Daniel Ketcha (Advisor), Ioana Pavel (Committee Member), Kenneth Turnbull (Committee Member)
Master of Science (MS)
Apoptosis is a highly complex, multi-step cellular pathway utilized to initiate cell suicide. The family of enzymes largely responsible for the process is the cystienyl aspartic acid proteases (caspases). This study details the design and synthesis of a new class of small molecule caspase inhibitors, namely arylidene oxindoles, which are comparable to the isatin family of inhibitors but which offer the advantage of incorporating three points of variability into the basic scaffold. Moreover, whereas the mode of action of isatins against caspases has been demonstrated to involve nucleophilic addition of the cysteine residue of the enzymes to the C-3 ketone carbonyl of these substrates, the efficacy of arylidene oxindoles might be expected to involve a Michael attack of the cysteine sulfur onto the beta-carbon of the heterocyclic system in a Michael fashion. Furthermore, NMR investigations into the E/Z isomerization of such arylidene oxindoles were conducted which show that with few exceptions, isomerization is occurring in polar solvents, in which case it was deemed unnecessary to chromatographically separate isomers prior to screening. Finally, the anti-apoptotic properties of the designed molecules were examined with Human Jurkat T lymphoma cell apoptosis in a DNA Ladder assay.
Department or Program
Department of Chemistry
Year Degree Awarded
Copyright 2011, all rights reserved. This open access ETD is published by Wright State University and OhioLINK.