Inhibitors of the enzyme sarco/endoplasmic reticulum Ca2+ATPase (SERCA) are valuable research tools for the study of the enzyme's role in physiological processes and they also have the potential of being developed into new anti- cancer agents. A series of 2,5-disubstitued hydroquinones will be synthesized and their ability to inhibit SERCA will be assessed in bioassays. Based on the results, computational techniques such as structure-activity relationship modeling and ligand docking will be used to develop models capable of predicting the activities of yet untested, hydroquinone-based compounds. With the aid of these models, compound libraries will be screened virtually for novel SERCA inhibitors that then will be obtained and tested in bioassays.
The research described in this application is aimed at the development of novel, hydroquinone-based inhibitors of the enzyme sarco/endoplasmic reticulum Ca2+ ATPase (SERCA). As documented by an impressively large number of publications on the naturally occurring inhibitor thapsigargin, SERCA inhibitors are of tremendous value for the study of the enzyme's role in physiological processes. In addition, it has been shown that SERCA inhibitors can be developed into prodrugs for the treatment of prostate cancer. Since hydroquinone-based compounds are structurally simple and quite different from other SERCA inhibitors, their synthesis from inexpensive starting materials is relatively straightforward. Thus, they have the potential of being developed into valuable alternatives to currently available agents with unique physicochemical and pharmacodynamic properties.
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