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

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Fang Wu, Heinz Gehring

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 spermin...Continue Reading

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Citations

May 9, 2013·Future Medicinal Chemistry·Thales KronenbergerCarsten Wrenger
Jun 19, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Miriam Marlene Medina-EnríquezAlba Laura Vargas-Ramírez
Feb 14, 2014·BioMed Research International·Thales KronenbergerCarsten Wrenger
Nov 27, 2009·Trends in Parasitology·Ingrid B MüllerCarsten Wrenger
Apr 2, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Fang WuHeinz Gehring

Related Concepts

Coenzymes
Enzyme Inhibitors
Ornithine Decarboxylase
Structure-Activity Relationship
Substrate Specificity
Drug Modeling
Cell Proliferation
Ornithine Decarboxylase Inhibitors
Analogs & derivatives
Antineoplastic Agents

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