| Autor: |
Aguilar A; 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., Sun W, Liu L, Lu J, McEachern D, Bernard D, Deschamps JR, Wang S |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2014 Dec 26; Vol. 57 (24), pp. 10486-98. Date of Electronic Publication: 2014 Dec 12. |
| DOI: |
10.1021/jm501541j |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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