Synthesis, in vitro, and in cell studies of a new series of [indoline-3,2'-thiazolidine]-based p53 modulators

J Med Chem. 2013 Jul 11;56(13):5407-21. doi: 10.1021/jm400311n. Epub 2013 Jun 26.

Abstract

Analogues of the previously described spiro[imidazo[1,5-c]thiazole-3,3'-indoline]-2',5,7(6H,7aH)-trione p53 modulators were prepared to explore new structural requirements at the thiazolidine domain for the antiproliferative activity and p53 modulation. In cell, antiproliferative activity was evaluated against two human tumor cell lines. Derivative 5-bromo-3'-(cyclohexane carbonyl)-1-methyl-2-oxospiro[indoline-3,2'-thiazolidine] (4n) emerged as the most potent compound of this series, inhibiting in vitro 30% of p53-MDM2 interaction at 5 μM and the cell growth of different human tumor cells at nanomolar concentrations. Docking studies confirmed the interactions of 4n with the well-known Trp23 and Phe19 clefts, explaining the reasons for its binding affinity for MDM2. 4n at 50 nM is capable of inducing the accumulation of p53 protein, inducing significant apoptotic cell death without affecting the cell cycle progression. Comparative studies using nutlin in the same cellular system confirm the potential of 4n as a tool for increasing understanding of the process involved in the nontranscriptional proapoptotic activities of p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Cycle / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Protein Binding / drug effects
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Thiazolidines / chemical synthesis
  • Thiazolidines / chemistry
  • Thiazolidines / pharmacology*
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / metabolism*
  • U937 Cells

Substances

  • Thiazolidines
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2