Publications by authors named "Éva Frank"

45 Publications

Antiproliferative and antimetastatic characterization of an exo-heterocyclic androstane derivative against human breast cancer cell lines.

Biomed Pharmacother 2021 May 19;140:111728. Epub 2021 May 19.

Institute of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary. Electronic address:

Cancer in general, and specifically gynaecological neoplasms, represents a major public health issue worldwide. Based on the effect of sex hormones on breast tumorigenesis and prognosis, as well as on the development of breast cancer metastases, modification of the steroid skeleton is a hotspot of research for novel anticancer agents. Numerous recent studies support that minor modifications of the androstane skeleton yield potent antiproliferative and antimetastatic drug candidates. The aim of the present study was to assess the antitumor and antimetastatic properties, as well as the mechanism of action of a D-ring-modified exo-heterocyclic androstadiene derivative named 17APAD. The test compound was found to be highly selective towards human breast cancer-derived cell lines (MCF-7, T47D, MDA-MB-361, MDA-MB-231) compared to non-cancerous fibroblast cells (NIH/3T3), and exerted superior effect compared to the clinically applied reference drug cisplatin. Changes in MCF-7- and MDA-MB-231 cell morphology and membrane integrity induced by the test substance were assessed by fluorescent double staining. Cell cycle disturbances were analyzed by flow cytometry, and concentration-dependent alterations were detected on breast cancer cell lines. Mitochondrial apoptosis induced by the test compound was demonstrated by JC-1 staining. Inhibitory effects on metastasis formation, including the inhibition of migration, invasion and intravasation were investigated in 2D and 3D models. Significant anti-migratory and anti-invasive effects on MCF-7 and MDA-MB-231 cells were detected after 24 h exposure in 2D wound healing and Boyden-chamber assays. The anti-intravasative properties of 17APAD were evident after 4 h of incubation in a co-culture 3D circular chemorepellent-induced defects (CCID) assay, and the level of inhibition at concentrations ≥2 µM was comparable to that exerted by the focal adhesion kinase inhibitor defactinib. Single cell mass cytometry revealed that chemosensitive subpopulations of MDA-MB-231 cells engaged to apoptosis were less positive for EGFR, CD274, and CD326, while the percentage of cells positive for GLUT1, MCT4, Pan-Keratin, CD66(a,c,e), Galectin-3 and TMEM45A increased in response to 17APAD treatment. Finally, the novel androstane analogue 17APAD had an outstanding inhibitory effect on tumour growth in the 4T1 orthotopic murine breast cancer model in vivo after 2 weeks of intraperitoneal administration. These findings support that substitution of the androsta-5,16-diene framework with a N-containing heterocyclic moiety at C17 position yields a molecular entity rational to be considered for design and synthesis of novel, effective antitumor agents, and 17APAD is worth further investigation as a promising anticancer drug candidate.
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http://dx.doi.org/10.1016/j.biopha.2021.111728DOI Listing
May 2021

Complex formation of an estrone-salicylaldehyde semicarbazone hybrid with copper(II) and gallium(III): Solution equilibria and biological activity.

J Inorg Biochem 2021 Jul 24;220:111468. Epub 2021 Apr 24.

Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary; MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.

The solution chemical properties such as proton dissociation, complex formation with copper(II) and gallium(III) ions in addition to antibacterial and antitumor activity of a novel tridentate salicyaldehyde semicarbazone-estrone hybrid (estrone-SC) and a related bicyclic compound (thn-SC) were investigated. The crystal structure of complex [Cu(thn-SCH)Cl] was studied by single crystal X-ray diffraction method. Estrone-SC and thn-SC form mono-ligand complexes with Cu(II) characterized by relatively high stability, however, they are much less stable than their thiosemicarbazone analogues. The neutral Cu(II) complexes with (O,N,O)(HO) coordination mode predominate at physiological pH. Estrone-SC and thn-SC are more efficient Ga(III) binders in comparison with thiosemicarbazones, although the complexes also suffer dissociation at pH 7.4. The Cu(II) complex of estrone-SC displayed significant cytotoxicity in A549, SW480 and CH1/PA cancer cells, and moderate apoptosis induction and ROS formation. The semicarbazone compounds did not exhibit antibacterial effect; unlike the related Cu(II)-thiosemicarbazone complexes represented by the fairly low MIC values (3-50 μM) obtained on the Gram-positive Staphylococcus aureus and Enterococcus faecalis bacteria.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111468DOI Listing
July 2021

Synthesis of dihydrotestosterone derivatives modified in the A-ring with (hetero)arylidene, pyrazolo[1,5-a]pyrimidine and triazolo[1,5-a]pyrimidine moieties and their targeting of the androgen receptor in prostate cancer.

J Steroid Biochem Mol Biol 2021 Apr 29;211:105904. Epub 2021 Apr 29.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary. Electronic address:

One of the main directions of steroid research is the preparation of modified derivatives in which, in addition to changes in physicochemical properties, receptor binding is significantly altered, thus a bioactivity different from that of the parent compound predominates. In the frame of this work, 2-arylidene derivatives were first synthesized by regioselective modification of the A-ring of natural sex hormone, 5α-dihydrotestosterone (DHT). After Claisen-Schmidt condensations of DHT with (hetero)aromatic aldehydes in alkaline EtOH, heterocyclizations of the α,β-enones were performed with 3-amino-1,2,4-triazole, 3-aminopyrazole and 3-amino-5-methylpyrazole in the presence of t-BuOK in DMF to afford 7'-epimeric mixtures of A-ring-fused azolo-dihydropyrimidines, respectively. Depending on the electronic demand of the substituents of the arylidene moiety, spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation of the heteroring led to triazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidines in good yields, while, using the Jones reagent as a strong oxidant, 17-oxidation also occurred. The crystal structures of an arylidene and a triazolopyrimidine product have been determined by single crystal X-ray diffraction and both were found to crystallize in the monoclinic crystal system at P2 space group. Most derivatives were found to diminish the transcriptional activity of androgen receptor (AR) in reporter cell line. The candidate compound (17β-hydroxy-2-(4-chloro)benzylidene-5α-androstan-3-one, 2f) showed to suppress androgen-mediated AR transactivation in a dose-dependent manner. We confirmed the cellular interaction of 2f with AR, described the binding in AR-binding cavity by the flexible docking and showed the ability of the compound to suppress the expression of AR-regulated genes in two prostate cancer cell lines.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105904DOI Listing
April 2021

