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Novel mutual prodrug of 5-fluorouracil and heme oxygenase-1 inhibitor (5-FU/HO-1 hybrid): design and preliminary in vitro evaluation.


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.

SUBMITTER: Salerno L 

PROVIDER: S-EPMC8231349 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Novel mutual prodrug of 5-fluorouracil and heme oxygenase-1 inhibitor (5-FU/HO-1 hybrid): design and preliminary <i>in vitro</i> evaluation.

Salerno Loredana L   Vanella Luca L   Sorrenti Valeria V   Consoli Valeria V   Ciaffaglione Valeria V   Fallica Antonino N AN   Canale Vittorio V   Zajdel Paweł P   Pignatello Rosario R   Intagliata Sebastiano S  

Journal of enzyme inhibition and medicinal chemistry 20211201 1


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 <i>in vitro</i> chemical and enzymatic hydrolysis stability. Predicted <i>in silico</i> physicochemical properties of the newly synthesised hybrid (<b>3</b>) demonstrated a drug-like profile with suitable Absorption, Distribution, Metabolism, and Excretion (ADME) properties and low toxic liabilities. Preliminary cytotoxicity evaluation to  ...[more]

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