Eric Fossum (Committee Member), Daniel Ketcha (Advisor), Kenneth Turnbull (Committee Member)
Master of Science (MS)
A range of substituted 1H-indole-2,3-diones (isatins) was synthesized to assess their capability to inhibit caspases and prevent apoptosis in Jurkat T cells. The key steps in the synthesis of such molecules involved electrophilic substitution of the C-5 position of the isatin nucleus (if necessary), N-alkylation, Wolff-Kishner reduction of the C-3 carbonyl group and finally, Knoevenagel condensation. The design and synthesis of such potential inhibitors was guided by SAR studies of peptide based inhibitors such as "Q-VD-O-Ph", as well as small-molecule inhibitors based upon the isatins scaffold. Previously, 3-(2,6-difluorobenzylidene)-5-nitroindolin-2-one has been shown to inhibit apoptosis in human Jurkat T cells at 5 μM activity. Herein, it is shown that by increasing the functionality of such oxindole derived inhibitors from two points of variability (e.g., 1-(2,6-difluorobenzyl)-3-((pyridin-4-yl)methylene)indolin-2-one), to three points of variability by adding an electron-withdrawing group such as a chlorine atom at the C-5 position, the potency of the molecules against apoptosis was approximately increased up to 2-fold. Several other 3-substituted benzylidene derivatives were tested against human Jurkat T cells and were found to be active at micromolar concentrations.
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.