Health Care Professional Students' Perceptions of Teamwork and Roles After an Interprofessional Critical Care Simulation.

Dimens Crit Care Nurs 2021 May-Jun 01;40(3):174-185

Background: Educational opportunities for health care professional students to learn collaborative communication and the roles and responsibilities of other disciplines are minimal unless faculty are intentional about facilitating this interdisciplinary learning.

Objectives: The aim of this study was to determine how a simulation-enhanced interprofessional education (Sim-IPE) teaching strategy fostered communication and interdisciplinary awareness between students from multiple disciplines.

Method: This pretest-posttest design surveyed undergraduate students from 5 disciplines. The Student Perceptions of Interprofessional Clinical Education-Revised tool examined students' perceptions of teamwork and roles after an in-depth, multistate critical care simulation experience.

Results: All students' perceptions of teamwork increased after the Sim-IPE. More experience in the health care field is associated with an increased perception of teamwork and roles/responsibilities.

Discussion: On the basis of these findings, the critical care Sim-IPE was an effective teaching strategy to increase the perception of roles and responsibilities of interprofessional critical care team members with applicability to many other specialty topics.
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http://dx.doi.org/10.1097/DCC.0000000000000472DOI Listing
April 2021

Case Report of an Influenza Outbreak in the Sports Medicine Setting.

Curr Sports Med Rep 2021 Apr;20(4):185-187

Departments of Family Medicine and Orthopaedics, Penn State Hershey Medical Center, Hershey, PA.

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http://dx.doi.org/10.1249/JSR.0000000000000827DOI Listing
April 2021

Androstano-arylpyrimidines: Novel small molecule inhibitors of MDR1 for sensitizing multidrug-resistant breast cancer cells.

Eur J Pharm Sci 2021 Jan 8;156:105587. Epub 2020 Oct 8.

Department of Biochemistry and Molecular Biology, Doctoral School of Biology, University of Szeged, Közép fasor 52, H-6726, Szeged, Hungary. Electronic address:

Apart from the numerous physiological functions of MDR1, it is widely known for its role in granting multidrug resistance to cancer cells. This ATP-driven transmembrane protein exports a wide range of chemotherapeutic agents from cancer cells, thereby deterring drugs to reach effective intracellular concentrations. Thus, inhibition of MDR1 expression or function would be a viable option to enhance the accumulation of cytotoxic agents in cancer cells which in turn could improve significantly the success rate of chemotherapy. Although, several pharmacological inhibitors have been designed and tested in the past, due to their unsuccessful translation to clinical application, there is still ongoing research to find suitable compounds to manipulate MDR1 function and potentially overturn multidrug resistance. In the present study, we demonstrate that novel DHT-derived A-ring-fused arylpyrimidinone derivatives, based on their acetylation status, can inhibit MDR1 efflux activity in MDR1 overexpressing multidrug-resistant breast adenocarcinoma cells. Strikingly, all derivatives carrying an acetoxy group on the sterane d-ring were highly potent in hindering Rhodamine 123 export via MDR1, however deacetylated molecules were not capable to exert a similar effect on multidrug resistant cancer cells. The possible molecular and cellular mechanisms underlying the efflux pump inhibiting function of acetylated derivatives were dissected using the most potent MDR1 inhibitor, compound 10g and its deacetylated counterpart (11g). Importantly, molecule 10g was able to sensitize drug resistant cells to doxorubicin-induced apoptosis, further verifying the highly advantageous nature of efflux pump inhibition upon chemotherapy. Our experiments also revealed that neither mitochondrial damage, nor MDR1 gene regulation could lay behind the MDR1 inhibitory function of compound 10g. Molecular docking studies were carried out to analyze the interactions of 10g and 11g with MDR1, however no significant differences in their binding properties were observed. Nevertheless, our results indicate that the ER stress inducing potential of molecule 10g might be the fundamental mechanism behind its inhibitory action on MDR1. With additional studies, our work can yield a structural platform for a new generation of small molecule MDR1 inhibitors to sensitize drug resistant cancer cells and at the same time it elucidates the exemplary involvement of endoplasmic reticulum stress in the molecular events to defeat multidrug resistance.
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http://dx.doi.org/10.1016/j.ejps.2020.105587DOI Listing
January 2021

Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds.

Molecules 2020 Sep 4;25(18). Epub 2020 Sep 4.

Department of Organic Chemistry, Doctoral School of Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.

