ChemMedChem. 2023 Feb 9. doi: 10.1002/cmdc.202300047. Online ahead of print.
ABSTRACT
In 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 lines. 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 ROS levels.
PMID:36756924 | DOI:10.1002/cmdc.202300047
