Synthesis and Anti-Cancer Evaluation of Spiro-indolinone Derivatives

The spiro-indolin-2-one compounds were synthesized by a series of compounds with good p53-MDM2 binding inhibitory activity found in thestructure-based design strategy of Wang and his group.

Spiro-indolinone

From the result of p53-MDM2 complex crystal structure, tryptophan residues on the indole ring of p53 is the most critical binding element for p53 binding MDM2 protein, which was buried in the hydrophobic pocket, and indole on the NH and MDM2 formed a hydrogen bond. Wang and his team members used computer-assisted drug screening to find compounds that mimic the indole ring and found that the structural properties of 2-indolinone were most consistent with that of indole. 6-chloro-2-indolinone was identified as a predominant fragment on the basis of previous work on peptide compounds and Nutlin (Trp pocket with key chlorine atoms capable of occupying MDM2 protein). The Spiro cyclic backbone provides the necessary platform for introducing side chains so that the hydrophobic side chains can be inserted into Leu and Phe pockets. The crystal structures of the resulting compounds MI-63 and MDM2 were recently reported by Popowicz et al. Read more>>>>>>>>>