Although the hormone independent cytotoxic activity of several estradiol derivatives endowed with a simple substituent at C-2 has been reported so far, 2-heterocyclic and 2,3-condensed analogs are less investigated from both synthetic and pharmacological points of view. Therefore, novel A-ring-connected 2-pyrazoles of estradiol and, for comparison, their structurally simplified non-steroidal pairs were synthesized from estradiol 3-methyl ether and 6-methoxy-1,2,3,4-tetrahydronaphthalene. Friedel-Crafts acetylation of the protected phenolic compounds and subsequent -demethylation led to -substituted derivatives regioselectively, which were converted to arylhydrazones with phenylhydrazine, 4-tolylhydrazine and 4-chloro-phenylhydrazine, respectively, under microwave conditions. The hydrazones were subjected to cyclization with the Vilsmeier-Haack reagent immediately after preparation and the ring closure/formylation sequence resulted in steroidal and non-steroidal 4'-formylpyrazoles in moderate to good yields. During reductive transformations, 4-hydroxymethyl-pyrazoles were obtained, while oxidative lactonization of the 4-formylpyrazole moiety with the phenolic OH in the presence of the Jones reagent afforded A-ring-integrated pyrazolocoumarin hybrids and related analogs. Steroidal pyrazoles, which were produced as C-17 acetates due to acetylation of C-17 OH during the primary Friedel-Crafts reaction, underwent deacetylation in alkaline methanol to furnish 2-heterocyclic estradiol derivatives. Pharmacological studies revealed the overall and cancer cell-specific cytotoxicity of the derivatives and the half maximal inhibitory concentrations were obtained for the most promising compounds.
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http://dx.doi.org/10.3390/molecules25184039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571145PMC
September 2020

Solution equilibrium, structural and cytotoxicity studies on Ru(η-p-cymene) and copper complexes of pyrazolyl thiosemicarbazones.

J Inorg Biochem 2020 01 22;202:110883. Epub 2019 Oct 22.

Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. Electronic address:

Solution chemical properties of two bidentate pyrazolyl thiosemicarbazones 2-((3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Me-pyrTSC), 2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Ph-pyrTSC), stability of their Cu(II) and Ru(η-p-cymene) complexes were characterized in aqueous solution (with 30% DMSO) by the combined use of UV-visible spectrophotometry, H NMR spectroscopy and electrospray ionization mass spectrometry in addition to their solid phase isolation. The solid phase structures of Me-pyrTSC∙HO, [Ru(η-p-cymene)(Me-pyrTSC)Cl]Cl and [Cu(Ph-pyrTSCH)] were determined by single crystal X-ray diffraction. High stability mononuclear Ru(η-p-cymene) complexes with (N,S) coordination mode are formed in the acidic pH range, and increasing the pH the predominating dinuclear [(Ru(η-p-cymene))(L)] complex with μ-bridging sulphur donor atoms is formed (where L is the deprotonated thiosemicarbazone). [CuL] and [CuL] complexes show much higher stability compared to that of complexes of the reference compound benzaldehyde thiosemicarbazone. [CuL] complexes predominate at neutral pH. Me-pyrTSC and Ph-pyrTSC exhibited moderate cytotoxicity against human colonic adenocarcinoma cell lines (IC = 33-76 μM), while their complexation with Ru(η-p-cymene) (IC = 11-24 μM) and especially Cu(II) (IC = 3-6 μM) resulted in higher cytotoxicity. Cu(II) complexes of the tested thiosemicarbazones were also cytotoxic in three breast cancer and in a hepatocellular carcinoma cell line. No reactive oxygen species production was detected and the relatively high catalase activity of SUM159 breast cancer cells was decreased upon addition of the ligands and the complexes. In the latter cell line the tested compounds interfered with the glutathione synthesis as they decreased the concentration of this cellular reductant.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110883DOI Listing
January 2020

Stereocontrolled synthesis of the four possible 3-methoxy and 3-benzyloxy-16-triazolyl-methyl-estra-17-ol hybrids and their antiproliferative activities.

Steroids 2019 12 16;152:108500. Epub 2019 Sep 16.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. Electronic address:

The four possible isomers of each of 3-methoxy- and 3-benzyloxyestra-1,3,5(10)-trien-17-ols (5-8 and 9-12) were converted through 16-p-tosyloxymethyl- or 16-bromomethyl derivatives into their 3-methoxy- and 3-benzyloxy-16-azidomethylestra(1,3,5(10)-triene derivatives (13-16 and 17-20). The regioselective Cu(I)-catalyzed 1,3-dipolar cycloaddition of these compounds with different terminal alkynes afforded novel 1,4-disubstituted diastereomers (21a-f, 22a-f, 23a-f, 24a-f and 25a-f, 26a-f, 27a-f, 28a-f). The antiproliferative activities of the structurally related triazoles were determined in vitro with the microculture tetrazolium assay on four malignant human cell lines of gynecological origin (Hela, SiHa, MCF-7 and MDA-MB-231).
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http://dx.doi.org/10.1016/j.steroids.2019.108500DOI Listing
December 2019

Stereoselective synthesis of new type of estradiol hybrid molecules and their antiproliferative activities.

Steroids 2019 08 11;148:63-72. Epub 2019 May 11.

Depertment of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. Electronic address:

To prepare new type of estrane hybrid molecules, we chose 3-methoxy- and 3-benzyloxy-17β,16β-epoxymethylene-estra-1,3,5(10)-trienes as starting materials (2 and 5). These steroid oxetanes were transformed with ethylene glycol in the presence of BF.OEt into 3-methoxy- and 3-benzyloxy-16β-(2'-oxa-4'-hydroxy)butyl-17β-hydroxy-estra-1,3,5(10)-trien-17β-ols (3a and 6a). Iodination of the terminal hydroxy group afforded iodo derivatives 3b and 6b, which underwent one-pot 3-O-alkylation with unprotected ascorbic acid to yield 3c and 6c. The same process with salicylic acid led to 2-O-alkylated salicylic acid derivatives 3d and 6d. Iodo derivatives 3b and 6b underwent nucleophilic exchange reaction with NaN furnishing the corresponding azido compounds 3e and 6e. These compounds were subjected to azide-alkyne CuAAC reactions with phenylacetylene and their p-substituted derivatives to form 1,4-substituted triazoles 3f-h and 6f-h. The reduction of 3e and 6e with hydrazine hydrate in the presence of Raney Ni provided the corresponding amino derivatives 3i and 6i. These compounds were reacted further with varied substituted benzoic acids to deliver terminal benzamido derivatives 3j-m and 6j-m. We determined the in vitro antiproliferative activities of compounds 2, 5, 3a-m and 6a-m by means of MTT assays on a panel of human adherent cancer cell lines A2780, MCF-7, MB-231 and SiHa.
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http://dx.doi.org/10.1016/j.steroids.2019.02.016DOI Listing
August 2019

Anti-Cancer Activity of Novel Dihydrotestosterone-Derived Ring A-Condensed Pyrazoles on Androgen Non-Responsive Prostate Cancer Cell Lines.

