Triaryl-substituted Schiff bases are high-affinity subtype-selective ligands for the estrogen receptor.
We have explored the isoelectronic replacement of the C═C double bond found at the core of many nonsteroidal estrogen ligands with a simple Schiff base (C═N). Di- and triaryl-substituted imine derivatives were conveniently prepared by the condensation of benzophenones with various anilines without the need for phenolic hydroxy protection. Most of these imines demonstrated high affinity for the estrogen receptors, which, in some cases exceeded that of estradiol. In cell-based assays, these imines profiled as ERα agonists but as ERβ antagonists, showing preferential reliance on the N-terminal activation function (AF1), which is more active in ERα. X-ray analysis revealed that the triaryl-imines distort the ligand-binding pocket in a new way: by controlling the separation of helices 3 and 11, which appears to alter the C-terminal AF2 surface that binds transcriptional coactivators. This work suggests that C═N for C═C substitution might be more widely considered as a general strategy for preparing drug analogues.
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education, State Key Laboratory of Virology, Wuhan University School of Pharmaceutical Sciences , Wuhan 430071, China.
Zong-Quan
ZQ
Liao
Chune
C
Dong
Kathryn E
KE
Carlson
Sathish
S
Srinivasan
Jerome C
JC
Nwachukwu
Robert W
RW
Chesnut
Abhishek
A
Sharma
Kendall W
KW
Nettles
John A
JA
Katzenellenbogen
Hai-Bing
HB
Zhou
D007097:Imines / Q000138:chemical synthesis* / Q000378:metabolism; D008024:Ligands; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D012545:Schiff Bases; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D007097:Imines; D008024:Ligands; D011960:Receptors, Estrogen; D012545:Schiff Bases