Discovery of SI 1/20 and SI 1/22 as Mutual Prodrugs of 5‐Fluorouracil and Imidazole‐Based Heme Oxygenase 1 Inhibitor with Improved Cytotoxicity in DU145 Prostate Cancer Cells

Abstract

AbstractIn this work, we extend the concept of 5‐fluorouracil/heme oxygenase 1 (5‐FU/HO‐1) inhibitor hybrid as an effective strategy for enhancing 5‐FU‐based anticancer therapies. For this purpose, we designed and synthesized new mutual prodrugs, named SI 1/20 and SI 1/22, in which the two active parent drugs (i. e., 5‐FU and an imidazole‐based HO‐1 inhibitor) were connected through an easily cleavable succinic linker. Experimental hydrolysis rate, and in silico ADMET predictions were indicative of good drug‐likeness and pharmacokinetic properties. Novel hybrids significantly reduced the viability of prostate DU145 cancer cells compared to the parent compounds 5‐FU and HO‐1 inhibitor administered alone or in combination. Interestingly, both compounds showed statistically significant lower toxicity, than 5‐FU at the same dose, against non‐tumorigenic human benign prostatic hyperplasia (BPH‐1) cell line. Moreover, the newly synthesized mutual prodrugs inhibited the HO‐1 activity both in a cell‐free model and in vitro, as well as downregulated the HO‐1 expression and increased the reactive oxygen species (ROS) levels.