed products in both pathways. In vitro antiproliferative activity of prepared compounds evaluated on five human cancer cell lines revealed that N, N-1, 3-bis-(1, 2, 3-triazole)-5- bromouracil (5-7) and 5, 6-disubstituted furo[2, 3- d]pyrimidine-2-one-1, 2, 3-triazole 34a hybrids exhibited the most pronounced cytostatic acitivities against hepatocellular carcinoma (HepG2) and cervical carcinoma (HeLa) cells with higher potencies than the reference drug 5- fluorouracil. Cytostatic effect of pyrimidine-2, 4-dione-1, 2, 3-triazole hybrid 7 in HepG2 cells could be attributed to the Wee-1 kinase inhibition and abolishment of sphingolipid signaling mediated by acid ceramidase and sphingosine kinase 1. Importantly, this compound proved to be a nonmitochondrial toxicant, which makes it a promising candidate for further lead optimization and development of a new and more efficient agent for the treatment of hepatocellular carcinoma.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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