Comparing hydrazine-derived reactive groups as inhibitors of quinone-dependent amine oxidases

Abstract

Lysyl oxidase has emerged as an important enzyme in cancer metastasis. Its activity has been reported to become upregulated in several types of cancer, and blocking its activity has been shown to limit the metastatic potential of various cancers. The small-molecules phenylhydrazine and β-aminopropionitrile are known to inhibit lysyl oxidase; however, issues of stability, toxicity, and poorly defined mechanisms limit their potential use in medical applications. The experiments presented herein evaluate three other families of hydrazine-derived compounds – hydrazides, alkyl hydrazines, and semicarbazides – as irreversible inhibitors of lysyl oxidase including determining the kinetic parameters and comparing the inhibition selectivities for lysyl oxidase against the topaquinone-containing diamine oxidase from lentil seedlings. The results suggest that the hydrazide group may be a useful core functionality that can be developed into potent and selective inhibitors of lysyl oxidase and eventually find application in cancer metastasis research.

Keywords:

• Lysyl oxidase
• hydrazine
• enzyme kinetics
• irreversible inhibition

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding

Financial support was provided by Clark University. AAB, ESS, and MJS would like to acknowledge LEEP fellowships, James and Ada Bickman Summer Research Fellowships, and a Gustaf H. Carlson Summer Research Fellowship provided by Clark University as well as partial summer fellowships provided by PCI Synthesis Inc.