Ösztrán vázas vegyületek A- és D-gyűrűben történő módosítása

Our work was started with the aromatic halogenation of 13α-estrone. 3-O-Methyl- and 3-O-benzyl-protected 13α-estrone were successfully reacted with N-iodo-, N-bromo- or N-chlorosuccinimide to afford 2-, 4- and 2,4-bis-substituted derivatives at ring A. These were formed in short reaction times and good yields. Conversions could be significantly influenced by changing the solvent of the reaction and varying the quantity of the reactant. The presence of the phenolic OH group facilitates both mono- and double substitution. 3-Protected compounds yielded only monosubstituted derivatives. The 3-O-benzyl ether showed reduced reactivity, only bromination and chlorination occurred in this case. Similar halogenations of 17-deoxy-13α-estrone with N-halosuccinimide were carried out to synthesize 2-, 4- and 2,4-bis-substituted derivatives. A comparison of the results obtained in the halogenation of 17-oxo and 17-deoxy starting compounds allowed the conclusion that analogous derivatives were formed in different ratios. In the 17-deoxy series in some cases major changes in conditions were required to have the desired compounds. We have developed a convenient synthetic microwave procedure for Sonogashira coupling using the synthesized halogen compounds as starting materials. The reaction of 2-iodo-3-O-methyl-13α-estrone with phenylacetylene could efficiently be achieved using Pd(PPh3)4 catalyst and CuI cocatalyst in dimethylformamide in the presence of Et3N as a base, at 50 °C in 20 min in a microwave reactor. After establishing the most favourable reaction conditions using phenylacetylene as the alkyne partner, the method was successfully adapted to compounds with phenolic 3-OH function by the change of solvent to acetonitrile. We extended the scope of the steroid component to 4-iodo derivatives. We found that elevation of the reaction temperature to 80 °C and the change of catalyst to Pd(PPh3)2Cl2 facilitated substitution at C-4. Iodo compounds bearing phenolic OH required the changing of solvent to tetrahydrofuran. We isolated the desired 4-phenethynyl compound in short time and excellent yield. The protocol developed for phenylacetylene was successfully extended to the synthesis of 4-(4’-subst.)phenethynyl derivatives. We carried out the semihydrogenation of certain compounds synthesized by Sonogashira coupling. Microwave-assisted partial saturation of (4’-methoxyphenyl)ethynyl compounds was achieved in the 3-methyl ether series. We applied DMF/KOH as the hydrogen source and Pd(PPh3)2Cl2 as the catalyst. Under the applied conditions, cis-alkenes were formed from 2-phenethynyl derivatives while 4-phenethynyl derivatives led to trans-alkenes chemo- and stereoselectively. Semihydrogenation of compounds bearing phenolic OH did not result in 2- or 4-phenethenyl compounds; rather, formation of benzo[b]furans occurred. Additionally, we transformed 2- and 4-phenethynyl derivatives in ethyl acetate under 20 bar H2 with palladium-on-charcoal to 2- and 4-phenethyl derivatives, respectively, in excellent yields. We performed not only C–C but C–N cross couplings as well starting from the ring A halogenated derivatives. We have developed an efficient protocol for the Buchwald–Hartwig amination of 2-bromo-3-O-methyl-13α-estrone with aniline. An optimization process was performed by the systematic changes of catalyst, base and ancillary ligand. We compared conventional heating and microwave-assisted heat transfer and found that microwave irradiation shortened reaction times significantly. The highest yields were achieved by using Pd(OAc)2 as catalyst, KOtBu as base and XPhos as ancillary ligand at 100 °C in a microwave reactor. With the best reaction conditions in hand, couplings at C-2 were extended to monosubstituted anilines bearing substituents at ortho, meta or para positions with varied electronic properties. All couplings proceeded with high yields. We noticed that the electronic nature of the substituents influenced the conversion slightly but their position did not have any effect. 4-Bromo-3-O-methyl- and 2- or 4-bromo-3-O-benzyl-13α-estrone were successfully aminated with aniline without the need for changing reaction conditions established for couplings at C-2. Coupling with benzophenone imine instead of aniline was performed in order to gain 2- or 4-amino derivatives. 2- and 4-(N-diphenylmethylideneamino)-13α-estrones were efficiently transformed into the appropriate amino counterparts in a subsequent reaction step. Liberation of the NH2 function was achieved by Brønsted acid in the case of 3-methyl ethers and via hydrogenolysis from the 3-benzyl ether using palladium-on-charcoal catalyst..

