Multicomponet synthesis of steroids analogs with complex side chains as nuclear receptor ligands in nematodes and mammalians

GALIGANANA M; ATORRESI CI; CASTRO OA; SANTILLAN ZABALA V.J; GOLA GF; RAMIREZ JA; MAZAIRA G; GALILEA A.

Dusseldorf

Conferencia; 7Th International Conference on Multicomponent reactions and Related Chemistry; 2018

Heinrich-Heine-Universitat of Dusseldorf

P-16GabrielGola 08/28/2018, Tuesday, 17:00-20:00 Multicomponent synthesis of steroid analogs with complex side chains as nuclear receptor ligands in nematodes and mammaliansG. F.Gola , A. Galileaa,c, C. l. Attorresi C, V. Santillán Zabalab, G.l. Mazaira' M. D. Galignianad, O. A. Castrob,e, J. A. Ramrreza,cMulticomponent reactions offer many advantages over traditional synthetic approaches in drug discovery. In particular, the Ugi four-component reaction (U-4CR) allows to generatechemical librarles with enhanced structural complexity and diversity.1 In this work wedescribe the synthesis of a small set of steroids of general structure 3 having highly diversa side chains, which were constructed using a traditional U-4CR The acidic component of the U-4CR, steroid 2, was obtained from pregnenolone 1 in three steps_2-4 In addition to formaldehyde, various amines (R1-NH2) and isonitriles (R:z-NC)(Scheme) 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 the one hand, we chose the DAF-12 nuclear receptor of the nematode C. elegans. The endogenous steroidal ligand of DAF-12{dafachronic acid) modulates the developmental status along the lifespan of this organism.As this receptor bears high homology to other nuclear receptors found in mammals, it is usually considerad a good model for the discovery of new compounds with potential clinical use. On the other hand, the compound library was evaluated as ligands of the progesterone receptor, a prototype of a more evolved nuclear receptor. Comparing the differential activities of the compounds in both systems, an attempt at assessing the promiscuity of the nuclear receptors as steroid sensors is discussed.References:1 A. Dt)mling, l. Ugi, Angew. Chemie 2000, 39, 3168-3210.2 W. Zeinyeh, Z. Mahiout, S. Radix, T. Lomberget, A. Dumoulin, R. Barret, C. Grenot, L.Rocheblave, E. L. Matera, C. Dumontet, etal., Steroids2012, 77,1177-1191.3 J. Rey, T. J. C. O'Riordan, H. Hu, J. P. Snyder, A. J. P. White, A. G. M. Barrett,European J. Org. Chem. 2012, 1, 3781-3794.4 F. K. Yoshimoto, M. C. Desilets, R. J. Auchus, J. Steroid Biochem. Mol. Biol. 2012,128,38-50.