Design and synthesis of spirocyclic ligands of glucocorticoid receptors

Abstract

Spirocyclic indazoles were designed as potential ligands for the glucocorticoid receptors (GRs). A short and efficient synthetic sequence was developed allowing the preparation of pure diastereomeric spirocyclic analogs of fluorocortivazol. Our studies also revealed a new application of Burgess reagent leading to a ring expansion. The structures and conformations of several key intermediates and products were confirmed by single crystal X-ray diffraction analysis. Conformational assignments were also supported by DFT calculations. As a proof of concept we tested the affinity of diastereomeric compounds 13b and 14b for the GRs. Rewardingly, it was found that 14b showed a promising IC50 of 27 nM.

Dehydration reactions in polyfunctional natural products

“…Examples of unexpected reactivity has been observed in dehydrations with the Burgess reagent, such as ring expansion chemistry of (48) or dehydrative cyclization of a hydroxylated N-oxide derivative (50) (Scheme 9). 66,67 More recently, the oxidative potential of the Burgess reagent has been explored through reactivity similar to the Pfitzner-Moffatt conditions and other new uses for the reagent have been demonstrated in formation of cyclic sulfamides and sulfamidates from 1,2substituted amino alcohols or diols. 68,69 The reagent has also been employed for conversion of Bayliss-Hillman adducts into carbamates.…”

A tribute to Professor Ghosez

“…[33][34][35] He also synthesized new selective ligands for the human glucocorticoid and progesterone receptors (treatment of allergic and inflammatory diseases), and one of the synthesized ligands turned out to be very potent in human A549 IL6 inhibition assays, being 10-fold more potent than prednisolone. 36,37 In addition, he synthesized new cationic oxidants, looked at the functionalization of C60 and made an excursion into the world of foldamers. This list is only a small part of what Léon Ghosez has achieved.…”