Identification and structure-activity relationship studies of 3-methylene-2-norbornanone as potent anti-proliferative agents presumably working through p53 mediated apoptosis.
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.
Reddy
N Laxma
NL
Ricerca Biosciences, 7528 Auburn Road, Concord, OH 44077, USA. reddy_l@ricerca.com
Hill
Jeanette
J
Ye
Long
L
Fernandes
Prabhavathi B
PB
Stout
David M
DM
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009154:Mutation; D009636:Norbornanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects* / Q000378:metabolism
C497854:3-methylene-2-norbornanone; D000970:Antineoplastic Agents; D009636:Norbornanes; D016159:Tumor Suppressor Protein p53