Novel Polypharmacological Therapies For Co-Targeting Central And Peripheral Nervous System Cancers
Student: Nasiha Rahim, 2014-2015
Sponsor: Prof. Brandon Ashfield - Chemistry, Notre Dame, IN
Our goal is to develop effective brain and nervous system cancer drug treatment options by designing small molecules that exhibit activity against glioblastomas and neuroblastomas, BBB permeability, minimal normal tissue toxicity, and promising pharmacokinetics. The objective of this proposal is to design, synthesize, and evaluate the cytotoxicity and BBB transcytosis properties of spiroquinolizidine-oxindole derivatives using an innovative formal phosphine-mediated [4+1] cycloaddition. Our synthetic strategy is based on the design of an innovative metal-free coupling strategy to assemble quaternary centers is a highly stereoselective fashion. By exploiting isatins as C3-carbene oxindole equivalents, we have established a highly convergent and modularly flexible strategy toward the structurally diverse spiroquinolizidine-oxindole subset of Strychnos indole alkaloids. The clinical relevance and impact of this proposal is that our approach will ultimately facilitate the detailed in vivo studies necessary to identify lead compounds that are sufficiently cytotoxic and brain penetrant.