Buchwald-Hartwig cross coupling of 13α-estrone

Use of catalysts and alternatives of traditional heating are important part of environmentallyfriendly processes and sustainable chemistry. Here we aimed to develop a suitable method for Buchwald-Hartwig amination of 13α-estrone by microwave assisted synthesis

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

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

facile Pd-catalyzed C(sp2)–N coupling to provide a range of 2- or 4-[(subst.)phenyl]amino-13α-estrone derivatives has been achieved under microwave irradiation. The reactions were mediated with the use of Pd(OAc)2 as a catalyst and KOt-Bu as a base in the presence of X-Phos as a ligand. The desired products have been obtained in good to excellent yields. The nature and the position of the aniline substituent at the aromatic ring influenced the outcome of the couplings. 2-Amino-13α-estrone was also synthesized in a two-step protocol including an amination of 2-bromo-13α-estrone 3-benzyl ether with benzophenone imine and subsequent hydrogenolysis

Comparative investigation of the in vitro inhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

The inhibitory effects of 13-epimeric estrones, D-secooxime and D-secoalcohol estrone compounds on human placental 17β-hydroxysteroid dehydrogenase type 1 isozyme (17β-HSD1) were investigated. The transformation of estrone to 17β-estradiol was studied by an in vitro radiosubstrate incubation method. 13α-Estrone inhibited the enzyme activity effectively with an IC50 value of 1.2 μM, which indicates that enzyme affinity is similar to that of the natural estrone substrate. The 13β derivatives and the compounds bearing a 3-hydroxy group generally exerted stronger inhibition than the 13α and 3-ether counterparts. The 3-hydroxy-13β-D-secoalcohol and the 3-hydroxy-13α-D-secooxime displayed an outstanding cofactor dependence, i.e. more efficient inhibition in the presence of NADH than NADPH. The 3-hydroxy-13β-D-secooxime has an IC50 value of 0.070 μM and is one of the most effective 17β-HSD1 inhibitors reported to date in the literature. © 2016 Informa UK Limited, trading as Taylor & Francis Group

Synthesis of Novel C-2- or C-15-Labeled BODIPY—Estrone Conjugates

Novel BODIPY–estrone conjugates were synthesized via Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC). Estrone-alkynes or an estrone-azide as starting compounds were synthesized via Michael addition or Sonogashira reaction as key steps. Fluorescent dyes based on BODIPY-core were provided by azide or alkyne functional groups. Fluorescent labeling of estrone was efficiently achieved at the C-2 or C-15 position. The newly-elaborated coupling procedures might have a broad applicability in the synthesis of fluorescent-labeled estrone conjugates suitable for biological assays

Synthesis and in vitro pharmacological evaluation of N-[(1-benzyl-1,2,3-triazol-4-yl)methyl]-carboxamides on d-secoestrone scaffolds

<p>An efficient synthesis of several <i>N</i>-[(1-benzyl-1,2,3-triazol-4-yl)methyl]carboxamides in the 13β- and 13α-d-secoestrone series is reported. Novel triazoles were synthesized via the Cu(I)-catalyzed azide–alkyne cycloaddition of steroidal alkynyl carboxamides and <i>p</i>-substituted benzyl azides. Each of the products was evaluated <i>in vitro</i> by means of MTT assays for antiproliferative activity against a panel of human adherent cancer cell lines (HeLa, MCF-7, A431 and A2780). Some of them exhibited activities similar to those of the reference agent cisplatin. On change of the substitution pattern of the benzyl group of the azide, great differences in the cell growth-inhibitory properties were observed. The <i>p</i>-alkylbenzyl-substituted triazoles selectively exerted high cytostatic action against A2780 cells, with IC₅₀ values of 1 µM. We investigated the potential inhibitory action exerted on the human 17β-HSD1 activity of the new secosteroids. Three triazoles effectively suppressed the estrone to 17β-estradiol conversion with IC₅₀ values in low micromolar range.</p

Syntheses and Antiproliferative Effects of D-homo- and D-secoestrones

Abstract Substituted and/or heterocyclic D-homoestrone derivatives were synthetized via the intramolecular cyclization of a δ-alkenyl-D-secoaldehyde, -D-secoalcohol or -D-secocarboxylic acid of estrone 3-benzyl ether. The D-secoalcohol was modified at three sites in the molecule. The in vitro antiproliferative activities of the new D-homo- and D-secoestrone derivatives were determined on HeLa, MCF-7, A431 and A2780 cells through use of MTT assay. D-Homoalcohols 3 and 5 displayed cell line-selective cytostatic effects against ovarian and cervical cell lines, respectively. Two D-secoestrones (6 and 12c) proved to be effective, with IC50 values comparable with those of the reference agent cisplatin. A selected compound (6) was tested by tubulin polymerization assay and its cancer specificity was additionally determined by using noncancerous human fibroblast cells