Our research efforts combine synthetic organic chemistry with computational, biochemical, and molecular biological tools. The long-term goal of our research is the development of selective strategies for the treatment of cancer and infectious diseases. Our approach focuses on developing new chemistry and new probes to explore promising drug targets and advance our understanding of natural products with interesting biological activity. Topics of current interest include:
G-Quadruplex DNA Dynamics and Biological Roles:
The interaction of small molecules with nucleic acids continues to be an area of great interest. Recently, our efforts have focused on unusual nucleic acid structures known as G-quadruplexes, which form from guanine-rich DNA and RNA sequences. While evidence for the existence of these structures in cells is growing, much remains unknown concerning their dynamics and biological roles. We design, synthesize and study G-quadruplex DNA ligands in order to better understand the functional effects of non-covalently targeting these structures. We are also designing molecular probes that covalently target G-quadruplexes. We are using these probes to shed light on the dynamic nature of these structures in cells, an essential aspect for understanding their biological roles.
Facile Rearrangements Leading to Reactive Intermediates:
The enediyne-class of antitumor antibiotics exert their potent cytotoxic effects through a Bergman cyclization of an enediyne core to produce a 1,4-didehydrobenzene diradical intermediate, which abstracts hydrogen atoms from the DNA ribose backbone, resulting in DNA strand scission. Inspired by the Bergman cyclization and related diradical-generating cyclizations of enyne allenes, we are exploring alternate cyclization that afford diradical or carbene intermediates. These systems are based on nitrogen-containing analogs of enediynes and enyne allenes. Nitrogen substitution has a profound impact on both the rate of the cyclization and the reactivity of the resulting intermediates. Understanding the origin of these effects may lead to the design of improved cytotoxic drugs for treating cancer.
Chemistry of N-Alkynylazoles:
N-alkynylazoles are an underexplored class of compounds in which an acetylene group is bonded to the nitrogen atom of a five-membered heteroaromatic ring. In analogy to ynamines and ynamides, these N-alkynylazoles may display polarization of the carbon-carbon triple bond leading to interesting optical properties and regioselective addition and cyclization reactions. As part of our interest in rearrangements of aza-enediynes, we have found that thermal rearrangement of 1,x-dialkynylimidazoles affords carbene intermediates. This rearrangement has potential application in the synthesis and in targeting of therapeutically important proteins.
Targeting Kinases Using Unique Chemistry:
Mitogen-activated protein kinases (MAPKs) are important components of signaling cascades that regulate many normal cellular events. MAPK pathways can also play an important role in cancer cell survival. We are exploring new approaches to inhibiting these kinases employing the unique chemistry of N-alkynylazoles. One approach focuses on targeting the sites responsible for recognizing MAPK protein substrates’ and regulators’ docking domains. These recruitment sites may serve as superior drug targets leading to increased selectivity and durability of inhibition. An alternative approach exploits the facile carbene generating rearrangements of 1,x-dialkynylimidazoles and related compounds in designing irreversible inhibitors of these kinases.
We are exploring a number of polyphenolic and heterocyclic natural products with interesting biological activity. These efforts generally begin with efficient total syntheses, providing sufficient supplies of natural products and analogs for mechanistic studies. These studies often identify promising targets and superior analogs that may be exploited in the search for new antibacterial and antitumor agents with increased selectivity and potency. Examples of compounds that we are investigating include the novel, bis(benzoxazole) Streptomyces natural product, UK-1; the bee propolis-derived polyphenol caffeic acid phenethyl ester (CAPE); and the African potato-derived polyphenol rooperol.
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