Int J Mol Sci 2019 May 2;20(9). Epub 2019 May 2.

Department of Biochemistry and Molecular Biology, University of Szeged, Közép fasor 52., H-6726 Szeged, Hungary.

Regioselective synthesis of novel ring A-fused arylpyrazoles of dihydrotestosterone (DHT) was carried out in two steps under facile reaction conditions. Aldol condensation of DHT with acetaldehyde afforded a 2-ethylidene derivative regio- and stereo-selectively, which was reacted with different arylhydrazines in the presence of iodine via microwave-assisted oxidative cyclization reactions. The 17-keto analogs of steroidal pyrazoles were also synthesized by simple oxidation in order to enlarge the compound library available for pharmacological studies and to obtain structure-activity relationship. The antiproliferative activities of the structurally related heteroaromatic compounds were tested in vitro on human cervical and breast adenocarcinoma cell lines (HeLa, MCF-7 and MDA-MB-231) and on two androgen-independent malignant prostate carcinoma cell lines (PC-3 and DU 145). Based on primary cytotoxicity screens and IC assessment, a structure-function relationship was identified, as derivatives carrying a hydroxyl group on C-17 exhibit stronger activity compared to the 17-one counterparts. Cancer cell selectivity of the derivatives was also determined using non-cancerous MRC-5 cells. Furthermore, the proapoptotic effects of some selected derivatives were verified on androgen therapy refractive p53-deficient PC-3 cells. The present study concludes that novel DHT-derived arylpyrazoles exert cancer cell specific antiproliferative activity and activate apoptosis in PC-3 cells.
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http://dx.doi.org/10.3390/ijms20092170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539495PMC
May 2019

Microwave-Assisted Stereoselective Heterocyclization to Novel Ring d-fused Arylpyrazolines in the Estrone Series.

Molecules 2019 Feb 4;24(3). Epub 2019 Feb 4.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.

Microwave-assisted syntheses of novel ring d-condensed 2-pyrazolines in the estrone series were efficiently carried out from steroidal ,-enones and hydrazine derivatives. The ring-closure reaction of 16-benzylidene estrone 3-methyl ether with hydrazine in acetic acid resulted in a 2:1 diastereomeric mixture of two 16,17- fused pyrazolines, which is contrary to the former literature data for both stereoselectivity and product structure. However, the cyclization reactions of a mestranol-derived unsaturated ketone with different arylhydrazines in acidic ethanol furnished the heterocyclic products in good to excellent yields independently of the substituents present on the aromatic ring of the reagents applied. The MW conditions also permitted the ring-closure reaction with -nitrophenylhydrazine which is unfavorable under conventional heating. Moreover, the transformations led to the heterocyclic compounds stereoselectively with a 16,17- ring junction without being susceptible to spontaneous and promoted oxidation to pyrazoles.
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http://dx.doi.org/10.3390/molecules24030569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384934PMC
February 2019

Microwave-assisted synthesis of biologically relevant steroidal 17--pyrazol-5'-ones from a norpregnene precursor by a side-chain elongation/heterocyclization sequence.

Beilstein J Org Chem 2018 8;14:2589-2596. Epub 2018 Oct 8.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.

Multistep syntheses of novel 17β-pyrazol-5'-ones in the Δ-androstane series were efficiently carried out from pregnenolone acetate. A steroidal 17-carboxylic acid was first synthesized as a norpregnene precursor by the bromoform reaction and subsequent acetylation. Its CDI-activated acylimidazole derivative was then converted to a β-ketoester containing a two carbon atom-elongated side chain than that of the starting material. A Knorr cyclization of the bifunctional 1,3-dicarbonyl compound with hydrazine and its monosubstituted derivatives in AcOH under microwave heating conditions led to the regioselective formation of 17--heterocycles in good to excellent yields. The suppression of an acid-catalyzed thermal decarboxylation of the β-ketoester and thus a significant improvement in the yield of the desired heterocyclic products could be achieved by the preliminary liberation of the arylhydrazines from their hydrochloride salts in EtOH in the presence of NaOAc. The reaction rates were found to depend on the electronic character of the substituent present in the phenylhydrazine applied. The antiproliferative activities of the structurally related steroidal pyrazol-5'-ones and their deacetylated analogs were screened on three human adherent breast cancer cell lines (MCF7, T47D and MDA-MB-231): the microculture tetrazolium assay revealed that some of the presented derivatives exerted cell growth inhibitory effects on some of these cell lines comparable to those of the reference compound, cisplatin.
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http://dx.doi.org/10.3762/bjoc.14.236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6204839PMC
October 2018

Investigation of pH and substituent effects on the distribution ratio of novel steroidal ring D- and A-fused arylpyrazole regioisomers and evaluation of their cell-growth inhibitory effects in vitro.

