RESUMO
An androstane (17ß-hydroxy-17α-picolyl-androst-5-en-3ß-yl-acetate (derivative A)) cancer inhibitor was successfully captured in a carrier made of nano-sized hydroxyapatite (HAp) coated with chitosan-PLGA polymer blends (Ch-PLGA). In our previous studies, we demonstrated that it was convenient to use spherical HAp/Ch-PLGA carriers as vehicles to target the lungs following intravenous administration. In this study, we used emulsification and subsequent freeze-drying to load the spherical HAp/Ch-PLGA carriers with varying contents of the derivative A, in order to examine the selective toxicity towards cancerous/healthy lung cells. The XRD and FT-IR techniques confirmed the drug loading process, and the content of the poorly water soluble derivative A was estimated directly via the DSC technique. The particles were spherical in shape with the d50 distribution varying between 167 and 231â¯nm, whereas the content of the derivative A ranged from 6.5 to 19.3â¯wt%. Cell-selective cytotoxicity was examined simultaneously on two cell lines: human lung carcinoma (A549 ATCC CCL 185) and human lung fibroblasts (MRC-5 ATCC CCL 171). All particles exhibited nearly three times larger cytotoxicity towards cancer cells (A549) than towards healthy cells (MRC5), where the particles with the derivative A content of 6.5â¯wt% allowed for the viability of healthy cells >80%. Ninety-six hours after the treatment of cells with particles with different contents of derivative A (after incubation and recovery), recovery was faster in damaged healthy cells than in cancerous cells.
Assuntos
Androstanos/química , Quitosana/química , Durapatita/química , Ácido Láctico/química , Nanocompostos/química , Ácido Poliglicólico/química , Células A549 , Androstanos/metabolismo , Androstanos/farmacologia , Varredura Diferencial de Calorimetria , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Humanos , Neoplasias Pulmonares/patologia , Microscopia de Força Atômica , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
Physicochemical characterization of steroid analogs (triazole, tetrazole, toluenesulfonylhydrazide, nitrile, dinitrile and dione) is considered to be a very important step in further drug selection. This study applies to the determination of lipophilicity of previously synthesized steroid derivatives using reversed-phase high-performance liquid chromatography (RP HPLC). Chemometric aspect of chromatographic lipophilicity is given throughout multiple linear regression (MLR) quantitative structure-retention relationships (QSRR) approach. Minimal inhibitory concentration (MIC) is determined for two steroid derivatives possessing antimicrobial activity against Staphylococcus aureus. Molecular docking study was performed in order to identify the compound with the most promising potential as human cytochrome P450 CYP17A1inhibitor. Identified 3ß-hydroxyandrost-5-eno[16,17-d]-1,2,3-triazole (I.2.) could be recommended for further trials for anticancer drugs and subjected to the absorption, distribution, metabolism, excretion and toxicity (ADMET) evaluation.
Assuntos
Anti-Infecciosos , Antineoplásicos , Esteroides , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Linhagem Celular Tumoral , Cromatografia de Fase Reversa/métodos , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Humanos , Modelos Lineares , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroides/química , Esteroides/farmacologiaRESUMO
The present paper deals with chromatographic lipophilicity determination of twenty-nine selected steroid derivatives using reversed-phase high-performance liquid chromatography (RP HPLC) combined with two mobile phase, acetonitrile-water and methanol-water. Chromatographic behavior of four groups (triazole and tetrazole, toluenesulfonylhydrazide, nitrile and dinitrile and dione) of selected steroid derivatives was studied. Investigated compounds were grouped using principal component analysis (PCA) according to their logk values for both mobile phases. Grouping was in the very good accordance with the polarity and lipophilicity of the investigated compounds. QSRR (quantitative structure-retention relationship) approach was used to model chromatographic lipophilicity behavior using molecular descriptors. Modeling was performed using linear regression (LR) and multiple linear regression (MLR) methods. The most influential molecular descriptors were lipophilicity descriptors that are important for molecules ability to pass through biological membranes and geometrical descriptors. All established LR-QSRR and MLR-QSRR models were statistically validated by standards, cross- and external validation parameters as well as with two graphical methods. According to all these assessments, MLR models were better for chromatographic lipophilicity prediction. It was shown that chromatographic systems with methanol-water were better for modeling of logk than systems with acetonitrile-water, as well as the systems that contained lower volume fractions of organic component in mobile phase. Modeling was performed in order to obtain lipophilicity profiles of investigated compounds as future drug candidates of biomedical importance.
