Structural requirements for novel coenzyme‐substrate derivatives to inhibit intracellular ornithine decarboxylase and cell proliferation

Abstract

Creating transition-state mimics has proven to be a powerful strategy in developing inhibitors to treat malignant diseases in several cases. In the present study, structurally diverse coenzyme-substrate derivatives mimicking this type for pyridoxal 5'-phosphate-dependent human ornithine decarboxylase (hODC), a potential anticancer target, were designed, synthesized, and tested to elucidate the structural requirements for optimal inhibition of intracellular ODC as well as of tumor cell proliferation. Of 23 conjugates, phosphopyridoxyl- and pyridoxyl-L-tryptophan methyl ester (pPTME, PTME) proved significantly more potent in suppression proliferation (IC(50) up to 25 microM) of glioma cells (LN229) than alpha-DL-difluoromethylornithine (DFMO), a medically used irreversible inhibitor of ODC. In agreement with molecular modeling predictions, the inhibitory action of pPTME and PTME toward intracellular ODC of LN229 cells exceeded that of the previous designed lead compound POB. The inhibitory active compounds feature hydrophobic side chain fragments and a kind of polyamine motif (-NH-(CH(X))(4)-NH-). In addition, they induce, as polyamine analogs often do, the activity of the polyamine catabolic enzymes polyamine oxidase and spermine/spermidine N(1)-acetyltransferase up to 250 and 780%, respectively. The dual-action mode of these compounds in LN229 cells affects the intracellular polyamine metabolism and might underlie the more favorable cell proliferation inhibition in comparison with DFMO.

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

“…For example, after a 48 h treatment the EC 50 was 3.0 mM in L1210 cells (mouse leukemia) 55 , 0.5 mM in L5178 cells (mouse lymphoma) 55 , 2.5 mM in B16 cells (mouse melanoma) 56 and 33.3 mM in BE(2)-C cells (human neuroblastoma) 57 . On the other hand, the EC 50 was higher than 0.5 mM after 72 h treatment of LN229 cells (human glioblastoma) 58 . If one compares the cytotoxic effect caused by NCAO and DFMO in the cancer cell lines tested in this study, it becomes evident that NCAO outperforms DFMO in all cancer cell lines.…”

Vitamin B6-Dependent Enzymes in the Human Malaria ParasitePlasmodium falciparum: A Druggable Target?

“…Additionally, several other PLP-dependent enzymes have already been exploited as drug targets such as the γ -aminobutyric acid GABA aminotransferase by the drug vigabatrin for treatment of epilepsy [60], the alanine racemase in microbicides [61], or the ornithine decarboxylase (ODC) in cancer research [62]. In particular, the ODC was also subject to drug discovery approaches against protozoan parasites but not limited as outlined below to the aspartate aminotransferase (AspAT) and the serine hydroxymethyltransferase (SHMT).…”

Modulation of Intestinal Epithelial Cell Proliferation, Migration, and Differentiation In Vitro by Astragalus Polysaccharides

“…ODC has been shown to be crucial to cell growth by experimental approaches that interfere with the enzyme’s function. For example, inhibition of ODC activity by the specific inhibitor difluoromethylornithine arrests the growth of cultured cells in vitro [32]. ODC shows low expression in normal IECs but exhibits high levels of activity in IECs with high rates of proliferation and migration [33].…”