title: 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.
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.
authors.affiliation: University of Zagreb, Faculty of Chemical Engineering and Technology, Department of Organic Chemistry, Marulićev Trg 20, HR-10000 Zagreb, Croatia.
authors.forename: Tomislav
authors.initials: T
authors.lastname: Gregorić
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. Electronic address: msedic@biotech.uniri.hr.
authors.forename: Mirela
authors.initials: M
authors.lastname: Sedić
authors.affiliation: University of Rijeka, Department of Biotechnology, Radmile Matejčić 2, HR-51000 Rijeka, Croatia.
authors.forename: Petra
authors.initials: P
authors.lastname: Grbčić
authors.affiliation: University of Rijeka, Department of Biotechnology, Radmile Matejčić 2, HR-51000 Rijeka, Croatia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tomljenović Paravić
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
authors.initials: S
authors.lastname: Kraljević Pavelić
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: Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Bijenička 54, HR-10000 Zagreb, Croatia. Electronic address: robert.vianello@irb.hr.
authors.forename: Robert
authors.initials: R
authors.lastname: Vianello
authors.affiliation: 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.
authors.forename: Silvana
authors.initials: S
authors.lastname: Raić-Malić
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002384:Catalysis; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018360:Crystallography, X-Ray; D003500:Cyclization; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013107:Sphingolipids / Q000378:metabolism; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011743:Pyrimidines; D013107:Sphingolipids; D014230:Triazoles; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human
keywords: 5-endo-trig cyclization; Computational chemistry; Furo[2,3-d]pyrimidine-2-one; Sphingolipid signaling; Wee-1 kinase; X-ray analysis