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1.
J Steroid Biochem Mol Biol ; 233: 106362, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37451557

RESUMO

Cancer remains a major health concern worldwide. The most frequently diagnosed types of cancer are caused by abnormal production or action of steroid hormones. In the present study, the synthesis and structural characterization of new heterocyclic androstane derivatives with D-homo lactone, 17α-(pyridine-2''-ylmethyl) or 17(E)-(pyridine-2''-ylmethylidene) moiety are presented. All compounds were evaluated for their anti-proliferative activity against HeLa cervical cancer cell line and non-cancerous kidney MDCK cells, where A-homo lactam compound 9A showed the greatest selectivity. Based on in vitro binding assays, N-formyl lactam compound 18 appeared to be the strong and isoform-selective ligand for ERα, while compound 9A displayed binding affinity for the GR-LBD, but also inhibited aldo-keto reductase 1C4 enzyme. Out of four selected compounds, methylpyrazolo derivative 13 showed potential for aromatase binding, while in silico studies provided insight into experimentally confirmed protein-ligand interactions.


Assuntos
Androstanos , Antineoplásicos , Humanos , Ligantes , Androstanos/farmacologia , Androstanos/química , Esteroides/metabolismo , Lactamas/farmacologia , Relação Estrutura-Atividade , Proliferação de Células , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral
2.
RSC Med Chem ; 14(2): 341-355, 2023 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-36846371

RESUMO

Aldo-keto reductase 1C3 (AKR1C3) catalyzes the reduction of androstenedione to testosterone and reduces the effectiveness of chemotherapeutics. AKR1C3 is a target for treatment of breast and prostate cancer and AKR1C3 inhibition could be an effective adjuvant therapy in the context of leukemia and other cancers. In the present study, steroidal bile acid fused tetrazoles were screened for their ability to inhibit AKR1C3. Four C24 bile acids with C-ring fused tetrazoles were moderate to strong AKR1C3 inhibitors (37-88% inhibition), while B-ring fused tetrazoles had no effect on AKR1C3 activity. Based on a fluorescence assay in yeast cells, these four compounds displayed no affinity for estrogen receptor-α, or the androgen receptor, suggesting a lack of estrogenic or androgenic effects. A top inhibitor showed specificity for AKR1C3 over AKR1C2, and inhibited AKR1C3 with an IC50 of ∼7 µM. The structure of AKR1C3·NADP+ in complex with this C-ring fused bile acid tetrazole was determined by X-ray crystallography at 1.4 Å resolution, revealing that the C24 carboxylate is anchored to the catalytic oxyanion site (H117, Y55); meanwhile the tetrazole interacts with a tryptophan (W227) important for steroid recognition. Molecular docking predicts that all four top AKR1C3 inhibitors bind with nearly identical geometry, suggesting that C-ring bile acid fused tetrazoles represent a new class of AKR1C3 inhibitors.

3.
Beilstein J Org Chem ; 17: 2611-2620, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34760027

RESUMO

A practical and high-yielding Schmidt reaction for the synthesis of fused tetrazoles from bile acid precursors was developed. Mild reaction conditions using TMSN3 instead of hydrazoic acid as an azide source produced good yields of the desired tetrazoles. These conditions could be applied to other steroidal precursors. Additionally, an improved methodology for the synthesis of different ketone and enone precursors from cholic acid, deoxycholic acid, and chenodeoxycholic acid was established. Newly obtained tetrazole derivatives were characterized by NMR and X-ray diffraction spectroscopy. In a number of cases, preliminary antiproliferative tests of new compounds showed strong and selective activity towards certain tumor cell lines.

4.
Phytochemistry ; 192: 112958, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34560578

RESUMO

Wild chervil (Anthriscus sylvestris) is a widespread, wild-growing herbaceous plant from Apiaceae family, known for high content of lignans related to podophyllotoxin, and thus representing a promising new source for their industrial isolation. The data on detailed chemical profile of A. sylvestris lignans are still lacking. By combining fractionation with non-targeted LC-DAD-ESI-MS/MS metabolite profiling, we have identified, fully or tentatively, 46 lignans, 12 of which were never reported in A. sylvestris and 19 in any biological source. The dominant lignans were found to be nemerosin, yatein, deoxypodophyllotoxin, podophyllotoxin, podophyllotoxone and guayadequiol. In addition to well-known dibenzylbutyrolactones, aryltetralins and 7-oxygenated aryltetralins, we found several oxygenated lignan classes previously undescribed in A. sylvestris - 7-hydroxy, 7-oxo and 8-hydroxydibenzylbutyrolactones, a 7'-oxotetrahydrofuran and a 7-hydroxyarylnaphthalene. To facilitate future rapid classification and identification of lignans in raw extracts, UV, MS and NMR spectral features of different lignan classes are described.


