Synthesis of novel 13α-estrone derivatives by Sonogashira coupling as potential 17β-HSD1 inhibitors

Abstract

Novel 13α-estrone derivatives were synthesized by Sonogashira coupling. Transformations of 2- or 4-iodo regioisomers of 13α-estrone and its 3-methyl ether were carried out under different conditions in a microwave reactor. The 2-iodo isomers were reacted with para-substituted phenylacetylenes using Pd(PPh3)4 as catalyst and CuI as a cocatalyst. Coupling reactions of 4-iodo derivatives could be achieved by changing the catalyst to Pd(PPh3)2Cl2. The product phenethynyl derivatives were partially or fully saturated. Compounds bearing a phenolic OH group furnished benzofurans under the conditions used for the partial saturation. The inhibitory effects of the compounds on human placental 17β-hydroxysteroid dehydrogenase type 1 isozyme (17β-HSD1) were investigated by an in vitro radiosubstrate incubation method. Certain 3-hydroxy-2-phenethynyl or -phenethyl derivatives proved to be potent 17β-HSD1 inhibitors, displaying submicromolar IC50 values.

The first Pd-catalyzed Buchwald–Hartwig aminations at C-2 or C-4 in the estrone series

“…Based on recent literature results [ 18 , 20 ], we started to optimize the reaction conditions for the transformation of 2-bromo-13α-estrone 3-methyl ether ( 1 ) with aniline ( Table 1 ). Since the Pd source has been shown to be crucial in the amination step, two Pd catalysts were investigated.…”

“…Toluene was chosen as a solvent, and the reactions were carried out under microwave irradiation or thermal heating. The solvent was selected on the basis of literature data reported for other Pd-catalyzed reactions of estrone derivatives [ 18 , 20 ]. The pre-stirring of the reaction mixture without adding the aryl halide 1 was carried out at 60 °C for 5 min in a water bath, then aryl halide 1 was added and the mixture was irradiated in a microwave reactor at 150 °C for 10 min.…”

“…We recently described halogenations [ 19 ] and Sonogashira couplings on ring A of 13α-estrone and its 3-methyl ether [ 20 ]. The 13-epimer of natural estrone is a non-natural C-18 steroid containing cis junction of rings C and D [ 21 – 22 ].…”

“…Effective inhibition of 17β-HSD1 may result in an antitumor effect in hormone-dependent cancers [ 32 ]. It is known that several 2- or 4-substituted estrone derivatives possess substantial 17β-HSD1 inhibitory action [ 19 – 20 33 ]. The presence of a large lipophilic group on C-2 of estrone was found to be advantageous concerning the 17β-HSD1 inhibitory activity [ 33 ].…”

“…Nevertheless, we proved that certain 4-halogenated 13α-estrone 3-methyl ethers are also effective inhibitors [ 19 ]. Recently, we carried out the Pd-catalyzed C–C coupling of 2- and 4-iodo-13α-estrones as well as their 3-methyl ethers with p -substituted phenylacetylenes as terminal alkyne partners under microwave irradiation [ 20 ]. The regioisomerism markedly influenced the reaction conditions.…”