Deiters Lab

We are developing synthetic approaches to a variety of natural products and natural product analogs using our solid-supported microwave-mediated [2+2+2] cyclotrimerization technology. Target molecules include anthraquinones, anthracyclines, isoquinolines, and indanones. These natural products have a broad variety of biological activities, including anticancer, antibacterial, anti-HIV, and antiparasitic activity. Our synthetic strategies are designed to enable facile diversification of these structures and the rapid assembly of libraries of analogs. Recently, we accomplished the first total synthesis of an indanone natural product isolated from the filamentous marine cyanobacterium Lyngbya majuscula. Recently, we completed the total synthesis of the sesquiterpene alkaloid illudinine, which was isolated from the fungus Omphalotus olearius commonly known as Jack-O-Lantern. Other targets are shown below.

Combinatorial chemistry is a technology for systematically assembling molecular building blocks in many combinations to create thousands of diverse compounds. It is an important tool in modern medicinal chemistry. We are generating libraries of small organic molecules by using the advantages of solid-phase combinatorial synthesis combined with the advantages of [2+2+2] cyclotrimerizations as multi-component reactions.

We recently accomplished the first selective crossed cyclotrimerization reaction towards the synthesis of pyridines. An alkyne immobilized on a polysterene resin was reacted with a set of soluble alkynes and nitriles to generate an array of pyridines. We are currently extending this technology towards the synthesis of structurally diveres small molecule libraries.

In addition to our research on the regulation of microRNA function, we are trying to develop a more expedient technology of finding small molecules that modulate gene function, compared to the traditional drug discovery process. Specifically, we are exposing living organisms (e.g. Xenopus embryos) to our small molecule libraries and are screening for changes in phenotype (e.g. in growth, body morphology, movement, or reproductivity).

Traditional methods for studying gene functions in multicellular model organisms have several disadvantages, for example the potential of lethal phenotypes due to a lack of temporal control. We are developing novel tools based on the interplay of small organic molecules and proteins, DNA, or RNA, which enable temporal and spatial control of gene function using light. More specifically, we are working towards the photoregulation of transcription, translation, and the protein function itself. By using light as an input signal which can be controlled with high precision, these methods will be used to elucidate the function of genes in model organisms like zebrafish and C. elegans. These model organisms have the advantage of being completely transparent, allowing the laser irradition on a single cell level.

Selected publications:

Young, D. D. , Deiters, A. "Photochemical Activation of Protein Expression in Bacterial Cells", Angew. Chem. Int Ed. 2007, 46, 4290-4292. PDF

Lusic, H.; Young, D. D.; Lively, M. O.; Deiters, A. "Photochemical DNA Activation", Org. Lett. 2007, 9, 1903-1906. PDF

Selected publications:

Young, D. D., Deiters, A. "A General Approach to Chemo- and Regioselective Cyclotrimerization Reactions", Angew. Chem. Int Ed. 2007, 46, 5187-5190. PDF

Senaiar, R. S.; Young, D. D.; Deiters, A. "Pyridines via Solid-Supported [2+2+2] Cycloadditions", Chem. Commun. 2006, 1313-1315. PDF

Recently, we identified a small molecule which phenocopies a common birth defect, heterotaxia, in these embryos and we are using this molecule for the investigation of the biological pathway involved in this congenital disorder.

This research is conducted in collaboration with Dr. Nascone-Yoder.

Selected publications:

Teske, J. A.; Deiters, A. "Microwave-mediated Nickel-catalyzed Cyclotrimerization Reactions: Total Synthesis of Illudinine", J. Org. Chem. 2008, 73, 342-345. PDF

Senaiar, R. S.; Teske, J. A.; Young, D. D.; Deiters, A. "Synthesis of Indanones via Solid-Supported [2+2+2] Cyclotrimerization", J. Org. Chem. 2007, 72, 7801-7804. PDF

Selected publications:

Gumireddy, K.; Young, D. D.; Xiong, X.; Hogenesch, J. B.; Huang, Q.; Deiters, A. "Small Molecule Inhibitors of MicroRNA miR-21", Angew. Chem. Int. Ed. 2008, 47, 7482-7484. PDF

Glioblastomas are the most common and most aggressive types primary brain tumors. No targeted therapeutics for glioblastomas exists and the median survival time after diagnosis without any treatment is only 3 months. miRNA-21 has been proposed as a novel and promising therapeutic target, since it is highly over-expressed in clinical glioblastoma samples and glioblastoma cell lines. Recently, we discovered a highly specific miR-21 inhibitor - the first small molecule inhibitor of miRNA function - and a potential starting point for the development of new brain cancer therapeutics.

In collaboration with Dr. Qihong Huang, we are further investigating the mechanism of miR-21 inhibition and the potential of our compounds as chemotherapeutic agents in a mouse model of brain cancer.

MicroRNAs (miRNAs) are single-stranded noncoding RNAs of approximately 22 nucleotides. They are a novel class of gene regulators that function by binding to the 3' untranslated region of target messenger RNAs leading to either suppression of their translation or their degradation. miRNAs have recently been proposed as new targets for the development of therapeutics, as misregulation of miRNA levels is often indicative of a disease state.