Assuntos
Apiaceae , Lignanas , Extratos Vegetais , Podofilotoxina , Espectrometria de Massas em Tandem
5.
RSC Adv ; 11(59): 37449-37461, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-35496404

RESUMO

Steroid anticancer drugs are the focus of numerous scientific research efforts. Due to their high cytotoxic effects against tumor cells, some natural or synthetic steroid compounds seem to be promising for the treatment of different classes of cancer. In the present study, fourteen novel O-alkylated oxyimino androst-4-ene derivatives were synthesized from isomerically pure 3E-oximes, using different alkylaminoethyl chlorides. Their in vitro cytotoxic activity was evaluated against eight human cancer cell lines, as well as against normal fetal lung (MRC-5) and human foreskin (BJ) fibroblasts, to test the efficiency and selectivity of the compounds. Most derivatives displayed strong activity against malignant melanoma (G-361), lung adenocarcinoma (A549) and colon adenocarcinoma (HT-29) cell lines. Angiogenesis was assessed in vitro using migration scratch and tube formation assays on HUVEC cells, where partial inhibition of endothelial cell migration was observed for the 17α-(pyridin-2-yl)methyl 2-(morpholin-4-yl)ethyl derivative. Among the compounds that most impaired the growth of lung cancer A549 cells, the (17E)-(pyridin-2-yl)methylidene derivative bearing a 2-(pyrrolidin-1-yl)ethyl substituent induced significant apoptosis in these cells. In combination with low cytotoxicity toward normal MRC-5 cells, this molecule stands out as a good candidate for further anticancer studies. In addition, in vitro investigations against cytochrome P450 enzymes revealed that certain compounds can bind selectively in the active sites of human steroid hydroxylases CYP7, CYP17A1, CYP19A1 or CYP21A2, which could be important for the development of novel activity modulators of these enzymes and identification of possible side effects.

6.
J Ethnopharmacol ; 264: 113266, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32810621

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Bile traditionally was used in wound healing, having erodent, antioxidant and antimicrobial potential. Acinetobacter baumannii is a frequent etiological agent of wound infections, exhibiting high level of resistance to conventional antibiotics. AIM OF THE STUDY: To determine the effect of selected bile acid sodium salts and their 3-dehydro (i.e. 3-oxo) derivatives, as well as their combinations with commercial antibiotics against A. baumanniia, to confirm bile ethnopharmacological application in wound healing from aspect of microbiology. MATERIALS AND METHODS: The sensitivity of reference and multidrug resistant (MDR) A. baumannii strains to bile salts, their derivatives and conventional antibiotics were examined by a microtiter plate method. The interaction of bile salts/derivatives and antibiotics was examined by a checkerboard method and time kill curve method. The interaction of bile salts with ciprofloxacin in terms of micelles formation was examined by DOSY NMR technique. RESULTS: The bile salts sodium deoxycholate (Na-DCA) and sodium chenodeoxycholate (Na-CDCA), as well as their derivatives sodium 3-dehydro-deoxycholate (Na-3DH-DCA) and sodium 3-dehydro-chenodeoxycholate (Na-3DH-CDCA), potentiate antibiotic activity and resensitize A. baumannii. The bile salts and their derivatives enhance A. baumannii sensitivity to antibiotics, particularly those that should penetrate cell to exhibit activity. The sodium salts of bile acid derivatives, namely Na-3DH-DCA and Na-3DH-CDCA, showed synergy against both reference and MDR strain in combination with ciprofloxacin or gentamicin, while synergy with gentamicin was obtained in all combinations, regardless of bile salt type and bacterial strains. The synergy with Na-3DH-CDCA was further confirmed by the time-kill curve method, as bacterial number decreased after 12 h. NMR experiment revealed that this bile salt derivative and ciprofloxacin form co-aggregates when bile salts concentration was higher than critical micelle concentrations (CMC), which indicate the possibility that bile salts enhance ciprofloxacin cell penetration by membrane destabilization, contributing to the synergy. CONCLUSION: The synergistic interactions between bile salts or derivatives with ciprofloxacin and particularly gentamicin represent a promising strategy for the treatment of A. baumannii wound infections.


