Synthesis of conformationally constrained benzoylureas as BH3-mimetics.
The design of small molecules that mimic the BH3 domain and bind to Bcl-2 proteins has emerged as a promising approach to discovering novel anti-cancer therapeutics. We reveal the design and synthesis of conformationally constrained benzoylurea scaffolds as conformational probes. Central to helix mimicry, the intramolecular hydrogen bond in the benzoylurea plays a key role in the pre-organisation of the acyclic substrates for cyclisation via ring closing metathesis, providing efficient access to the constrained mimetics.
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria 3052, Australia.
Ryan M
RM
Brady
Effie
E
Hatzis
Theresa
T
Connor
Ian P
IP
Street
Jonathan B
JB
Baell
Guillaume
G
Lessene
D001554:Benzene / Q000737:chemistry*; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000378:metabolism; D003500:Cyclization; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000138:chemical synthesis* / Q000378:metabolism
D019253:Proto-Oncogene Proteins c-bcl-2; D014508:Urea; D001554:Benzene