Design of Chemically Stable, Potent, and Efficacious MDM2 Inhibitors That Exploit the Retro-Mannich Ring-Opening-Cyclization Reaction Mechanism in Spiro-oxindoles

Inhibition
of the MDM2–p53 protein–protein interaction
is being actively pursued as a new anticancer therapeutic strategy,
and spiro-oxindoles have been designed as a class of potent and efficacious
small-molecule inhibitors of this interaction (MDM2 inhibitors). Our
previous study showed that some of our first-generation spiro-oxindoles
undergo a reversible ring-opening-cyclization reaction that, from
a single compound in protic solution, results in an equilibrium mixture
of four dia­stereo­isomers. By exploiting the ring-opening-cyclization
reaction mechanism, we have designed and synthesized a series of second-generation
spiro-oxindoles with symmetrical pyrrolidine C2 substitution. These
compounds undergo a rapid and irreversible conversion to a single,
stable dia­stereo­isomer. Our study has yielded compound 31 (MI-1061), which binds to MDM2 with Ki = 0.16 nM, shows excellent chemical stability, and achieves
tumor regression in the SJSA-1 xenograft tumor model in mice.