CPL - Chalmers Publication Library
| Utbildning | Forskning | Styrkeområden | Om Chalmers | In English In English Ej inloggad.

The A-CD analogue of 16 beta,17 alpha-estriol is a potent and highly selective estrogen receptor beta agonist

Claire Sauvée ; Anja Schäfer ; Henrik Sundén ; J. N. Ma ; A. L. Gustavsson ; E. S. Burstein ; Roger Olsson
Medchemcomm (2040-2503). Vol. 4 (2013), 11, p. 1439-1442.
[Artikel, refereegranskad vetenskaplig]

Selective estrogen receptor beta (ER beta) agonists display neuroprotective properties in animal models and hold promise in the treatment of neurodegenerative diseases. In our quest to design, synthesize and evaluate potent and safe ER beta agonists, we focused on making an analogue of 16 beta,17 alpha-estriol (16,17-epiestriol), a potent and one of the most ER beta selective endogenous estrogens reported. Herein we disclose the synthesis and in vitro evaluation of an analogue based on the recently introduced A-CD scaffold. A 14-step synthesis based on the Hajos-Parrish ketone resulted in the discovery of (1S,2S,3aS,5S,7aS)-5-(4-hydroxyphenyl)-7a-methyloctahydro-1H-indene-1,2- diol (15). This A-CD analogue of 16 beta, 17 alpha-estriol is a highly selective (500-fold) ER beta full agonist over ER alpha with a pEC(50) of 7.7 at ER beta. Molecular modelling suggests that 15 turns around in the ligand-binding domain compared to estriol, thus the 7a-methyl occupies the alpha-face, which might explain the high selectivity.

Nyckelord: ALPHA, METABOLITES, INSIGHTS, BINDING, KETONES, LIGAND, SS DB, 1983, JOURNAL OF ORGANIC CHEMISTRY, V48, P4155



Denna post skapades 2013-12-06. Senast ändrad 2017-09-14.
CPL Pubid: 188563

 

Läs direkt!


Länk till annan sajt (kan kräva inloggning)


Institutioner (Chalmers)

Institutionen för kemi och molekylärbiologi (GU)

Ämnesområden

Kemi

Chalmers infrastruktur