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

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.

• Authors: Alessia Bertamino, Maria Soprano, Simona Musella, Maria Rosaria Rusciano, Marina Sala, Ermelinda Vernieri, Veronica Di Sarno, Antonio Limatola, Alfonso Carotenuto, Sandro Cosconati, Paolo Grieco, Ettore Novellino, Maddalena Illario, Pietro Campiglia, Isabel Gomez-Monterrey
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 13 Pg. 5407-21 (Jul 11 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23802716 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• 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, metabolism)
• Thiazolidines (chemical synthesis, chemistry, pharmacology)
• Tumor Suppressor Protein p53 (chemistry, metabolism)
• U937 Cells