2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2017 Jan 5:125:1247-1267. doi: 10.1016/j.ejmech.2016.11.028.
Tomislav Gregorić 1,  Mirela Sedić 2,  Petra Grbčić 3,  Andrea Tomljenović Paravić 3,  Sandra Kraljević Pavelić 4,  Mario Cetina 5,  Robert Vianello 6,  Silvana Raić-Malić 7
Affiliations

Affiliations

  • 1 University of Zagreb, Faculty of Chemical Engineering and Technology, Department of Organic Chemistry, 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. Electronic address: msedic@biotech.uniri.hr.
  • 3 University of Rijeka, Department of Biotechnology, Radmile Matejčić 2, HR-51000 Rijeka, Croatia.
  • 4 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.
  • 5 University of Zagreb, Faculty of Textile Technology, Department of Applied Chemistry, Prilaz Baruna Filipovića 28a, HR-10000 Zagreb, Croatia.
  • 6 Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Bijenička 54, HR-10000 Zagreb, Croatia. Electronic address: robert.vianello@irb.hr.
  • 7 University of Zagreb, Faculty of Chemical Engineering and Technology, Department of Organic Chemistry, Marulićev Trg 20, HR-10000 Zagreb, Croatia. Electronic address: sraic@fkit.hr.
PMID: 27875779 DOI: 10.1016/j.ejmech.2016.11.028
Abstract

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 non-mitochondrial 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.

Keywords

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

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