Faith E. Jacobsen

The Design of Inhibitors for Medicinally Relevant Metalloproteins

A number of metalloproteins are important medicinal targets for conditions ranging from pathogenic infections to cancer. Many but not all of these metalloproteins contain a zinc(II) ion in the protein active site. Small‐molecule inhibitors of these metalloproteins are designed to bind directly to the active site metal ions. In this review several metalloproteins of interest are discussed, including matrix metalloproteinases (MMPs), histone deacetylases (HDACs), anthrax lethal factor (LF), and others. Different strategies that have been employed to design effective inhibitors against these proteins are described, with an effort to highlight the strengths and drawbacks of each approach. An emphasis is placed on examining the bioinorganic chemistry of these metal active sites and how a better understanding of the coordination chemistry in these systems may lead to improved inhibitors. It is hoped that this review will help inspire medicinal, biological, and inorganic chemists to tackle this important problem by considering all aspects of metalloprotein inhibitor design.

Inflammatory hyperalgesia induces essential bioactive lipid production in the spinal cord.

J. Neurochem. (2010) 114, 981–993.

A novel heterocyclic atom exchange reaction with Lawesson's reagent : a one-pot synthesis of dithiomaltol

A one-pot reaction of maltol with Lawessons reagent generates dithiomaltol, a thiopyran-4-thione, via an unusual heterocyclic atom exchange (HCAE) reaction; only pyrones with proton or aliphatic substituents undergo the HCAE substitution.

A Macrophage Cell Model for Selective Metalloproteinase Inhibitor Design

The desire to inhibit zinc‐dependent matrix metalloproteinases (MMPs) has, over the course of the last 30 years, led to the development of a plethora of MMP inhibitors that bind directly to the active‐site metal. With one exception, all of these drugs have failed in clinical trials, due to many factors, including an apparent lack of specificity for MMPs. To address the question of whether these inhibitors are selective for MMPs in a biological setting, a cell‐based screening method is presented to compare the relative activities of zinc, heme iron, and non‐heme iron enzymes in the presence of these compounds using the RAW264.7 macrophage cell line. We screened nine different zinc‐binding groups (ZBGs), four established MMP inhibitors (MMPis), and two novel MMP inhibitors developed in our laboratory to determine their selectivities against five different metalloenzymes. Using this model, we identified two nitrogen donor compounds—2,2′‐dipyridylamine (DPA) and triazacyclononane (TACN)—as the most selective ZBGs for zinc metalloenzyme inhibitor development. We also demonstrated that the model could predict known nonspecific interactions of some of the most commonly used MMPis, and could also give cross‐reactivity information for newly developed MMPis. This work demonstrates the utility of cell‐based assays in both the design and the screening of novel metalloenzyme inhibitors.