Steroids 2017 10 10;126:35-49. Epub 2017 Aug 10.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. Electronic address:

Novel androstanopyrazoles have been efficiently synthesized from steroidal β-ketoaldehydes with different arylhydrazine hydrochlorides both under acidic and basic conditions. Knorr-type transformations of 16-hydroxymethylene-dehydroepiandrosterone containing its 1,3-dicarbonyl moiety on ring D, proved to be regioselective in pyridine at room temperature, while mixtures of regioisomers were obtained in acidic EtOH under reflux. Contrarily, the cyclocondensation reactions of 2-hydroxymethylene-dihydrotestosterone bearing its reactive functionalities on ring A, led to a mixture of pyrazole regioisomers in varying ratio depending on the applied medium. The regioisomeric distribution was found to depend on the electronic character of the substituent of the phenylhydrazine applied. After separating the related isomers by column chromatography, they were subjected to in vitro pharmacological studies to investigate their antiproliferative activities against three human breast malignant cell lines (MCF7, T47D, MDA-MB-231). Flow cytometry revealed that the most potent agents elicited a cell cycle disturbance on MDA-MB-231 and T47D cells.
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http://dx.doi.org/10.1016/j.steroids.2017.08.003DOI Listing
October 2017

Multicomponent access to androstano-arylpyrimidines under microwave conditions and evaluation of their anti-cancer activity in vitro.

J Steroid Biochem Mol Biol 2017 09 6;172:79-88. Epub 2017 Jun 6.

Department of Organic Chemistry, University of Szeged, Dóm tér 8., H-6720 Szeged, Hungary. Electronic address:

Novel ring D- and A-fused pyrimidines in the androstane series were efficiently synthesized within 10-15min in polar protic solvents under microwave irradiation via two kinds of multicomponent heterocyclization reactions followed by spontaneous or promoted oxidation. The rates of the one-pot catalyst-free transformations of steroidal β-ketoaldehydes, ammonium acetate and substituted benzaldehydes in EtOH were found to be affected slightly by the steric and electronic feature of the substituents on the aromatic ring of the arylaldehyde component and the different reactivities of rings D and A of the sterane core. At the same time, the acid-catalyzed Biginelli-type reaction of dihydrotestosterone acetate, urea and arylaldehydes, and subsequent Jones oxidation of the primarily formed dihydropyrimidinones led to the corresponding ring A-fused 1H-pyrimidin-2-ones in moderate yields independently of the substituents on the aromatic moiety. The synthesized compounds were tested in vitro on human cancer cell lines as well as on non-cancerous fibroblast cells by the MTT assay in order to investigate their biological effects. As a result of the pharmacological screen, a remarkable structure-function relationship has been observed as the acetylated Biginelli products exhibited higher toxicity compared to the deacetylated version of each compound. Furthermore, in case of three 2'-arylpyrimidine derivatives a strong prostate cancer cell specific activity has been identified.
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http://dx.doi.org/10.1016/j.jsbmb.2017.06.001DOI Listing
September 2017

Synthesis, functionalization and biological activity of arylated derivatives of (+)-estrone.

Bioorg Med Chem 2017 02 9;25(3):949-962. Epub 2016 Dec 9.

Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany; Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany. Electronic address:

Various novel arylated estrone derivatives, such as 2-aryl-, 4-aryl- and 2,4-diaryl-estrones, by Suzuki-Miyaura reactions. While the synthesis of 4-arylestrones could be carried out under standard conditions, the synthesis of 2-arylestrones and 2,4-diarylestrones required a thorough optimization of the conditions and it proved to be important to use sterically encumbered biaryl ligands. The best results were obtained by the use of RuPhos. Combination of developed Suzuki coupling reactions with subsequent cyclization reactions afforded more complex hybrid structures, containing dibenzofuran, benzocoumarin and steroid moieties. These derivatives were tested as pancreatic lipase inhibitors and it was found that most of the compounds exhibited inhibition of pancreatic lipase but the maximum inhibitory potential was shown by 4-arylestrones. All of the synthesized derivatives showed inhibitory values in the range of 0.82±0.01-59.7±3.12μM. The biological activity was also rationalized on the bases of docking studies.
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http://dx.doi.org/10.1016/j.bmc.2016.12.009DOI Listing
February 2017

Does Instruction Affect the Underlying Dimensionality of a Kinesiology Test?

J Appl Meas 2016;17(4):393-415

Nikolaus Bezruczko, 1524 E. 59th St., Chicago, IL 60637, USA,

Does effective instruction, which changes students' knowledge and possibly alters their cognitive functions, also affect the dimensionality of an achievement test? This question was examined by the parameterization of kinesiology test items (n = 42) with a Rasch dichotomous model, followed by an investigation of dimensionality in a pre- and post-test quasi-experimental study design. College students (n = 108) provided responses to kinesiology achievement test items. Then the stability of item difficulties, gender differences, and the interaction of item content categories with dimensionality were examined. In addition, a PCA/t-test protocol was implemented to examine dimensionality threats from the item residuals. Internal construct validity was investigated by regressing item content components on calibrated item difficulties. Measurement model item residuals were also investigated with statistical decomposition methods. In general, the results showed significant student achievement between pre and post testing, and dimensionality disturbances were relatively minor. The amount of unexpected item "shift" in an un-equated measurement dimension between pre and post testing was less than ten percent of the total items and largely concentrated among several unrelated items. An unexpected finding was a residual cluster consisting of several items testing related technical content. Complicating interpretation, these items tended to appear near the end of the test, which implicates test position as a threat to measurement equivalence. In general, the results across several methods did not tend to identify common threats and instead pointed to multiple sources of threats with varying degree of prominence. These results suggest conventional approaches to measurement equivalence that emphasize expedient overall procedures such as DIF, IRT, and factor analysis are probably capturing isolated sources of variability. Their implementation probably improves measurement equivalence but with substantial residual sources undetected.
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February 2017

Synthesis of novel 17-(4'-formyl)pyrazolylandrosta-5,16-dienes and their derivatives as potent 17α-hydroxylase/C17,20-lyase inhibitors or antiproliferative agents depending on the substitution pattern of the heteroring.

