Inhibition of Tumor Cell Growth by A Specific 6-Phosphofructo-2-kinase Inhibitor, N-Bromoacetylethanolamine Phosphate, and Its Analogues

• Published in: Bioscience, biotechnology, and biochemistry Vol. 64; no. 10; pp. 2047 - 2052
• Main Authors: HIRATA, Takafumi, WATANABE, Mitsuaki, MIURA, Shinji, IJICHI, Katsushi, FUKASAWA, Masashi, SAKAKIBARA, Ryuzo
• Format: Journal Article
• Language: English
• Published: Tokyo Japan Society for Bioscience, Biotechnology, and Agrochemistry 01.10.2000; Japan Society for Bioscience Biotechnology and Agrochemistry; Oxford University Press
• Subjects: 6-Phosphofructo-2-kinase; 6-phosphofructo-2-kinase inhibitors; Animals; Antineoplastic agents; Biological and medical sciences; Cell Division - drug effects; Drug Screening Assays, Antitumor; enzyme inhibitor; Enzyme Inhibitors - pharmacology; Ethanolamines - pharmacology; Female; General aspects; glycolysis; Humans; Lactic Acid - biosynthesis; Medical sciences; Mice; N-(2-ethoxyethyl)-bromoacetamide; N-(2-methoxyethyl)-bromoacetamide; N-(3-methoxypropyl)-bromoacetamide; N-Bromoacetylethanolamine phosphate; Neoplasms - metabolism; Neoplasms - pathology; Pharmacology. Drug treatments; Phosphofructokinase-2; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; tumor cell growth; Tumor Cells, Cultured; Antineoplastic agent; Enzyme; Transferases; Enzyme inhibitor; In vitro; Biological activity; Structure activity relation; Analog; Glycolysis; Carboxamide; Bromine Organic compounds; 6-Phosphofructo-2-kinase; Tumor cell
• ISSN: 0916-8451; 1347-6947
• DOI: 10.1271/bbb.64.2047

The high rate of glycolysis despite the presence of oxygen and mitochondria in tumor cells implies an important role for this process in cell division. The rate of glycolysis is assumed to be dependent on the cellular concentration of fructose 2,6-bisphosphate, the concentration of which in turn depends on a bifunctional enzyme and the ratio of this enzyme's 6-phosphofructo-2-kinase versus its fructose 2,6-bisphosphatase activities. To prove the hypothesis that inhibition of glycolysis in tumor cells by 6-phosphofructo-2-kinase inhibitors would cause inhibition of tumor cell proliferation, ten N-bromoacetylethanolamine phosphate analogues were designed, synthesized, and tested. They were screened for their activities against various human tumor cell lines to study the effects of inhibition of glycolysis on cell proliferation. The relationship between the structure of these compounds and their inhibitory activity on cell proliferation was also discussed. It was found that the activity of N-(2-methoxyethyl)-bromoacetamide, N-(2-ethoxyethyl)-bromoacetamide, and N-(3-methoxypropyl)-bromoacetamide was comparable to that of the positive control AraC. These three inhibitors showed in vivo anticancer effects in P388 transplant BDF 1 mice.