garner research group

Research

Organic Chemistry

My group is involved in the design and synthesis of biologically active molecules as well as the development of new enabling chemistries. In this context, our intellectual activities may be viewed as architecture (design and construction) on the molecular scale. Chemical synthesis (the discipline associated with building molecular structures) is the common element that underlies all of our research endeavors. Because synthesis is an integral part of the drug development process, this area of research is at the cutting edge of molecular based therapeutics. Students in the Garner group learn how to apply the tools of organic chemistry to important problems that span the traditional disciplines. Two of the research projects currently underway in my group are described below.

The first of these projects is concerned with the synthesis of an interesting class of natural products that are exemplified by the molecule bioxalomycin β1 (Figure 1). The bioxalomycins are potent cytotoxic agents that exhibit both antimicrobial and antitumor properties. These bacterial metabolites are believed to manifest their biological activity through covalent interaction with DNA. Chemical synthesis provides the key to developing new drugs from such natural leads. The bioxalomycins have not yet yielded to total synthesis. In this context, we are defining an efficient target-oriented synthesis (TOS) of bioxalomycin β1 that can be applied to a diversity-oriented synthesis (DOS) of rationally designed analogues. In this arena, success often depends on the exquisite understanding and control of chemical reactivity. We are using our unique skills and experience as chemists (molecular architects) to address these issues in the context of the bioxalomycin problem. Our synthetic approach is built upon core chemistry that provides access to the key structural features of bioxalomycin β1 in a single step via a novel dipolar cycloaddition reaction cascade. Our efforts have resulted in the development of efficient multicomponent and cascade processes that enable the synthesis of highly functionalized pyrrolidines with a high degree of chemoselectivity, regioselectivity, and stereoselectivity.

The second project involves the development of helical nucleopeptides (HNPs) as a novel chemical platform for antisense therapeutics. HNPs are novel chemical entities that merge the structural variability of proteins with the codified molecular recognition of nucleic acids (Figure 2). Helical nucleopeptides offer a particular advantage over existing antisense technologies by providing the opportunity to add chemical functionality that enhance transport, hybridization, and other important properties. We have already demonstrated the ability of helical nucleopeptides (αPNA subtype) to bind in a sequence-specific manner to complementary single stranded oligonucleotides, resist degradation by the proteases present in human serum, and become internalized without the need for any additional delivery vehicle. Because of their unique chemical design, antisense helical nucleopeptides could provide an attractive and specific means to achieve exquisite cellular control at the level of translation. We are currently interested in using antisense HNPs for the treatment of cancer. Antisense HNPs, either alone or in combination with other drugs, can be used to selectively trigger apoptosis in prostate cancer cells at any stage of the disease. This project is highly collaborative in nature, bringing together researchers from complementary departments and utilizing the University's superlative Cancer Center (http://cancer.cwru.edu/) to develop new therapeutics.