title: Synthesis, structure elucidation, determination of the lipophilicity and identification of antitumour activities in vitro of novel 3-(2-furanyl)-8-aryl-7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-ones with a low cytotoxicity towards normal human skin fibroblast cells.
abstract: Eleven novel 3-(2-furanyl)-8-aryl-7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-ones (12-22) were designed and obtained from appropriate 1-aryl-2-hydrazonoimidazolidines (1-11) by condensation reaction with 2-oxo-2-furanacetic acid and subsequent cyclocondensation of intermediate chain derivatives. IR, (1)H NMR and (13)C NMR spectra and elemental analyses confirmed the chemical structure of all the synthesized compounds. The reversed-phase HPLC method was optimized and proved to be applicable and reliable for the analysis of these unknown small molecules (12-22). These compounds were chromatographed on octadecyl silica (ODS) stationary phase and their hydrophobic parameters expressed as the log k(w) values were determined by RP-HPLC, using mixtures of methanol and water as mobile phases with different methanol concentrations. Octane-1-sulfonic acid sodium salt (OSA-Na) and 20% acetate buffer (pH 3.5) was added to the mobile phase (eluent containing 0.01 M/L OSA-Na in organic modifier (MeOH)-buffered mobile phase). The high values of regression coefficients (r >0.9841) for all the compounds investigated proved the excellent fit between experimental data and the Snyder-Soczewiński equation. Results obtained from the reversed-phase HPLC were compared both with those theoretically calculated and with those obtained from an ALOGPS 2.1. software by the use of nine different computational methods for estimation of log P. The predicted values of log P by use of AB log P algorithm revealed the best correlation with the experimental log k(w) values for the investigated solutes, since a good correlation (r=0.7760) between these quantities was found. The majority of novel imidazotriazinones were found to be evidently effective in vitro against human cancerous cells (HeLa and T47D) in an effective concentration of 50 μg/mL. Five compounds (13, 15, 16, 18 and 22) revealed remarkable antiproliferative activities and selective cytotoxicities for cancer cells over normal HSF cells. Therefore these ones may be considered as a basis for the design of novel useful non-toxic (13, 15 and 16) and low toxic (18 and 22) anticancer agents.
authors.affiliation: Chair and Department of Medical Chemistry, Medical University, Lublin, Poland. krzysztof.sztanke@umlub.pl
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Sztanke
authors.forename: Tomasz
authors.initials: T
authors.lastname: Tuzimski
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Sztanke
authors.forename: Jolanta
authors.initials: J
authors.lastname: Rzymowska
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Pasternak
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D056148:Chromatography, Reverse-Phase; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D014227:Triazines; C093444:1,2,4-triazine; C029899:imidazole