Eur J Med Chem 2016 Sep 8;120:284-95. Epub 2016 May 8.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720, Szeged, Hungary. Electronic address:

A series of novel 17-(4'-formyl)pyrazolylandrosta-5,16-dienes were efficiently synthesized in two steps from pregnadienolone acetate with monosubstituted hydrazines via the cyclization/formylation sequence of the primarily formed hydrazones on treatment with the Vilsmeier-Haack reagent. The products were further transformed by deacetylation and subsequent reduction in order to enlarge the compound library available for pharmacological studies. Moreover, 4'-formylpyrazoles containing H or Me on the heteroring-N were subjected to oxime formation and Ac2O-induced dehydration to furnish the corresponding 4'-cyano derivatives in good yields. The antiproliferative activities of the structurally related steroidal 17-exo-pyrazole derivatives were tested in vitro on four human adherent breast cancer cell lines (MCF7, T47D, MDA-MB-231 and MDA-MB-361): the microculture tetrazolium assay revealed that seven compounds exerted better cell growth-inhibitory effects on some or all these cell lines than those of the reference cisplatin. With regard to the well-known structural features that a potent C17,20-lyase inhibitor should possess, some relevant derivatives were tested in vitro from the aspects of their inhibitory effects on rat testicular enzyme, and one of them proved to exert noteworthy enzyme-inhibitory action, with an IC50 (26 nM) of the same order of magnitude as that of abiraterone.
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http://dx.doi.org/10.1016/j.ejmech.2016.05.006DOI Listing
September 2016

Microwave-assisted stereoselective approach to novel steroidal ring D-fused 2-pyrazolines and an evaluation of their cell-growth inhibitory effects in vitro.

Steroids 2016 08 3;112:36-46. Epub 2016 May 3.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. Electronic address:

Novel ring D-condensed 2-pyrazolines in the Δ(5)-androstene series were efficiently synthesized from 16-dehydropregnenolone or its acetate with different arylhydrazines or methylhydrazine, respectively, under microwave irradiation. The reactions are assumed to occur via hydrazone intermediates, followed by intramolecular 1,4-addition leading to the fused heteroring stereoselectively with a 16α,17α-cis ring junction. The synthesized compounds were subjected to in vitro pharmacological studies of their antiproliferative activities against four human breast (MCF7, T47D, MDA-MB-231 and MDA-MB-361) and three cervical (HeLa, C33A and SiHA) malignant cell lines. Flow cytometry revealed that the most potent agent elicited a cell cycle disturbance.
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http://dx.doi.org/10.1016/j.steroids.2016.04.014DOI Listing
August 2016

Stereocontrolled synthesis of the four 16-hydroxymethyl-19-nortestosterone isomers and their antiproliferative activities.

Steroids 2016 Jan 11;105:113-20. Epub 2015 Dec 11.

Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös u. 6., H-6720 Szeged, Hungary. Electronic address:

Novel 16-hydroxymethyl-19-nortestosterone diastereomers were prepared by Birch reduction from the corresponding 3-methoxy-16-hydroxymethylestra-1,3,5(10)-trien-17-ol isomers with known configurations. The synthesized compounds are 16α- and 16β-hydroxymethyl-substituted 19-nortestosterone and their 17α-epimers. To prepare 17α-19-nortestosterone, the Mitsunobu inversion reaction of 19-nortestosterone with different alkyl and aryl carboxylic acids was chosen. Deacylation of the new compounds by the Zemplén method yielded the required 17α-19-nortestosterone. The antiproliferative activities of the structurally related compounds were determined in vitro through microculture tetrazolium assays on a panel of human adherent cervical (HeLa, SiHa and C33A), breast (MCF-7, MDA-MB-231, MDA-MB-361 and T47D) and ovarian (A2780) cell lines. The 17α epimer of 19-nortestosterone demonstrated considerable activity, selectively for HeLa cells, with a calculated IC50 of 0.65 μM. The reference compound, cisplatin, displayed an order of magnitude higher IC50 (12.4 μM). The cancer selectivity of 17α-19-nortestosterone was tested by MTT assay performed with noncancerous human fibroblast cell line MRC-5. The results indicated that 17α-19-nortestosterone selectively disturbs the viability of HeLa cells without greatly affecting other cancer cell types and intact fibroblasts.
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http://dx.doi.org/10.1016/j.steroids.2015.12.003DOI Listing
January 2016

Efficient access to novel androsteno-17-(1',3',4')-oxadiazoles and 17β-(1',3',4')-thiadiazoles via N-substituted hydrazone and N,N'-disubstituted hydrazine intermediates, and their pharmacological evaluation in vitro.

