Design and synthesis of steroid mimetic libraries using solid phase techniques

<p>This thesis deals with the design and synthesis of biologically active ligands for nuclear hormone receptors using combinatorial techniques.</p><p>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.</p><p>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.</p><p>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.</p><p>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.</p><h3>List of scientific papers</h3><p>I. Ruda M, Bergman J, Koehler K, Ye L (2003). A solution-phase procedure for the preparation of 4-azasteroid mimetics. Heterocyclic Communications. 9(6): 571-4.</p><p>II. Ruda MC, Bergman J, Wu J (2002). Preparation of N-alkylated pyridones via selective N-alkylation of 2-alkoxypyridines on solid phase. J Comb Chem. 4(5): 530-5. <br><a href="https://pubmed.ncbi.nlm.nih.gov/12217027">https://pubmed.ncbi.nlm.nih.gov/12217027</a><br><br></p><p>III. Ruda M, Kann N, Gordon S, Bergman J, Nelson W, Agback P, Hagberg L, Koehler KF (2004). Solid phase synthesis of a 6-phenylquinolone-2(1H9-one library directed towards nuclear hormone receptors. [Manuscript]</p><p>IV. Ruda M, Olsen L, Gordon S, Bergman J, Nelson W, Agback P, Ericsson T, Hagberg L, Koehler KF, Kann N (2004). Solid phase synthesis of a benzoindazole-5-hydrazone library. [Manuscript]</p>