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.
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| 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>>>>>>>>>
