Synthesis of N-acetyl Glucosamine Analogs as Inhibitors for Hyaluronan Biosynthesis

Abstract

Elevated hyaluronan expression is a hallmark of many types of cancer. Therefore, inhibition of hyaluronan biosynthesis can potentially slow the growth of tumor cells. Herein, we explore a chain termination strategy to reduce hyaluronan synthesis by tumor cells. Several analogs of glucosamine were prepared, which contained modifications at the C-3 positions. These analogs can possibly cap the nonreducing end of a growing hyaluronan chain, thus lowering the amount of hyaluronan synthesized. Upon incubation with pancreatic cancer cells, a fluorine-containing glucosamine analog was found to exhibit significant inhibitory activities of hyaluronan synthesis. Furthermore, it drastically reduced the proliferation of cancer cells.

Supplemental materials are available for this article. Go to the publisher's online edition of Journal of Carbohydrate Chemistry to view the supplemental file.

Keywords:

• Biosynthesis
• Chain terminator
• Hyaluronan
• Inhibitor
• Salvage pathway

ACKNOWLEDGMENTS

We thank the National Institute of General Medical Sciences (R01 GM72667), NIH, for financial support of our work. This work was also partially supported by the Regional Innovation Strategy Support Program (City Area Type) of the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Supporting Information Available: Selected NMR spectra and images of the particle exclusion assay at low magnification.