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Synthesis of Isatin Derivatives Used for the Inhibition of Pro-Apoptotic Jurkat T Cells

Clay, Charles Michael
http://rave.ohiolink.edu/etdc/view?acc_num=wright1315518391

Abstract Details

2011, Master of Science (MS), Wright State University, Chemistry.
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.
Daniel Ketcha, PhD (Advisor)
Eric Fossum, PhD (Committee Member)
Kenneth Turnbull, PhD (Committee Member)
117 p.
Chemistry
Isatin; Oxindole; Benzylidene; N-alkylation; Knoevenagel condensation; Wolff-Kishner reduction; Apoptosis; Caspases; Caspase inhibitor; small molecule inhibitor; Biological Screening; DNA laddering; Q-VD-OPh

Recommended Citations

Citations

  • Clay, C. M. (2011). Synthesis of Isatin Derivatives Used for the Inhibition of Pro-Apoptotic Jurkat T Cells [Master's thesis, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright1315518391

    APA Style (7th edition)

  • Clay, Charles. Synthesis of Isatin Derivatives Used for the Inhibition of Pro-Apoptotic Jurkat T Cells. 2011. Wright State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=wright1315518391.

    MLA Style (8th edition)

  • Clay, Charles. "Synthesis of Isatin Derivatives Used for the Inhibition of Pro-Apoptotic Jurkat T Cells." Master's thesis, Wright State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=wright1315518391

    Chicago Manual of Style (17th edition)

wright1315518391
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© 2011, all rights reserved.
This open access ETD is published by Wright State University and OhioLINK.