Assuntos
Cromatografia de Fase Reversa/métodos , Modelos Moleculares , Esteroides/análise , Esteroides/química , Cromatografia Líquida de Alta Pressão/métodos , Análise de Componente Principal/métodos , Relação Quantitativa Estrutura-AtividadeRESUMO
In an earlier study we demonstrated that hydroxyapatite nanoparticles coated with chitosan-poly(d,l)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous injection into mice. In this study we utilize an emulsification process and freeze drying to load the composite HAp/Ch-PLGA particles with 17ß-hydroxy-17α-picolyl-androst-5-en-3ß-yl-acetate (A), a chemotherapeutic derivative of androstane and a novel compound with a selective anticancer activity against lung cancer cells. 1H NMR and 13C NMR techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The thermogravimetric and differential thermal analyses coupled with mass spectrometry were used to assess the thermal degradation products and properties of A-loaded HAp/Ch-PLGA. The loading efficiency, as indicated by the comparison of enthalpies of phase transitions in pure A and A-loaded HAp/Ch-PLGA, equaled 7.47wt.%. The release of A from HAp/Ch-PLGA was sustained, neither exhibiting a burst release nor plateauing after three weeks. Atomic force microscopy and particle size distribution analyses were used to confirm that the particles were spherical with a uniform size distribution of d50=168nm. In vitro cytotoxicity testing of A-loaded HAp/Ch-PLGA using MTT and trypan blue dye exclusion assays demonstrated that the particles were cytotoxic to the A549 human lung carcinoma cell line (46±2%), while simultaneously preserving high viability (83±3%) of regular MRC5 human lung fibroblasts and causing no harm to primary mouse lung fibroblasts. In conclusion, composite A-loaded HAp/Ch-PLGA particles could be seen as promising drug delivery platforms for selective cancer therapies, targeting malignant cells for destruction, while having a significantly lesser cytotoxic effect on the healthy cells.
Assuntos
Androstanos/química , Antineoplásicos/química , Quitosana/química , Durapatita/química , Ácido Láctico/química , Ácido Poliglicólico/química , Células A549 , Androstanos/farmacocinética , Androstanos/farmacologia , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Liberação Controlada de Fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos Endogâmicos C57BL , Microscopia de Força Atômica , Microscopia Confocal , Nanopartículas/química , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Espectroscopia de Infravermelho com Transformada de Fourier , TermogravimetriaRESUMO
Biological investigation was conducted to study in vitro antiproliferative and pro-apoptotic potential of selected 17α-picolyl and 17(E)-picolinylidene androstane derivatives. The antiproliferative impact was examined on six human tumor cell lines, including two types of breast (MCF-7 and MDA-MB-231), prostate (PC3), cervical (HeLa), colon (HT 29) and lung cancer (A549), as well as one normal fetal lung fibroblasts cell line (MRC-5). All derivatives selectively decreased proliferation of estrogen receptor negative MDA-MB-231 breast cancer cells after 48 h and 72 h treatment and compounds showed time-dependent activity. We used this cell line to investigate cell cycle modulation and apoptotic cell death induction by flow cytometry, expression of apoptotic proteins by Western blot and apoptotic morphology by visual observation. Tested androstane derivatives affected the cell cycle distribution and induced apoptosis and necrosis. Compounds had different and specific mode of action, depending on derivative type and exposure time. Some compounds induced significant apoptosis measured by Annexin V test compared to reference compound formestane. Higher expression of pro-apoptotic BAX, downregulation of anti-apoptotic Bcl-2 and cleavage of PARP protein were confirmed in almost all treated samples, but the lack of caspase-3 activation suggested the induction of apoptosis in caspase-independent manner. More cells with apoptotic morphology were observed in samples after prolonged treatment. Structure-activity relationship analysis was performed to find correlations between the structure variations of investigated derivatives and observed biological effects. Results of this study showed that some of the investigated androstane derivatives have good biomedical potential and could be candidates for anticancer drug development.
