| 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.1 As was described by Ohta et al,2 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.3 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. 4 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. |
