Zinc is widely recognized as being essential to all forms of life, and in particular that of humans. For example, the zinc enzyme 5-aminolevulinate dehydratase is necessary for the early steps of heme formation, and its inactivation by lead is one of the principal reasons why lead is poisonous to humans. Likewise, matrix metalloproteinases are an extremely important group of zinc enzymes that are involved in extracellular degradation and participate in embryonic development, wound healing, bone and growth development, and other physiological remodeling processes. However, despite the beneficial aspects of matrix metalloproteinases during normal biological processes, their activity in pathological situations when extracellular degradation is not required may have a most detrimental influence. In this regard, undesired matrix metalloprotease activity has been linked to a variety of cancers (including lung, breast, and colon cancer), arthritis, multiple sclerosis, and Alzheimer's disease. Zinc has also been reported to have beneficial therapeutic and preventative effects on infectious diseases and zinc gluconate lozenges have been proposed to shorten the length of the common cold in adults. The public health importance of zinc has recently been strongly emphasized, thereby making the bioinorganic chemistry of zinc an essential and critical area of investigation. In order to understand the many roles of zinc in biological systems, it is first absolutely essential to understand how the chemistry of zinc is modulated by its coordination environment. The intent of this proposal is to obtain a thorough understanding of the bioinorganic chemistry of zinc by investigating synthetic analogues that mimic both the structure and function of the active sites of zinc enzymes. This objective will be achieved by using specially constructed tripod ligands to afford synthetic analogues that will be amenable to structural, spectroscopic and mechanistic studies. During the previous grant period significant progress was made toward the stated goals. Specifically, three accomplishments merit further comment. Using [TptBu,Me]ZnX complexes, the group successfully prepared the first pair of Zn-hydroxide, Zn-aqua complexes. Reversible protonation of a Zn-hydroxide was demonstrated using a novel Bronsted acid to overcome problems of lability of the water ligand. With these two complexes in hand, differential reactivity toward carbon dioxide was demonstrated. Second, the group has made major progress in the preparation of ligands (and the corresponding metal complexes) that provide mixed donors, e.g. [N2O] or [N2S]. Third, the reactivity modeling of LADH has progressed enormously. Zinc alkoxide derivatives have been prepared and structurally authenticated. Alcohol exchange reactions have allowed for the extraction of thermodynamic parameters. Finally, and most notably, the zinc alkoxides react with aldehyde to yield products consistent with """"""""hydride"""""""" transfer; the key step in LADH catalysis. As another marker of excellent productivity, eleven papers have either been published or submitted in the previous grant period.
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