Graham B. Jones
Michael P. Pollastri, M. V. Sitkovskiĭ
Date of Award
Master of Science
Department or Academic Unit
College of Science. Department of Chemistry and Chemical Biology.
chemistry, adenosine receptor, bioconjugates, poly(ethylene) glycol, styrylxanthines
Bioconjugates, Adenosine - Receptors, Immunotherapy
Istradefylline (KW-6002) is one of many xanthines that act as antagonists of the A2A adenosine receptor (A2AR). While this molecule has recently been involved in phase III clinical trials as a target therapeutic for Parkinson's disease, its target pathway also implicated in tumorigenesis. As was described by Ohta et al, the oxygen-deprived hypoxic tumor microenvironment fosters increased production of adenosine, which up-regulates formation of cAMP following binding to the A2A receptor. Increased intracellular levels of cAMP are responsible for immunosuppression and misguided protection of cancerous cells. KW-6002 has shown efficacy in rescuing T-cell regulatory function in models of adoptive transfer immunotherapy.
Our current interest lies in developing bioconjugates of KW-6002 that retain selectivity for the A2A receptor, but achieve decreased blood-brain barrier permeability, as potential targeted therapeutics for hypoxic tumors. Specific conjugates of KW-6002 have the capability of not only targeting solid metastases, but also combating existing issues of aqueous solubility and short circulating half-life. Utilizing molecular modeling, functional derivatives conjugated to polyethylene glycols (PEGs) and gold nanoparticles (AuNPs) were designed and synthesized. A novel one-pot route to 8-substituted xanthines using bromodimethylsulfonium bromide (BDMS), previously developed by our laboratory, was used to afford the key intermediates. Preliminary analysis of the log P values of the PEGylated analogs, carried out using HPLC, suggest that these derivatives are more hydrophilic than KW-6002 and provide an impetus for further synthetic development of conjugates and radioimaging probes.
Thomas, Rhiannon, "Design and synthesis of adenosine receptor antagonist bioconjugates as anti-tumor immunotherapies" (2011). Chemistry Master's Theses. Paper 18. http://hdl.handle.net/2047/d200010301
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