The overall goal of this research is to develop and utilize asymmetric catalysis to synthesize anti-prostate cancer (PCa) flavanoids. PCa is the second most common cause of cancer death in US males, death with is usually caused by metastasis. New therapies to treat PCa will have a direct and beneficial impact on the health of the United States. Genistein, the principal isoflavone in soy, inhibits the initiating steps of cell detachment and cell invasion of prostate cancer cells as well as metastasis. Recently, we discovered that 2,3-dihydrogenistein maintains anti-invasive activity. This led us to believe that isoflavanones might be a class of compounds that is effective against PCa metastasis. The long-term goals of my research are to 1) develop and utilize asymmetric catalysis to synthesize enantioenriched isoflavanones that maintain anti-invasive activity but lack growth inhibitory activity and 2) synthesize and evaluate the flavanone natural products kurarinone isosilybin B. Our central hypothesis is that optically active flavanoids are underdeveloped molecules for the treatment of PCa and stereoselective methods to access these compounds will have a dramatic impact on the future of chemotherapy.
The specific aims of my research during the proposed grant period are:
Specific Aim 1 : Develop new catalytic asymmetric methods to access antimetastatic enantioenriched C3 substituted isoflavanones. Utilizing the binding site model for genistein that was recently developed by Scheldt and Bergan, we will be able to design and synthesize more potent and selective isoflavanones.
Specific Aim 2 : Synthesize the flavanone natural products kurarinone and isosilybin B. Both flavanones display anti-PCa activity, yet no enantioselective syntheses of these molecules has been reported. In order to discover the biological targets of our compounds and accordingly modify them, we have established a collaboration with Dr. Raymond Bergan, the Director of Experimental Therapeutics for the Robert H. Lurie Cancer Center at the Feinberg School of Medicine at Northwestern University. He directs a laboratory based research program focusing on the pharmacologic manipulation of PCa cell motility. He will evaluate our compounds for their antimetastatic efficacy and we will use the findings of his testing to synthesize more selective and potent isoflavanoids and optimize pharmacokinetic properties.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-GGG-F (29))
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Bini, Alessandra M
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Northwestern University at Chicago
Schools of Arts and Sciences
United States
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McDonald, Benjamin R; Nibbs, Antoinette E; Scheidt, Karl A (2015) A biomimetic strategy to access the silybins: total synthesis of (-)-isosilybin A. Org Lett 17:98-101
Farmer, Rebecca L; Biddle, Margaret M; Nibbs, Antoinette E et al. (2010) Concise syntheses of the abyssinones and discovery of new inhibitors of prostate cancer and MMP-2 expression. ACS Med Chem Lett 1:400-405
Nibbs, Antoinette E; Baize, Amanda-Lauren; Herter, Rachel M et al. (2009) Catalytic asymmetric alkylation of substituted isoflavanones. Org Lett 11:4010-3