Libraries from Libraries Approach to the Synthesis of Arylidene Oxindoles

Abstract

A libraries from libraries combinatorial chemistry approach was employed to synthesize fluorinated derivatives of both oxindoles and isatins as potential pharmaceuticals or targeting agents for imaging purposes related to cancer or Alzheimer\u27s disease. Synthesis for these fluorinated derivatives are described by routes involving, either: a) N-alkylation of 5-substituted isatins followed by Wolff-Kishner reduction to the corresponding oxindoles and final Knoevenagel condensation with aryl aldehydes, or; b) Wolff-Kishner reduction of the isatins followed by condensation and finishing with the N-alkylation of the aldol products. In specific cases, a click reaction followed the N-alkylation of the aldol products to form the isatin 1,2,3-triazole which could be utilized to perform radiochemistry with a [18F]-radiolabel for the imaging of cancer. The strategy for the synthesis of such potential inhibitors was guided by SAR studies of peptide based inhibitors, as well as small-molecule inhibitors based upon the isatins scaffold. Previously, it was shown increasing functionality by adding 3 points of variability with the incorporation of an electron-withdrawing group such as a chlorine atom at the C-5 position allowed for increased potency of the oxindole derived inhibitors. Herein, a library of arylidene oxindoles was synthesized utilizing 3 points of variability with the incorporation of the electron-withdrawing group fluorine. Furthermore, a novel alternative synthesis was established for the creation of arylidene oxindoles which allowed for increased functionality through the incorporation of N-propargyl inhibitors. Finally, the ability to create N-propargyl compounds lead to the synthesis of isatin 1,2,3-triazoles was also explored for the possibility as potential imaging agents for cancer