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Synthesis Of Isatin Derivatives Used For The Inhibition Of Pro-Apoptotic Jurkat T Cells, Charles Michael Clay
Synthesis Of Isatin Derivatives Used For The Inhibition Of Pro-Apoptotic Jurkat T Cells, Charles Michael Clay
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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 …
Novel Trisubstituted Arylidene Oxindoles With Potent Anti-Apoptotic Properties, Paul J. Repasky
Novel Trisubstituted Arylidene Oxindoles With Potent Anti-Apoptotic Properties, Paul J. Repasky
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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 …
Small Molecule Caspase Inhibitors Using Isatin And Oxindole Scaffolds And A Combinatorial Approach, Hagar Mahmoud Abdallah
Small Molecule Caspase Inhibitors Using Isatin And Oxindole Scaffolds And A Combinatorial Approach, Hagar Mahmoud Abdallah
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Quinolyl-valyl-O-methylaspartyl-[2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh) is a next generation broad spectrum caspase inhibitor, the effectiveness and reduced toxicity of which can be partially attributable to the carboxyterminal O-phenoxy group as well as the amino terminal quinolyl groups. We seek to incorporate some of these unique recognition elements onto small molecule derived protease inhibitors with drug like properties. Specifically, heterocyclic scaffolds such as isatins and oxindoles. Thus, isatins bearing electron withdrawing groups on C-5 and 2,6-difluorobenzyl moieties have been prepared by analogy to the well studied N-substituted 5-pyrrololidinylsulfonyl isatins. Moreover, 3-benzylidene oxindole derivatives bearing these structural motifs have also been prepared and their …