Assuntos
Androstanos/química , Androstanos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Caspase 3/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células HT29 , Células HeLa , Humanos , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Proteína X Associada a bcl-2/metabolismoRESUMO
The heterocyclic ring at C-17 position of the androstane compounds plays an important role in biological activity. The aim of the present study was to synthesize and evaluate potential antitumor activity of different A-modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives. In several synthetic steps, novel derivatives bearing the hydroximino, nitrile or lactame functions in A-ring were synthesized and characterized according to the spectral data, by mass analysis as well as XRD analysis (compounds 6, 13 and 15). The structurally most promising compounds 6, 11-17 were investigated as antitumor agents. The in vitro antiproliferative activity was evaluated against six human cancer cell lines: estrogen receptor negative (ER-) breast adenocarcinoma (MDA-MB-231); estrogen receptor positive (ER+) breast adenocarcinoma (MCF-7); prostate cancer (PC-3); human cervical carcinoma (HeLa); lung adenocarcinoma (A549) and colon adenocarcinoma (HT-29) using MTT assay. The results of the 48h incubation time in vitro tests showed that compound 15 was the most effective against PC-3 (IC50 6.6µM), compound 17 against MCF-7 (IC50 7.9µM) cells, while compound 16 exhibited strong antiproliferative effect against both, MCF-7 (IC50 1.7µM) and PC-3 (IC50 8.7µM) cancer cells. It was also found that compounds 16 and 17 induced apoptosis in MCF-7 cells (dicyano derivative 17 stronger then dioxime 16 and reference formestane), with no distinct changes in the cell cycle of MCF-7 cells.
Assuntos
Androstanos/síntese química , Antineoplásicos/síntese química , Androstanos/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Células HT29 , Células HeLa , Humanos , Células MCF-7 , Relação Estrutura-Atividade , Difração de Raios XRESUMO
17α-hydroxylase-C17,20-lyase (P45017α) is a key regulator enzyme of the steroid hormone biosynthesis in both the adrenals and the testes. Inhibition of this enzyme can block androgen synthesis in an early step, and may thereby be useful in the treatment of several androgen-dependent diseases. We developed radio-substrate in vitro incubation methods for the determination of the distinct 17α-hydroxylase and C17,20-lyase activities of the enzyme using rat testicular homogenate as enzyme source. With this method we have studied the inhibiting activity of selected steroidal picolyl and picolinylidene compounds. Tests revealed a substantial inhibitory action of the 17-picolinyliden-androst-4-en-3-one compound.
