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.
Highlights
Synthetic modifications of the naturally occurring female prehormone estrone may lead to compounds with diverse biological activities, for example with antitumor effect [1]
The results reveal a great influence of the 2,4-regioisomerism on the inhibition potential of the iodinated 3-methyl ethers 4 and 6, the phenylalkynyl 8 and 10 and the phenylalkyl 16 and 18 3-hydroxy compounds
The steroidal alkynes were chemo- and stereoselectively hydrogenated by transfer hydrogenation in a microwave reactor, furnishing alkenes or benzofurans depending on the nature of the substituent at C-3
Summary
Synthetic modifications of the naturally occurring female prehormone estrone may lead to compounds with diverse biological activities, for example with antitumor effect [1]. Several core-modified estrones have recently been produced and diversified in order to get selectively acting compounds [2,3,4]. The influence of inversion of the configuration at C-13 in 3,17-estradiols on their in vivo and in vitro estrogenic activity was shown by Poirier et al [5]. They demonstrated that 13 epimers exhibit no substantial binding affinity for the estrogen receptor alpha and no uterotropic activity. The 13α-estrane core may serve as fundamental moiety for the design of hormonally inactive estrone derivatives bearing promising biological activities. We recently published the syntheses and the in vitro biological
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