Multicomponent synthesis of steroid analogs with complex side chains as nuclear receptor ligands in nematodes and mammalians

GABRIEL F. GOLA; AGUSTÍN GALILEA; CECILIA I. ATTORRESI; VANESSA SANTILLÁN ZABALA; GISELA I. MAZAIRA; MARIO D. GALIGNIANA; OLGA A. CASTRO; JAVIER A. RAMIREZ

Congreso; 7th International Conference on Multicomponent Reactions and Related Chemistry; 2018

Multicomponent reactions offers many advantages over traditional synthetic approaches in the drug discovery process. In particular, the Ugi four-component reaction (U-4CR) allows to generate chemical libraries with enhanced structural complexity and diversity. In this work we describe the synthesis of a small set of steroids of general structure 3 having highly diverse side chains, which were constructed using a traditional U-4CR (Scheme). The acidic component of the U-4CR, steroid 2, was obtained from pregnenolone 1 in three steps. In addition to formaldehyde, various amines (R1-NH2) and isonitriles (R2-NC) were conveniently chosen to obtain the desired side chains.Finally, these compounds were used for studies involving their interactions (as agonist or antagonist) with two nuclear receptors. On one hand, we chose the DAF-12 nuclear receptor of the C. elegants. The endogenous steroidal ligand of DAF-12 (dafachronic acid) modulates the developmental status along the lifespan of this nematode. As this receptor shares a high homology to other nuclear receptors found in mammals, it is usually considered a good model for the discovery of new compounds with potential clinical use. On the other hand, the compounds library was evaluated as ligands of the progesterone receptor, a prototype of a more evolved NR. Comparing the differential activities of the compounds in both systems, an attempt to assess the promiscuity of the NR as steroid sensors is discussed.