Assuntos
Esteroide 17-alfa-Hidroxilase/metabolismo , Esteroides/farmacologia , Animais , Masculino , Ratos , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Testículo/efeitos dos fármacos , Testículo/enzimologiaRESUMO
We report the synthesis of steroidal 16,17-seco-16,17a-dinitriles and investigate their antitumor cell properties. Compounds were evaluated for anticancer potential by in vitro antiproliferation studies, molecular docking and virtual screening. Several compounds inhibit the growth of breast and prostate cancer cell lines (MCF-7, MDA-MB-231 and PC3), and/or cervical cancer cells (HeLa). Supporting this, molecular docking predicts that steroidal 16,17-seco-16,17a-dinitriles could bind with high affinity to multiple molecular targets of breast and prostate cancer treatment (aromatase, estrogen receptor α, androgen receptor and 17α-hydroxylase) facilitated by D-seco flexibility and nitrile-mediated contacts. Thus, 16,17-seco-16,17a-dinitriles may be useful for the design of inhibitors of multiple steroidogenesis pathways. Strikingly, 10, a 1,4-dien-3-on derivative, displayed selective submicromolar antiproliferative activity against hormone-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cells (IC50 0.52, 0.11µM, respectively). Ligand-based 3D similarity searches suggest AKR1C, 17ß-HSD and/or 3ß-HSD subfamilies as responsible for this antiproliferative activity, while fast molecular docking identified AKR1C and ERß as potential binders-both targets in the treatment of hormone-independent breast cancers.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Nitrilas/química , Nitrilas/farmacologia , Esteroides/química , Esteroides/farmacologia , Antineoplásicos/síntese química , Aromatase/metabolismo , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Receptor alfa de Estrogênio/metabolismo , Feminino , Células HeLa , Humanos , Masculino , Simulação de Acoplamento Molecular , Nitrilas/síntese química , Próstata/efeitos dos fármacos , Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Esteroides/síntese químicaRESUMO
A convenient microwave assisted solvent free synthesis as well as conventional synthesis of salicyloyloxy and 2-methoxybenzoyloxy androstane and stigmastane derivatives 7-19 from appropriate steroidal precursors 1-6 and methyl salicylate is reported. The microwave assisted synthesis in most cases was more successful regarding reaction time and product yields. It was more environmentally friendly too, compared to the conventional method. The antioxidant activity and cytotoxicity of the synthesized derivatives were evaluated in a series of in vitro tests, as well as their inhibition potency exerted on hydroxysteroid dehydrogenase enzymes (Δ(5)-3ßHSD, 17ßHSD2 and 17ßHSD3). All of the tested compounds were effective in OH radical neutralization, particularly compounds 9, 11 and 14, which exhibited about 100-fold stronger activity than commercial antioxidants BHT and BHA. In DPPH radical scavenging new compounds were effective, but less than reference compounds. 2-Methoxybenzoyl ester 10 exhibited strong cytotoxicity against MDA-MB-231 cells. Most compounds inhibited growth of PC-3 cells, where salicyloyloxy stigmastane derivative 15 showed the best inhibition potency. Compounds 9, 10 and 11 were the best inhibitors of 17ßHSD2 enzyme. X-ray structure analysis and molecular mechanics calculations (MMC) were performed for the best cytotoxic agents, compounds 10 and 15. A comparison of crystal and MMC structures of compounds 10 and 15 revealed that their molecules conformations are stable even after releasing of the influence of crystalline field and that the influence of crystal packing on molecular conformation is not predominant.
Assuntos
Androstanos/síntese química , Sequestradores de Radicais Livres/síntese química , Éteres de Hidroxibenzoatos/síntese química , Salicilatos/síntese química , Androstanos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Sequestradores de Radicais Livres/farmacologia , Humanos , Éteres de Hidroxibenzoatos/farmacologia , Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Concentração Inibidora 50 , Micro-Ondas , Conformação Molecular , Salicilatos/farmacologiaRESUMO
The rational preselection of drug candidates includes also correlation between physico-chemical properties (lipophilicity, as the key one) and pharmacokinetic properties, as well as pharmacodynamic activity. Lipophilicity can be determined alternatively by chromatographic methods. Chromatographic behavior of nineteen newly synthesized derivatives of 16-cyano-16,17-seco-5-androstene has been studied by reversed-phase and normal-phase thin-layer chromatography (RP- and NP-TLC). Commercial plates RP-C18-HPTLC and water-dioxane and water-acetonitrile, as well as Lux(®) silica gel plates and toluene-dioxane and toluene-acetonitrile mixtures with different volume fractions of the solvents were used. Retention constants RM(0) and C0 for each compound were determined and correlated with (i) theoretical log P values and (ii) pharmacokinetic predictors determined in silico. Significant linear relationship was found between RP TLC retention constants, RM(0), and computational logP values as well as between NP TLC retention constants, C0, and logP. Lipophilicity values for the analytes, determined by RP TLC and NP TLC, were also correlated with computer calculated absorption constants, affinity for plasma proteins, volume of distribution and logarithm of blood-brain permeation. Significant linear relationships were obtained. These relations were further improved by introducing other regressors, as molecular size descriptors (molecular mass and/or volume) and a molecular polarity descriptor (total polar surface area). Retention parameters, RM(0) and C0, are recommended for lipophilicity expression of analyzed compounds. In silico pharmacokinetic descriptors for the analytes can be expressed as function of the lipophilicity determined by chromatographic methods, the size and the polarity of the molecules expressed as molecular mass/volume and total polar surface area. The analyzed seco-androstene derivatives have adequate lipophilicity which should provide druglikeness and good pharmacokinetic profiles and they can be recommended for further studies in which their biological activity would be examined.
