title: Design of chemically stable, potent, and efficacious MDM2 inhibitors that exploit the retro-mannich ring-opening-cyclization reaction mechanism in spiro-oxindoles.
abstract: 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.
authors.affiliation: University of Michigan Comprehensive Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan , 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, United States.
authors.forename: Angelo
authors.initials: A
authors.lastname: Aguilar
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
authors.forename: Donna
authors.initials: D
authors.lastname: McEachern
authors.forename: Denzil
authors.initials: D
authors.lastname: Bernard
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Deschamps
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D003500:Cyclization; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000078183:Oxindoles; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C000595875:4-(6''-chloro-4'-(3-chloro-2-fluorophenyl)-2''-oxodispiro(cyclohexane-1,2'-pyrrolidine-3',3''-indoline)-5'-carboxamido)benzoic acid; D000970:Antineoplastic Agents; D007211:Indoles; D000078183:Oxindoles; D013141:Spiro Compounds; C022960:2-oxindole; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2