Computational and experimental evaluation of ornithine derivatives as ornithine decarboxylase inhibitors

Abstract

Polyamines play a relevant role in living cells because they are involved in several biological processes such as cell proliferation, transcription, and translation. In this article, we report the synthesis and in vitro evaluation of an ornithine analogue (6) as an ornithine decarboxylase (ODC) inhibitor. Docking studies of ornithine and some of its derivatives (1-6) on ODC were performed. The results showed that the affinity of 6 for ODC was lower than iodide compounds (4 and 5) by both docking simulations and kinetic experiments. However, the former was less toxic than 4 and 5. Finally, it is important to mention that the docking procedure showed several interactions between the ligands on Cys 360 and pyridoxal 5 0 phosphate (PLP), which could explain in part their ODC inhibitory effects.

N-ω-chloroacetyl-l-ornithine, a new competitive inhibitor of ornithine decarboxylase, induces selective growth inhibition and cytotoxicity on human cancer cells versus normal cells

“…The kinetics study reveals that NCAO inhibited rat liver ODC, and that this inhibition was competitive with respect to the substrate, L-ornithine. These experimental results agree with the computational docking simulations done by Correa-Basurto et al 26 , who reported that NCAO binds to the active site of ODC with high affinity. The docking procedure showed that NCAO can interact with PLP and Cys328 in the active site of the enzyme.…”

“…Therefore, a compound was sought with a less reactive alkylating group, leading to the design and synthesis of NCAO. In vivo tests showed low toxicity 26 . The present study demonstrates the inhibitory action of NCAO on three human tumor cell lines.…”

“…However, despite having a high affinity to ODC, DFMO has proved to have poor transport into cells, as evidenced by cell-based assays and animal models 3,11 . Since docking studies have shown that the chlorine atom of NCAO can interact with Cys328 in the ODC active site 26 , we decided to determine whether NCAO is an irreversible inhibitor of ODC. No irreversible inhibition was found for up to 2 h. It is possible that the alkylating or acylating reaction requires more time.…”

“…Cell culture medium components were purchased from Invitrogen, Gibco (Carlsbad, CA). N-o-chloroacetyl-L-ornithine was prepared by following an established procedure 26 .…”

“…A recent study 26 proposed another potential ODC inhibitor. Computational docking simulations indicated that N-x-chloroacetyl-L-ornithine (NCAO) (Figure 1) should inhibit rat liver ODC with high affinity, and in vivo assays showed its potential properties for inhibiting cell proliferation with low toxicity.…”