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. 2021 Dec;36(1):1378-1386.
doi: 10.1080/14756366.2021.1928111.

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

Loredana Salerno  1 , Luca Vanella  1 , Valeria Sorrenti  1 , Valeria Consoli  1 , Valeria Ciaffaglione  1 , Antonino N Fallica  1 , Vittorio Canale  2 , Paweł Zajdel  2 , Rosario Pignatello  1 , Sebastiano Intagliata  1
Affiliations

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

Loredana Salerno et al. J Enzyme Inhib Med Chem. 2021 Dec.

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.

Keywords: 5-fluorouracil; HO-1 inhibitors; Mutual prodrugs; anticancer agents; heme oxygenase 1; hybrid compounds.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Chemical structure of 5-FU, succinic acid, HO-1 inhibitor (1), and 5-FU/HO-1 hybrid (3).
Scheme 1.
Scheme 1.
Reagents and conditions: (i) succinic anhydride, triethylamine, dry methylene chloride, reflux, 6 h; (ii) 1-hydroxymethyl-5-fluorouracil, EDC·HCl, DMAP, dry methylene chloride/acetonitrile (1:1, v/v), rt, 12 h.
Figure 2.
Figure 2.
In vitro chemical stability of 5-FU/HO-1 hybrid (3) at different pHs. Data are representative of three independent experiments and values are expressed in mean ± SEM.
Figure 3.
Figure 3.
Hydrolysis rate of 3 in porcine esterase solution. A linear pseudo-first-order plot of the ln AUCt vs. time was observed. k = 5.07 × 10−3 min−1; t1/2 = 136 min; r = 0.999. Data are representative of three independent experiments and values are expressed in mean ± SEM.
Figure 4.
Figure 4.
Effect on cell viability of tested compounds in (a) DU145, and (b) A549 cancer cells. Cell viability is expressed as fold change in viability from the control in treated cells (72 h). Data are presented as mean ± SEM (n = 8) of four independent experiments. * Significant vs. untreated control cells: p < 0.05.
Figure 5.
Figure 5.
Effect on cell viability of tested compounds in BEAS cells. Cell viability is expressed as fold change in viability from the control in treated cells (72 h). Data are presented as mean ± SEM (n = 8) of four independent experiments. * Significant vs. untreated control cells: p < 0.05; # Significant vs. 5-FU treated cells: p < 0.05.
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