Assuntos
Androstenos/sangue , Androstenos/química , Absorção , Acetonitrilas/química , Androstenos/análise , Barreira Hematoencefálica , Cromatografia Líquida , Cromatografia em Camada Fina , Dioxanos/química , Humanos , Modelos Lineares , Tamanho da Partícula , Permeabilidade , Relação Quantitativa Estrutura-Atividade , Solventes , Tolueno/química , Água/químicaRESUMO
New 17-picolyl and 17-picolinylidene androstane derivatives, 3-10, 15, 18, 19, 22 and 23, were synthesized starting from 17α-picolyl-androst-5-en-3ß,17ß-diol (1) and 17(Z)-picolinylidene-androst-5-en-3ß-ol (2). Reaction of 1 with m-chloroperoxybenzoic acid gives 5α,6α-epoxy N-oxide derivative 3, or, with Jones reagent, 3,6-dione derivative 4; while 17α-picolyl-androst-5-en-3ß,4α,17ß-triol (5) or 3ß,4ß,17ß-triol (6) derivatives are obtainable from 1 using SeO(2) in dioxane. Base-catalyzed tosyl group elimination from 7 or 9 affords AB conjugated derivatives 8 and 10. Oppenauer oxidation of 1 and 2 yields 4-en-3-one derivatives 11 and 12, which, with H(2)O(2) in 4 M NaOH, affords 4α,5α and 4ß,5ß-epoxides 13, 14, 16 and 17. New 4-methoxy-3-keto derivatives 15 and 18 were obtained from 13 and 14, or, with methanol in 4 M NaOH, from 16 and 17. Reduction of 11 with NaBH(4) gives 22, which was then acetylated to obtain 23. All new derivatives were screened for antitumor activity against human breast adenocarcinoma ER+, MCF-7; human breast adenocarcinoma ER-, MDA-MB-231; prostate cancer AR-, PC-3; human cervix carcinoma, HeLa; and colon cancer, HT-29 cells; as well as one human non-tumor cell line, MRC-5. Compounds 3, 5, 6, 8, 10, 18, 19 and 22 exhibited significant antitumor activity against MDA-MB-231 breast cancer cells; while 5, 6 and 10 also showed strong cytotoxicity against HT-29. Only compound 19 exhibited significant activity against MCF-7 breast cancer cells. No compounds displayed cytotoxicity against non-tumor MRC-5 cells.
Assuntos
Androstanos/síntese química , Androstanos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Androstanos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Técnicas de Química Sintética , Humanos , Concentração Inibidora 50RESUMO
Starting from 3beta-hydroxy-17-oxo-16,17-secoandrost-5-ene-16-nitrile (1), the new 16,17-secoandrostane derivatives 4-9 were synthesized. On the other hand, 3beta-hydroxy-17-oxa-D-homoandrost-5-ene-16-one (10) yielded the new d-homo derivatives 12, 13 and 15. In vitro antiproliferative activity of selected compounds against three tumor cell lines (human breast adenocarcinoma ER+, MCF-7, human breast adenocarcinoma ER-, MDA-MB-231, prostate cancer AR-, PC-3, and normal fetal lung fibroblasts, MRC-5) was evaluated. Compounds 3 and 12 showed strong antiproliferative activity against PC-3 cells, the IC(50) values being 2 microM and 0.55 microM, respectively. Compounds 6 (10 microM) and 14 (9 microM) showed moderate activity against MDA-MB-231 cells. The synthesized compounds 1-3, 5-8, 10 and 12-15 were not toxic to normal fetal lung fibroblasts cells, MRC-5.
