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Solid-phase synthesis of a 6-phenylquinolin-2(1H)-one library directed toward nuclear hormone receptors

M. Ruda ; Nina Kann (Institutionen för kemi- och bioteknik, Organisk och analytisk kemi) ; S. Gordon ; J. Bergman ; W. Nelson ; P. Agback ; L. Hagberg ; K. F. Koehler
Journal of combinatorial chemistry (1520-4766). Vol. 7 (2005), 4, p. 567-573.
[Artikel, refereegranskad vetenskaplig]

A library of 6-phenylquinolin-2(1H)-ones with diversity at position I and the ortho, meta, and para positions of the pendant phenyl ring has been synthesized using solid-phase parallel synthetic techniques. A key step in the synthesis of the library is a tandem alkylation cleavage in which diversity can be introduced at position 1 simultaneously to the cleavage from the resin. The yields of this step were significantly improved over what has previously been reported by addition of cesium carbonate to scavenge the acid that is formed during the reaction. Furthermore, we have shown that the solid support linkage is tolerant to Suzuki coupling and etherification reaction conditions and that selective cleavage of the linkage can take place in the presence of esters. The resulting 6-phenylquinolin-2(1H)-one library was screened against a panel of nuclear hormone receptors (androgen, estrogen alpha and beta isoforms, glucocorticoid, mineralocorticoid, and progesterone). Certain members of this library display moderate affinity for several of these receptors, and consequently, the 6-phenylquinolin-2(1H)-one core of the library may be considered a privileged structure for nuclear hormone receptors. In contrast, other members of the library display high selectivity for a particular receptor. The highest affinity ligand (9{2,1,1}) possesses an affinity of 330 nM for the androgen receptor, whereas the most selective ligand (9{2,4,1}) displays an affinity of 900 nM for the androgen receptor and a selectivity of 140-fold over the next highest affinity receptor.



Denna post skapades 2007-02-05. Senast ändrad 2013-06-03.
CPL Pubid: 10540

 

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Institutioner (Chalmers)

Institutionen för kemi- och bioteknik, Organisk och analytisk kemi (2005-2005)

Ämnesområden

Läkemedelskemi

Chalmers infrastruktur