Blood-brain barrier (BBB) remains one of the most elusive biological barriers in terms of selective small molecule penetration. There have been countless efforts to cross this barrier by absorptive techniques (nanoparticles), conjugation (peptide penetrating), and BBB destabilization techniques. Unfortunately, each of these strategies has had only marginal success when it comes to small molecule penetration. Also, when it comes to efficiency, these strategies fail to allow rapid crossing or provide concentration at therapeutic thresholds. Once, and if, a compound crosses the BBB it is pumped back out into the blood rapidly by efflux pumps. These efflux pumps are necessary for the brain to restrict any unwanted and biologically dangerous molecules, and any disruption of these pumps can lead to fatal consequences. To this end, our laboratory has undertaken a first of its kind investigation into the role of rigidity and planarity on BBB penetration. Through the construction of new chemical screening libraries, via intermediates of our total synthesis route towards Brocazine F, our laboratory has explored the effects of rigidity as a means of penetration of the BBB via diffusion transport. To be presented is our current approach at the development of a new class of chemical screening libraries via these intermediates. Unlike current approaches, our construction of screening libraries allows for greater synthetic manipulation and enhanced versatility in core structural alterations. These new libraries have been used to explore penetration of the BBB and has proven new insight into the roles of specific physicochemical properties and their roles upon BBB transport. Also to be discussed will be our general conclusions and future directions.

Investigations into blood-brain barrier transport: Effects of physicochemical properties and small molecule chaperone synthesis

255th National Meeting (2018)

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