Assuntos
Androstanos/síntese química , Androstanos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Androstanos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50RESUMO
The chromatographic behavior of seven 16-oximino derivatives of 3beta-hydropxy-5-androstene have been investigated using the normal-phase (NP) HPTLC chromatographic mode of the type silica-non-polar diluent (benzene)-polar modifier (acetonitrile, ethyl acetate, or dioxane). The linear relationship between the retention constants (R(M)) and the logarithm of the organic modifier content in the mobile phase allowed for the calculation of R(M)0 values. The influence of substituent in the molecule on extrapolated retention data is discussed. To better understand the retention mechanism in the separation of androstene compounds, the functional group contributions (tauX) were compared with Hansch substituent constants (pi). An attempt to quantitate the lipophilicity of the investigated compounds using normal phase thin-layer chromatographic R(M)0 value was made. Also, the relative lipophilicity values determined previously by RPC as well as activity were compared with NPC data.
Assuntos
Androstenos/química , Androstenos/síntese química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia em Camada Fina/métodos , Acetatos/química , Acetonitrilas/química , Cromatografia , Temperatura Alta , Modelos Químicos , Modelos Moleculares , Peso Molecular , Relação Quantitativa Estrutura-AtividadeRESUMO
The title compounds, C22H31NO3 and C20H27NO2, have similar conformations except in the molecular geometry and the bonding of two of the rings. These differences lead to marked differences in the biological activities of these compounds. Molecules of both compounds are linked by weak C-H...O hydrogen bonds in the crystal structures.
Assuntos
Androstenos/química , Inibidores da Aromatase/química , Nitrilas/química , Androstenos/farmacologia , Inibidores da Aromatase/farmacologia , Cristalografia por Raios X , Ligação de Hidrogênio , Conformação Molecular , Estrutura Molecular , Nitrilas/farmacologia , Relação Estrutura-AtividadeRESUMO
D-Homo derivatives in the androstane and estrane series, 12-19, were synthesized by a fragmentation-cyclization reaction of 16-oximino-17-hydroxy-17-substituted derivatives 3-9, or by cyclization of the corresponding D-seco derivatives 20-26. The structures were confirmed by X-ray analysis of compounds 12 and 16. Preliminary assessment of inhibitory effects of D-homo derivatives from androstane series towards aromatase, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17 alpha-hydroxylase/C17-20 lyase (P450c17) and 17 beta-HSD indicated much lower inhibitory potential compared to previously tested activity of another type of D-modified steroids, namely D-seco derivatives. Also, assessment of potential antiestrogenic activity of derivatives from estrane series showed absence of such an activity.
Assuntos
Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Homosteroides/síntese química , 17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , 3-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Androstenos/química , Androstenos/farmacologia , Animais , Inibidores da Aromatase , Inibidores Enzimáticos/farmacologia , Estranos/química , Estranos/farmacologia , Moduladores de Receptor Estrogênico/síntese química , Moduladores de Receptor Estrogênico/química , Moduladores de Receptor Estrogênico/farmacologia , Homosteroides/química , Homosteroides/farmacologia , Células Intersticiais do Testículo/enzimologia , Masculino , Estrutura Molecular , Ratos , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The title molecule, C(26)H(30)O(3), shows a novel chemical rearrangement of the substituents at position 17, i.e. an alpha-orientation of the hydroxy group and a beta-orientation of the bulky benzyl moiety. The packing arrangement consists of coils formed by O(2)...O(3) hydrogen bonds along the c axis. The compound shows complete loss of oestrogenic activity, and neither does it exhibit an antagonistic effect.