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International Journal of Medicinal Chemistry
Volume 2017, Article ID 4852537, 8 pages
https://doi.org/10.1155/2017/4852537
Research Article

Fluorinated Adenosine A2A Receptor Antagonists Inspired by Preladenant as Potential Cancer Immunotherapeutics

1Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA
2New England Tissue Protection Institute, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA
3Gordon Center for Medical Imaging and Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital and Department of Radiology, Harvard Medical School, 55 Fruit St., Boston, MA 02114, USA
4Clinical and Translational Science Institute, Tufts University, 800 Washington Street, Boston, MA 02111, USA

Correspondence should be addressed to Graham B. Jones; ude.stfut@senoj.maharg

Received 15 May 2017; Revised 31 August 2017; Accepted 13 September 2017; Published 19 October 2017

Academic Editor: Rosaria Volpini

Copyright © 2017 Gengyang Yuan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Antagonism of the adenosine receptor on T cells blocks the hypoxia-adenosinergic pathway to promote tumor rejection. Using an in vivo immunoassay based on the Concanavalin A mouse model, a series of antagonists were studied and identified preladenant as a potent lead compound for development. Molecular modeling was employed to assist drug design and subsequent synthesis of analogs and those of tozadenant, including fluorinated polyethylene glycol PEGylated derivatives. The efficacy of the analogs was evaluated using two in vitro functional bioassays, and compound 29, a fluorinated triethylene glycol derivative of preladenant, was confirmed as a potential immunotherapeutic agent.