Synthesis of A-ring halogenated 13α-estrone derivatives as potential 17β-HSD1 inhibitors

• 13α-Estrone and some of its 3-ethers were subjected to aromatic halogenations.
• The substituent on C-3 greatly affected the chemo- and the regioselectivity.
• Some of the novel compounds proved to be potent against human 17β-HSD1 in vitro.
• Mono- and bis-iodo derivatives in the 3-OH series exerted substantial inhibition.
• The 4-halo-substituted 3-methyl ethers effectively suppressed the E1–E2 conversion.

13α-Estrone and its 3-methyl or benzyl ether were halogenated in ring A with N-bromo- or N-iodosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin as electrophile triggers. The chemo- and regioselectivities of the reactions depended greatly on the nature of the substituent on C-3. Bromination of the ethers led to 2- and 4-regioisomers. Bis-halogenation occurred only in the case of the phenolic derivative. Iodination and bromination resulted in similar products, except that the 3-benzyl ether could not be iodinated under the applied conditions. The potential inhibitory action of the new halogenated 13α-estrones on human 17β-hydroxysteroid dehydrogenase 1 activity was investigated via in vitro radiosubstrate incubation. Some compounds proved to be effective inhibitors, with IC50 values in the submicromolar range.

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