Cu(II) complex of an estradiol derivative with potent anti‐inflammatory properties

Abstract

In the present study, the A‐ring of estradiol was converted to an acetylsalicylic structure which was further complexed with Cu(II). The aim was to combine the anti‐inflammatory properties of estrogens with those of Cu(II) complexes. Key intermediate of the synthesis was 2‐formyl‐estradiol (2) which was prepared in quantitative yield through reaction of the phenoxymagnesium bromide of estradiol with formaldehyde in the presence of HMPA. For a successful reaction, an excess of ethylmagnesium bromide was required, and the mechanism is discussed. The target complex 5 exhibited potent anti‐inflammatory properties, comparable to those of indomethacin, in the carrageenan‐induced rat paw edema. This biological activity was not due either to the steroidal ligand or to the complexed Cu(II) alone.

ortho-Formylation of oxygenated phenols

“…Both groups obtained 2-formyl estradiol (94) in a combined yield of 94% after hydrolysis of the corresponding formate ester. 197,204 A side reaction that occurs with the Casiraghi method is the trans esterification of the 17E-hydroxyl group with methyl formate (97) (Figure 29 An indirect route to 2-formylestradiol (94) is by aromatization of 2-hydroxymethylene-19-nortestosterone (98) with DDQ in dioxane ( Figure 30). 205,206 This method was also applied to compound 99 for the synthesis of the corresponding 2-formylestrogen (100) (Figure 30).…”