Identification and structure-activity relationship studies of 3-methylene-2-norbornanone as potent anti-proliferative agents presumably working through p53 mediated apoptosis

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 22; pp. 5645 - 5649
• Main Authors: LAXMA REDDY, N, HILL, Jeanette, LONG YE, FERNANDES, Prabhavathi B, STOUT, David M
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 15.11.2004
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Cell Division - drug effects; Cell Line, Tumor; Drug Screening Assays, Antitumor; General aspects; Humans; Medical sciences; Miscellaneous; Molecular Structure; Mutation; Norbornanes - chemical synthesis; Norbornanes - chemistry; Norbornanes - pharmacology; Pharmacology. Drug treatments; Structure-Activity Relationship; Tumor Suppressor Protein p53 - drug effects; Tumor Suppressor Protein p53 - metabolism; Antineoplastic agent; Structure activity relation; p53 Protein; Refolding; Bicyclic compound; Selectivity; Mutation; Chemical synthesis; Conformational changes; Apoptosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.08.048

We have identified a novel series of alpha-methylene carbonyl compounds through structure-activity relationship (SAR) studies with high levels of anti-proliferative activities. The lead molecule, 3-methylene-2-norbornanone (3) showed potent activity (LC(50)=3-8 microM) against mutant p53 cell types and many fold selectivity (>13-29) over wild-type p53 cells. Further, compound 3 and its analogs showed refolding of mutant p53 protein comparable to their anti-proliferative activities suggesting possible interaction with mutant p53 protein.