Synthesis and Evaluation of Ornithine Decarboxylase Inhibitors with Oxime Moiety and MCF-7 Breast Cancer Cells

Hyunshun Shin

doi:10.4172/2167-0501.1000111

Abstract

Cell proliferation can be regulated by small, aliphatic polyamines, and it is suggested that tumor tissues have significantly higher polyamine levels than surrounding tissues. The major biologically active polyamines present in mammalian cells are putrescine, spermidine, and spermine. The Ornithine Decarboxylase (ODC) catalyzes the decarboxylation of ornithine to produce putrescine which is precursor of polyamine synthesis. We report here the synthesis of 2-Amino-5-(Hydroxyimino) Pentanoic Acid (AHPA), based on the substrate of ODC, L-ornithine, derivatized with oxime functionality. In molecular docking studies, the E-isomer AHPA binds to ODC more favorably than does the Z-isomer. In addition, the growth of MCF-7 (Michigan Cancer Foundation–7) breast cancer cells in the presence of AHPA was significantly reduced. These results implicate that AHPA a potentialt can be explored as a potential of cancer chemotherapy.

Highlights

Cancer is the second most common cause of death for Americans and accounts for nearly 1 of every 4 deaths in the US [1,2]
The finding that inhibitors of polyamine biosynthesis can prevent, or at least limit cancer cell growth [6,7,8,9], together with the fact that polyamine concentrations are elevated in multiple cancer tissues [10,11,12], has made polyamine metabolism a promising target for cancer chemoprevention and therapy
The first critical step is the synthesis of putrescine via the decarboxylation of ornithine, which is catalyzed by the enzyme Ornithine Decarboxylase (ODC) [13,14]

Summary

Introduction

Cancer is the second most common cause of death for Americans and accounts for nearly 1 of every 4 deaths in the US [1,2]. We report the design and synthesis of 2-amino5-(hydroxyimino) pentanoic acid (AHPA), 6, which contains an oxime functional group. The molecular docking study was conducted to extend Structure-Activity Relationship (SAR) studies based on AHPA with ODC (PDB code 2ON3).

Results

Conclusion