Novel mutual prodrug of 5-fluorouracil and heme oxygenase-1 inhibitor (5-FU/HO-1 hybrid): design and preliminary in vitro evaluation |
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Authors: | Loredana Salerno,Luca Vanella,Valeria Sorrenti,Valeria Consoli,Valeria Ciaffaglione,Antonino N. Fallica,Vittorio Canale,Pawe Zajdel,Rosario Pignatello,Sebastiano Intagliata |
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Affiliation: | aDepartment of Drug and Health Sciences, University of Catania, Catania, Italy;bDepartment of Organic Chemistry, Jagiellonian University Medical College, Kraków, Poland |
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Abstract: | In this work, the first mutual prodrug of 5-fluorouracil and heme oxygenase1 inhibitor (5-FU/HO-1 hybrid) has been designed, synthesised, and evaluated for its in vitro chemical and enzymatic hydrolysis stability. Predicted in silico physicochemical properties of the newly synthesised hybrid (3) demonstrated a drug-like profile with suitable Absorption, Distribution, Metabolism, and Excretion (ADME) properties and low toxic liabilities. Preliminary cytotoxicity evaluation towards human prostate (DU145) and lung (A549) cancer cell lines demonstrated that 3 exerted a similar effect on cell viability to that produced by the reference drug 5-FU. Among the two tested cancer cell lines, the A549 cells were more susceptible for 3. Of note, hybrid 3 also had a significantly lower cytotoxic effect on healthy human lung epithelial cells (BEAS-2B) than 5-FU. Altogether our results served as an initial proof-of-concept to develop 5-FU/HO-1 mutual prodrugs as potential novel anticancer agents. |
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Keywords: | Mutual prodrugs hybrid compounds anticancer agents 5-fluorouracil heme oxygenase 1 HO-1 inhibitors |
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