Inflammatory processes associated with the over-production of tumor necrosis-alpha (TNF-alpha), a potent activator of the immune system accompany numerous neurodegenerative diseases. TNF-alpha has been validated as a drug target with the development of the inhibitors Enbrel and Remicade (fusion antibodies) as prescription medications. Both, however, are large macromolecules that require direct injection and have limited brain access. The classical drug, thalidomide is being increasingly used in the clinical management of a wide spectrum of immunologically-mediated and infectious diseases, and cancers. The NIA inventors developed and assessed novel thio analogs of lenalidomide (Celegene's Revlimid and an analog of thalidomide) as immunomodulatory agents, with the potential to reduce chronic systemic and central nervous system inflammation. These compounds were synthesized and evaluated for their TNF-alpha inhibitory activity. This invention was extended from the inventors' prior work to develop potent compounds to reduce neuroinflammation as a treatment strategy for neurodegenerative disorders. The current studies focus the compounds activity in classical models of neurodegeneration as well as cancer.