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

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 aprecursor 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 can be explored as a potential agent of cancer chemotherapy. 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]. An estimated 229,060 new cases of invasive breast cancer are expected to occur among women in the US during 2012; about 2,190 new cases are expected in men [1,2]. Cancer is a disease related to uncontrolled growth and spread of abnormal cells [2]. Targeting the polyamine pathway has been studied in possible therapeutic approaches [3]. One of the most promising areas for the development of novel anti-cancer therapeutics is polyamine biosynthesis [4,5]. The finding that inhibitors of polyamine biosynthesis can prevent, or at least limit cancer cell growth [6-9], together with the fact that polyamine concentrations are elevated in multiple cancer tissues [10-12], has made polyamine metabolism a promising target for cancer chemoprevention and therapy. The major biologically active polyamines present in mammalian cells are putrescine, spermidine, and spermine [3]. These molecules are synthesized in sequence starting from ornithine, which is derived from the amino acid arginine through the action of the enzyme arginase (Scheme 1). 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]. Subsequent steps involve the production of spermidine through the addition of Decarboxylated S-Adenyosylmethionine (DAM) to the putrescine by spermidine synthase. A second DAM is then added to spermidine to produce spermine [15-17] (Scheme 1). Difluoromethylornithine (DFMO), an inhibitor of the first enzyme in the mammalian polyamine biosynthetic pathway, ornithine decarboxylase, is approved for use in trypanosomiasis and has shown promise in the therapy of brain tumors [18]. DFMO was originally evaluated as an antitumor agent in the early 1980s, with limited success. Phase I studies suggested a dose of 2.25 g/m2 every 6 h for patients with advanced solid tumors or lymphomas [19]. Phase II studies were carried out with melanoma patients including small cell lung carcinoma, colon cancer, and prostate cancer [20-22]. The drug was generally well tolerated, although significant but infrequent adverse effects including thrombocytopenia (a relative decrease of platelets in blood), transient hearing loss, and osmotic diarrhea were In this present study, 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). Although we synthesize the mixture of E and Z isomers of 2-Amino-5-(Hydroxyimino) Pentanoic Acid (AHPA), we can anticipate that the E isomer has a better binding affinity than the Z-isomer based on a molecular docking study. In *Corresponding author: Hyunshun Shin, Department of Chemistry and Biochemistry, McMurry University, McM station Box 158, Abilene, TX 79697, USA, Tel: 325-793-3879; Fax: 325-793-4770; E-mail: [email protected], [email protected] Received November 30, 2012; Accepted December 26, 2012; Published December 28, 2012 Citation: Shin H, Whitehead H, Zhou X, Banta KL, Spencer JV, et al. (2013) Synthesis and Evaluation of Ornithine Decarboxylase Inhibitors with Oxime Moiety and MCF-7 Breast Cancer Cells. Biochem Pharmacol 2:111. doi:10.4172/21670501.1000111 Copyright: © 2013 Shin H, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Citation: Shin H, Whitehead H, Zhou X, Banta KL, Spencer JV. (2013) Synthesis and Evaluation of Ornithine Decarboxylase Inhibitors with Oxime Moiety and MCF-7 Breast Cancer Cells. Biochem Pharmacol 2:111. doi:10.4172/2167-0501.1000111