Eur J Med Chem 2015 Jun 7;98:13-29. Epub 2015 May 7.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. Electronic address:

A series of novel 17-exo-oxadiazoles and -thiadiazoles in the Δ(5) androstene series were efficiently synthesized from pregnenolone acetate and pregnadienolone acetate via multistep pathways. 17β-(1',3',4')-Oxadiazoles were obtained in high yields by the phenyliodonium diacetate-induced oxidative ring closure of semicarbazone and N-acylhydrazones derived from 3β-acetoxy- and 3β-hydroxyandrost-5-ene-17β-carbaldehydes. For the synthesis of analogous Δ(16)-17-oxadiazolyl derivatives, N,N'-disubstituted hydrazine intermediates were prepared from 3β-acetoxyandrosta-5,16-diene-17-carboxylic acid, which then underwent cyclodehydration in the presence of POCl3. The cyclization of steroidal N,N'-diacylhydrazines containing a saturated ring D with the Lawesson reagent afforded 17β-(1',3',4')-thiadiazoles in good yields. Most of the products were subjected to deacetylation in basic media in order to enlarge the compound library available for pharmacological studies. All of these derivatives were screened in vitro for their antiproliferative effects against four malignant human adherent cell lines (HeLa, A2780, MCF7 and A431) by means of the MTT assay. The 3β-hydroxy derivatives of the newly-synthesized 17-exo-heterocycles were tested in vitro to investigate their inhibitory effects on rat testicular C17,20-lyase. One of the 1,3,4-oxadiazolyl derivatives proved to exert noteworthy enzyme-inhibitory action, with an IC50 (0.065 μM) of the same order of magnitude as that of abiraterone.
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http://dx.doi.org/10.1016/j.ejmech.2015.05.010DOI Listing
June 2015

Lewis acid-induced intramolecular access to novel steroidal ring D-condensed arylpyrazolines exerting in vitro cell-growth-inhibitory effects.

Mol Divers 2015 Aug 18;19(3):511-27. Epub 2015 Apr 18.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, 6720, Hungary.

Novel androstenoarylpyrazolines were synthesized stereoselectively by the BF3-induced intramolecular 1,3-dipolar cycloaddition of alkenyl hydrazones obtained from a steroidal D-seco-aldehyde with differently substituted arylhydrazines. The reaction rates were observed to be affected significantly by the electronic character of the substituents on the aromatic moiety. The cyclizations are assumed to follow a stepwise rather than a pure concerted mechanism, to afford arylpyrazolidines as primary products. Spontaneous oxidation of the saturated N,N-heterocycles under the reaction conditions led to pyrazoline derivatives in good to excellent yields. In in vitro antiproliferative studies on a panel of breast cancer cells (MCF7, T47D, MDA-MB-231, and MDA-MB-361), some of the 3-deacetylated cycloadducts exerted marked growth inhibitory activities, with IC(50) values in the range 3.56-9.32 μm, which are comparable to that for the reference agent cisplatin.
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http://dx.doi.org/10.1007/s11030-015-9593-3DOI Listing
August 2015

A click approach to novel D-ring-substituted 16α-triazolylestrone derivatives and characterization of their antiproliferative properties.

PLoS One 2015 18;10(2):e0118104. Epub 2015 Feb 18.

Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged, Hungary.

A simple and efficient synthesis of novel, D-ring substituted estrone derivatives containing a 16α-triazolyl moiety is described. Two epimeric azido alcohols (16α-azido-17α-hydroxy and 16α-azido-17β-hydroxy) of estra-1,3,5(10)-triene-3-methyl ether were prepared, followed by copper(I)-catalyzed azide-alkyne cycloaddition with various terminal alkynes. The steroidal triazoles were obtained in high yields and their activities against three human cancer cell lines (HeLa, MCF7 and A431) were screened. The most effective analogs were submitted to additional experiments in order to characterize their antiproliferative properties. As evidenced by flow cytometry, the selected steroids induced a disturbance in the HeLa cell cycle in a concentration- and exposure-dependent manner, through an increase of the hypodiploid population (subG1) and a cell cycle arrest in the G2/M phase. A noncancerous human fibroblast cell line (MRC5) was used to determine the selectivities of these compounds. Fluorescent microscopy after Hoechst 33258 - propidium iodide (HOPI) double staining revealed nuclear condensation and disturbed cell membrane integrity. The enhanced activities of caspase-3 and caspase-9 without activation of caspase-8 in the treated cells indicated the activation of the intrinsic pathway of apoptosis. The levels of cell cycle regulators (CDK1, cyclin B1/B2 and cdc25B) were decreased and the ratio Bax/Bcl-2 was increased 24 h after the treatment of HeLa cells (determined at an mRNA level by means of an RT-PCR technique). Under the same conditions, two agents elicited substantially increased degrees of phosphorylation of stathmin, as evidenced by Western blotting. The presented results demonstrate that these steroids can be regarded as appropriate structural scaffolds for the design and synthesis of further steroid analogs as innovative drug candidates with good efficacy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118104PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4333823PMC
January 2016

Regio- and stereoselective access to novel ring-condensed steroidal isoxazolines.

Steroids 2014 Sep 10;87:76-85. Epub 2014 Jun 10.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. Electronic address:

Novel 5α-androstanes containing an isoxazoline moiety condensed to ring A or D were efficiently synthetized by 1,3-dipolar cycloadditions of aryl nitrile oxides to steroidal α,β-unsaturated ketones. During the ring closures, regioisomers in which the O terminus of the nitrile oxide dipoles is attached to the β-carbon of the dipolarophile were formed in a stereoselective manner to furnish exclusively 1α,2α- or 15β,16β-condensed heterocycles. The cyclic enone moiety of the six-membered ring A proved to be less reactive than that of the five-membered ring D, but all the reactions were affected significantly by the substitution pattern of the nitrile oxide. 17-Deacetylation of the primary products resulted in aromatization or simultaneous hydroxylation, depending on the base applied for the ring A-fused heterocycles, while retro-Dieckmann-like fragmentation was observed partially or completely for the ring D-fused analogues during 3-deacetylation.
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http://dx.doi.org/10.1016/j.steroids.2014.05.019DOI Listing
September 2014

Synthesis of novel steroidal 16-spiroisoxazolines by 1,3-dipolar cycloaddition, and an evaluation of their antiproliferative activities in vitro.

