Design and synthesis of steroid mimetic libraries using solid phase techniques

Abstract

This thesis deals with the design and synthesis of biologically active ligands for nuclear hormone receptors using combinatorial techniques.

In the first part, a 5,6,6a,7,8,9,10,10a-octahydrobenzo[f]quinolin-3(4H)-one tricyclic core structure was designed mimicking the ABC-rings of a steroid. The core structure was synthesized from 7,8-dihydroquinoline-2,5(1H,6H)-dione with the AB-rings already in place. Two different approaches towards the preparation of the C-ring were tested, i.e. using either a Robinson annulation or a Diels-Alder cyclization where only the latter accomplished the formation of the C-ring. The ligands prepared showed low affinity for the nuclear hormone receptors AR, ER, GR, MR, PR, however, and this core structure was therefore abandoned.

The second part consists of a study of selective N-alkylation of 2-pyridones. A solid phase method was developed where 2-halopyridines were attached to a Wang-resin and subsequently treated with alkyl halides to alkylate and cleave the substrate in tandem, thus generating N-alkylated-pyridones.

In the third part, a 6-phenylquinolin-2(1H)-one core structure is mimicking the ABD-rings of a steroid. The core structure was prepared from from 6-bromo-2-chloroquinoline and subsequently attached to a Wang-resin, whereupon the Dring was added to the 6-bromo moiety of the quinoline via a Suzuki-coupling. The phenolic position was alkylated, and the product was cleaved from the resin using the tandem alkylation cleavage method described earlier to generate N-alkylated 6-phenyl-quinolones. This library showed moderate to high affinity towards nuclear hormone receptors.

In the final section, a new core structure was designed, fusing a pyrazole-ring onto the Aring on an AB-steroid ring system to generate a benzoindazole scaffold. Buchwald's palladium catalyzed alpha-arylation method was initially employed to derivatize the scaffold at the 6-position, but the reaction failed when transferred to solid phase. The 6phenyl-benzoindazole core structure was then redesigned to a benzoindazole-5hydrazone scaffold, introducing diversity at the hydrazone moiety. Best results were obtained using a solid phase approach, and the scope and limitations in terms of the substituents was thus investigated.