Diastereomeric Spirooxindoles as Highly Potent and Efficacious MDM2 Inhibitors

Citations Over TimeTop 10% of 2013 papers

Abstract

Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.

Related Papers

• → On the Chemistry of the Resveratrol Diastereomers(2003)42 cited
• → Diastereomer-Differentiating Photochemistry of β-Arylbutyrophenones: Yang Cyclization versus Type II Elimination(2005)25 cited
• → NMR INVESTIGATIONS ON DIASTEREOMERIC MIXTURES OF BIS(DIALKOXYTHIOPHOSPHORYL) SULFANES AND -POLYSULFANES CONTAININGsec. BUTOXY GROUPS. ASSIGNMENT OF31P,13C AND1H NMR SIGNALS IN A MIXTURE OF SEVEN DIASTEREOMERS USING SHIFT-CORRELATED 2D NMR SPECTRA(1991)12 cited
• → Compound Separation by Cyclic, Selective Dissolution. Isolation of Diastereomeric, 1β-Methylcarbapenem Key Intermediates(1993)3 cited
• → Synthesis of threo-4,5-dihydroxy diastereomers of sphinganine(1975)