Mol Divers 2014 Aug 2;18(3):521-34. Epub 2014 Apr 2.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, 6720, Hungary,

Efficient synthesis of novel 16-spiroisoxazolines in the androst-5-ene series was carried out by 1,3-dipolar cycloadditions of different aryl nitrile oxides to 3β-acetoxy-16-methylene-androst-5-en-17-one. During the intermolecular ring closures, the attack of the O terminus of the nitrile oxide dipole from the α side on C-16 predominated for steric reasons permitting the reactions to occur in a regio- and stereoselective manner. The minor isomers in which the angular methyl group on C-13 and the O atom of the isoxazoline heteroring were in the β, β-cis orientation were obtained in a yield of only ~10 %. Moreover, the conversions were influenced to a certain extent by the substituents on the aromatic moiety of the 1,3-dipoles. The stereostructures of the related diastereomers were confirmed by 2D NMR methods. Deacetylation of the primarily formed main products resulted in the corresponding 3β-OH analogs, which were further reduced to furnish 3β, 17β-diols. All of the synthetized compounds were subjected to in vitro pharmacological studies in order to investigate their antiproliferative effects on three malignant human adherent cell lines (HeLa, MCF7, and A431).
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http://dx.doi.org/10.1007/s11030-014-9516-8DOI Listing
August 2014

Anticancer and multidrug resistance-reversal effects of solanidine analogs synthetized from pregnadienolone acetate.

Molecules 2014 Feb 17;19(2):2061-76. Epub 2014 Feb 17.

Laboratory of Functional Genomics, Institute of Genetics, Biological Research Center, Hungarian Academy of Sciences, Temesvári krt. 62, Szeged 6726, Hungary.

A set of solanidine analogs with antiproliferative properties were recently synthetized from pregnadienolone acetate, which occurs in Nature. The aim of the present study was an in vitro characterization of their antiproliferative action and an investigation of their multidrug resistance-reversal activity on cancer cells. Six of the compounds elicited the accumulation of a hypodiploid population of HeLa cells, indicating their apoptosis-inducing character, and another one caused cell cycle arrest at the G2/M phase. The most effective agents inhibited the activity of topoisomerase I, as evidenced by plasmid supercoil relaxation assays. One of the most potent analogs down-regulated the expression of cell-cycle related genes at the mRNA level, including tumor necrosis factor alpha and S-phase kinase-associated protein 2, and induced growth arrest and DNA damage protein 45 alpha. Some of the investigated compounds inhibited the ABCB1 transporter and caused rhodamine-123 accumulation in murine lymphoma cells transfected by human MDR1 gene, expressing the efflux pump (L5178). One of the most active agents in this aspect potentiated the antiproliferative action of doxorubicin without substantial intrinsic cytostatic capacity. The current results indicate that the modified solanidine skeleton is a suitable substrate for the rational design and synthesis of further innovative drug candidates with anticancer activities.
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http://dx.doi.org/10.3390/molecules19022061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271930PMC
February 2014

A facile access to novel steroidal 17-2'-(1',3',4')-oxadiazoles, and an evaluation of their cytotoxic activities in vitro.

Bioorg Med Chem Lett 2014 Mar 31;24(5):1265-8. Epub 2014 Jan 31.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary. Electronic address:

Novel types of 17-exo-heterocycles in the Δ(5) androstene series carrying an 1,3,4-oxadiazole moiety were efficiently synthesized via aldehyde N-acylhydrazone intermediates, obtained from the microwave-assisted condensation of 3β-hydroxy- or 3β-acetoxyandrost-5-ene-17β-carbaldehyde with different acylhydrazides. The subsequent phenyl iodonium diacetate-induced oxidative cyclization proceeded under mild conditions. The synthesized compounds were subjected to in vitro pharmacological studies to investigate their antiproliferative activities on four malignant adherent cell lines (HeLa, MCF7, A2780 and A431), and exhibited the highest potency against HeLa cells, some of them revealing action comparable to that of the reference agent cisplatin.
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http://dx.doi.org/10.1016/j.bmcl.2014.01.069DOI Listing
March 2014

An efficient approach to novel 17-5'-(1',2',4')-oxadiazolyl androstenes via the cyclodehydration of cytotoxic O-steroidacylamidoximes, and an evaluation of their inhibitory action on 17α-hydroxylase/C₁₇,₂₀-lyase.

Eur J Med Chem 2013 22;70:649-60. Epub 2013 Oct 22.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.

Novel 17-exo-oxadiazoles in the androst-5-ene series were efficiently synthesized in a two-step sequence via the corresponding O-acylamidoxime intermediates (obtained from steroidal 17-carboxylic acids and amidoximes in the presence of coupling reagent), which then underwent tetrabutylammonium fluoride-induced cyclocondensation under mild reaction conditions. The synthesized compounds were subjected to in vitro pharmacological studies to investigate their inhibitory effect on rat testicular C₁₇,₂₀-lyase and their antiproliferative action on four malignant human adherent cell lines (HeLa, MCF7, A2780 and A431). One of the oxadiazolyl derivatives proved to exert significant enzyme-inhibitory action (IC₅₀ = 0.60 μM), while some of the isolated O-acylated amidoxime intermediates displayed high cytotoxic activities on all examined cell lines, with IC₅₀ values in the range 0.22-3.94 μM.
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http://dx.doi.org/10.1016/j.ejmech.2013.10.038DOI Listing
September 2014

Rare case of a dislocated spleen in a patient with B-cell lymphoma.

J Clin Oncol 2013 Apr 18;31(12):e206-7. Epub 2013 Mar 18.

Department of Hematology, Klinikum Schwabing, Koelner Platz 1, 80804 Munich, Germany.

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http://dx.doi.org/10.1200/JCO.2012.44.4877DOI Listing
April 2013