B.S., Marquette University (1972) Ph.D., University of Illinois (1976) NIH Postdoctoral Fellowship, Cornell University (1976-78) Alfred P. Sloan Foundation Fellow (1985-89)

Organic Chemistry

Our research interests include development of new strategies for organic synthesis based on organophosphorus compounds, design and synthesis of metabolic probes, and total synthesis of biologically active natural products. The natural products we target often are terpenoids with anticancer potential. Past goals included (+)-jatrophone (1), while more recent targets include agents such as schweinfurthin A (2) and kampanol (3) which display interesting profiles of biological activity. Through collaboration with the National Cancer Institute, the activity of our products is determined and new analogs are designed. The synthesis of complicated targets often requires development of new approaches to the formation of a particular substructure. This is part of the challenge, and the opportunity, of synthetic chemistry. A major focus of our efforts has been development of new methods for formation of carbon-phosphorus bonds and new applications of organophosphorus compounds in organic synthesis. For example, we have explored use of electrophilic phosphorus reagents for preparation of otherwise inaccessible phosphonates. These methodologies lead to new strategies for facile assembly of complex molecules and become key parts of our total syntheses. They also can be applied in preparation of novel enzyme inhibitors. Our interests in terpenoid synthesis and organophosphorus chemistry have combined in several investigations of isoprenoid metabolism. In collaboration with Prof. Raymond J. Hohl (Internal Medicine and Pharmacology) we have designed and prepared novel terpenoid bisphosphonates (4) that serve as inhibitors of geranylgeranyl diphosphate synthase. In collaboration with Prof. Sarah A. Holstein (Internal Medicine) we are working to develop potent and selective inhibitors of the downstream enzyme geranylgeranyl transferase II. Through synthesis and bioassay of isoprenoid pyrophosphate analogues, we hope to clarify their value as potential anti-cancer agents and learn how to modulate isoprenoid metabolism. These studies also draw on our interest in C-P bond formation to generate new motifs for phosphorus-containing enzyme inhibitors. For example, we recently reported synthesis of alkyl-1,1,1-trisphosphonates (5), and have begun to explore the chemistry of this system.

Prodrugs of organophosphorus compounds: crossing the membrane barrier. Wiemer, A. J. and Wiemer, D. F. in Topics in Current Chemistry (128) Phosphorus Chemistry, Montchamp, J. L., editor. 2014, accepted for publication. Synthesis and biological evaluation of a phosphonate phosphoantigen prodrug. Hsiao, C. C.; Lin, X.; Barney, R. J.; Shippy, R. R.; Li, J.; Vinogradova, O.; Wiemer, D. F.; Wiemer, A. J. Phosphorus, Sulfur, Silicon Relat. Elem. 2014, accepted 8/25/14; posted online 11/3/14. Synthesis of a phosphoantigen prodrug that potently activates Vγ9Vδ2 T-lymphocytes. Hsiao, C. C.; Lin, X.; Barney, R. J.; Shippy, R. R.; Li, J.; Vinogradova, O.; Wiemer, D. F.; Wiemer, A. J. Chemistry & Biology 2014, 21, 945–954. Synthesis of isoprenoid bisphosphonate ethers through C-P bond formations: potential inhibitors of geranylgeranyl diphosphate synthase. Zhou, X.; Reilly, J. M.; Loerch, K. A.; Hohl, R. J.; Wiemer, D. F. Beilstein – J. Org. Chem. 2014, 10, 1645–1650. Opportunities and challenges in development of phosphoantigens as Vγ9Vδ2 T cell agonists. Wiemer, D. F.; Wiemer, A. J. Biochemical Pharmacology, 2014, accepted. Geranyl and Neryl Triazole Bisphosphonates as Inhibitors of Geranylgeranyl Diphosphate Synthase. Zhou, X.; Feree, S. D.; Wills, V. S.; Born, E. J.; Tong, H.; Wiemer, D. F.; Holstein, S. A. Bioorg. Med. Chem. 2014, 22, 2791–2798. Structure Activity Relationships of Schweinfurthin Indoles. Kodet, J. G.; Beutler, John A.; Wiemer, D. F. Bioorg. Med. Chem. 2014, 22, 2542–2552. Stilbenes as κ-selective, non-nitrogenous opioid receptor antagonists. Hartung, A. M.; Beutler, J. A.; Navarro, H. A.; Wiemer, D. F.; Neighbors, J. D. J. Nat. Prod. 2014, 77, 311-319. Synthesis of Indole Analogues of the Natural Schweinfurthins. Kodet, J. G.; Wiemer, D. F. J. Org. Chem. 2013, 78, 9291 - 9302. Electronic aromatic prenylation via cascade cyclization, Kodet, J. G.; Topczewski, J. J.; Gardner, K. D.; Wiemer, D. F. Tetrahedron, 2013, 69, 9212 - 9218. Triazole-based inhibitors of geranylgeranyl transferase II. Zhou, X. Hartman, S.; Born, E. J. Smits, J. P.; Holstein, S. A.; Wiemer, D. F. Bioorg. Med. Chem. Lett.2013, 23, 764–766. Direct Conversion of Benzylic and Allylic Alcohols to Phosphonates, Richardson, R. M.; Wiemer, D. F. Organic Synthesis 2013, 90, 145 – 152. Synthesis of dialkyl and diaryl benzylphosphonates through a ZnI2-mediated reaction. Richardson, R. M.; Barney, R. J.; Wiemer, D. F. Tetrahedron Lett. 2012, 53. Functional evaluation of a fluorescent schweinfurthin: Mechanism of cytotoxicity and intracellular quantification. Kuder, C. H.; Neighbors, J. D.; Wiemer, D. F.; Hohl, R. J. Mol. Pharm.2012, 82, 9–16. Exploration of Cascade Cyclizations Terminated By Tandem Aromatic Substitution: Total Synthesis of (+)-Schweinfurthin A. Topczewski, J. J.; Kodet, J. G.; Wiemer, D. F. J. Org. Chem. 2011, 76, 909–919. First Total Synthesis of (+)-Vedelianin, a Potent Anti-Proliferative Agent. Topczewski, J. J.; Wiemer, D. F. Tetrahedron Letters, 2011, 52, 1628–1630. A direct conversion of benzylic and allylic alcohols to phosphonates. Barney, R. J.; Richardson, R. M.; Wiemer, D. F. J. Org. Chem. 2011, 76, 2875–2879. Geranylgeranyl diphosphate synthase: emerging therapeutic target. Wiemer, A. J.; Wiemer, D. F.; Hohl, R. J. Nature: Clinical Pharmacology and Therapeutics, 2011, 90 805–812. Synthesis and Reactivity of Alkyl-1,1,1-trisphosphonate Esters. Smits, J. P.; Wiemer, D. F. J. Org. Chem. 2011, 76, 8807–8813. DOI: 10.1021/jo201523w A Novel Bisphosphonate Inhibitor of Squalene Synthase combined with a Statin and Nitrogenous Bisphosphonate in vitro. Wasko, B. M.; Smits, J. P.; Shull, L. W.; Wiemer, D. F., and Hohl, R. J. Lipid Research, 2011, 52, 1957–1964.