INBRE

The current proposal has resulted from the effort of Dr. Helen Benes to match the expertise and interests of the principal investigator with an appropriate mentor. Dr. Wangila, the principal investigator, has been interested in the synthesis of novel superoxidase dismutase (SOD) mimetics, but has little experience in biomedical research. Dr. Sudhir Shah, who would serve as a mentor, has a longstanding interest in the role of oxidants in renal disease. Dr. Shah has published numerous articles in this field in peer-reviewed journals, has received support from the National Institutes in Health and Veterans Administration for this work, and is considered an expert in this field. It is anticipated that there will be a close collaboration between Dr. Wangila and Dr. Shah, with Dr. Wangila providing the expertise in sythesizing SOD and learning the model systems to be studied in Dr. Shah’s laboratory.

Superoxide dismutase is an important antioxidant to control the free-radical reactions related to superoxide generated in a biological system. However, it has a large molecular size and a short lifespan in vivo limits its clinical use. Extensive studies have been carried out to find the suitable SOD mimetic to substitute it. In order to act as an SOD mimetic, a compound should be non-toxic, stable, easily able to reach its targets, and retain high SOD activity in vivo. Many compounds have shown SOD-like activity in vitro; however, no metal-dependent SOD mimetic can really replace it.

The interest in synthesizing essential metallo-element complexes results from the fact that superoxide dimutase has two important metals in its structure, copper and zinc. The CuZn superoxide dismutase (CuZnSOD) catalyzes the dismutation reaction of the toxic superoxide radical to molecular oxygen and hydrogen peroxide; further, hydrogen peroxide is catalyzed by the enzyme catalase to water and oxygen. These processes form a crucial part of the cellular antioxidant defense mechanism.

The objective of this proposal is to develop additional small molecular-weight, lipophilic essential metallo-element complexes with SOD mimetic activity that can possibly be used as therapeutic agents in diseases related to oxidative stress and their role in moderating the aging process. The complexes will be synthesized by established methods and identified using IR, UV/VIS, elemental analysis, and x-ray crystallography; partition coefficients will be determined using spectrophotometer or atomic absorption; and SOD mimetic activity determinations will be done with xanthine/xanthine oxidase superoxide generating system. These complexes will be tested in vitro with hypoxia reoxygenation and/or cisplatin-induced injury in cultured renal tubular epithelial cells and/or freshly isolated tubules as described in detail in Dr. Shah’s previous publications.

Synthesize of Zn(II)Cu(II)-diisopropylsalicylate, Zn(II)Mn(II)-diisopropylsalicylate, Mn(II)Cu(II)-diisopropylsalicylate,Zn(II)Cu(II)ditertiarybutylsalicylate, and Zn(II)Mn(II)ditertiarybutylsalicylate.
Determine the superoxide dimutase (SOD) activity of the complexes.
Determine partition coefficient of newly synthesized complexes.
Test for therapeutic activity in a biological system.
Determine the relationship between lipophilicity, SOD activity, and therapeutic activity.

The students will have a major role in synthesizing and identifying these essential metallo-element complexes. They will collect and interpret IR and UV/VIS spectra on all newly prepared complexes in addition to determining their SOD mimetic activity and partition coefficients. Finally the students will write scientific papers and presenting them at scientific forums.

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Updated 10/31/2005

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and the National Center for Research Resources (P20 RR-16460).

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