Design and Delivery of Novel Chemotherapeutics to Treat Nervous System Cancers:

A persistent challenge in the treatment of primary and metastatic brain tumors is the design of a drug or drug delivery system that can penetrate the blood-brain barrier (BBB) that protects the brain and CNS from endogenous and exogenous toxins, such as chemotherapeutics. In order for substrates in the systemic circulation to cross the BBB, they must either passively diffuse or be actively transported. Recent findings indicate that compounds with greater lipophilicity, fewer H-bond donors, fewer positive charges, and lower polar surfaces tend to have greater BBB permeability. Although these properties may lead to enhanced membrane permeability, drug efflux transporters in the BBB and blood-CSF barrier can remove drug candidates from the CNS. The unexplained efflux of chemotherapies back into the systemic circulation is a serious impediment to effective primary and metastatic brain cancer drug development.

To address the aforementioned issues, we are currently examining a series of spirooxindole  alkaloid natural products. Utilizing innovative new synthetic approaches toward C–C and C–N bond construction developed in our lab, we can now rapidly construct and screen small molecules for pre-clinical efficacy. Through collaborations with the Indiana University Simon Cancer Center and the Herman B. Wells Center for Pediatric Research, our efforts focus on the design, synthesis, and biological evaluation of pharmacophores for anti-glioblastoma and anti-neuroblastoma activity.

Selected Publications:

1. White, E. E.; Rodriguez, K. X.; Ashfeld, B. L. “Stereochemical Implications in the Synthesis of 3,3´-Spirocyclopropyl Oxindoles from β-Aryl/Alkyl-Substituted Alkylidene Oxindoles.” Tetrahedron, 2015, Accepted manuscript, in press, DOI: 10.1016/j.tet.2015.06.004.

• Invited article for the Symposium-in-Print in honor of Professor Barry M. Trost for receipt of the Tetrahedron Award for Creativity in Organic Synthesis.

2. Haugen, K. C.; Rodriguez, K. X.; Chavannavar, A. P.; Oliver, A. P.; Ashfeld, B. L. “Phosphine-Mediated Addition of 1,2-Dicarbonyls to Diazenes: An Umpolung Approach toward N-Acyl Hydrazone Synthesis.” Tetrahedron Lett.2015, 56 (23), 3527-3530.

• Invited article for the Symposium-in-Print in honor of Professor Harry Wasserman.

3. Gianino, J. B.; Campos, C. A.; Lepore, A. J.; Pinkerton, D. M.; Ashfeld, B. L. “Redox and Lewis Acid Relay Catalysis: A Titanocene/Zinc Catalytic Platform in the Development of Multicomponent Coupling Reactions.” J. Org. Chem. 2014, 79 (24), 12083-12095.

• Invited manuscript for the special issue titled Mechanisms in Metal-Based Organic Chemistry.