Assuntos
Acinetobacter baumannii/efeitos dos fármacos , Anti-Infecciosos/administração & dosagem , Ácidos e Sais Biliares/administração & dosagem , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Acinetobacter baumannii/fisiologia , Ácidos e Sais Biliares/isolamento & purificação , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/fisiologia , Sinergismo Farmacológico , Humanos , Testes de Sensibilidade Microbiana/métodos
7.
Steroids ; 157: 108596, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32068078

RESUMO

This paper describes the synthesis of a new A-homo lactam D-homo lactone androstane derivative from dehydroepiandrosterone. To evaluate the impact of the introduction of nitrogen in the parental scaffold on biological activity, a new androstane enamide-type lactam derivative was prepared and characterized. The new compound as well as starting compounds were screened for cytotoxic, anti-angiogenic and anti-inflammatory activities using several human cancer cell lines (MCF-7, MDA-MB-231, PC3, CEM, G-361, HeLa), endothelial (HUVEC) and non-tumour (MRC-5 and BJ) cell lines. Strong cytotoxic and anti-inflammatory activity with a broad therapeutical window was demonstrated by the A-homo lactam D-homo lactone androstane derivative. The induction of apoptosis in treated PC3 cultures was confirmed using apoptotic morphology screening and a fluorescent double-staining method. New A-homo lactam D-homo lactone androstane derivative induced apoptosis more than the tested reference compounds, Formestane and Doxorubicin. An in silico ADME analysis showed that the compounds possess drug-like properties.


Assuntos
Androstanos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Selectina E/antagonistas & inibidores , Lactonas/farmacologia , Androstanos/química , Androstanos/isolamento & purificação , Anti-Inflamatórios/química , Anti-Inflamatórios/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Selectina E/biossíntese , Humanos , Lactonas/química , Lactonas/isolamento & purificação , Conformação Molecular , Imagem Óptica , Relação Estrutura-Atividade
8.
Biochim Biophys Acta ; 1850(7): 1345-53, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25840355

RESUMO

BACKGROUND: Bile salts are steroidal biosurfactants. Micellar systems of bile salts are not only important for solubilization of cholesterol, but they also interact with certain drugs thus changing their bioavailability. METHODS: The number-average aggregation numbers (n¯) are determined using the Moroi-Matsuoka-Sugioka thermodynamic method. Critical micellar concentrations were determined by spectrofluorometric method using pyren and by surface tension measurements. RESULTS: Micelles of ethylidene derivatives possess the following values for n¯: 7-Eth-D (n¯=11 (50 mM)-n¯=14.8 (100 mM)); 12-Ox-7-Eth-L (n¯≈8.8, without concentration dependence) and 7,12-diOx-3-Eth-Ch (n¯≈2.9, without concentration dependence). In the planes n¯-ln k and ln CMC-ln k derivative 7-Eth-D is outlier in respect to hydrophobic linear congeneric groups. CONCLUSION: Gibbs energy of formation for 7-Eth-D anion micelles in addition to the Gibbs energy of hydrophobic interactions consists excess Gibbs energy (GE) from hydrogen bond formation between building blocks of micelles. Gibbs energy of formation for 7,12-diOx-3-Eth-Ch and 12-Ox-7-Eth-L anion micelle is determined by the Gibbs energy of hydrophobic interactions. Relative increase in hydrophobicity and aggregation number for ethylidene derivatives is larger when ethylidene group is introduced from the C7 lateral side of steroidal skeleton then it is when ethylidene group is on C3 carbon. GENERAL SIGNIFICANCE: Position of outlier towards hydrophobic congeneric groups from n¯-ln k and ln CMC-ln k planes indicates the existence of excess Gibbs energy (GE) which is not of hydrophobic nature (formation of hydrogen bonds). For the bile salt micelles to have GE (formation of secondary micelles) it is necessary that steroidal skeleton possesses C3-α-(e)-OH and C12-α-(a)-OH groups.


Assuntos
Ácidos e Sais Biliares/química , Colesterol/química , Micelas , Esteroides/química , Algoritmos , Ácidos e Sais Biliares/síntese química , Ácido Desoxicólico/síntese química , Ácido Desoxicólico/química , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Modelos Químicos , Estrutura Molecular , Solubilidade , Espectrometria de Fluorescência , Esteroides/síntese química , Tensão Superficial , Termodinâmica , Ácido Ursodesoxicólico/síntese química , Ácido Ursodesoxicólico/química
9.
ScientificWorldJournal ; 2014: 152972, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25685831

RESUMO

Bile salt aggregates are promising candidates for drug delivery vehicles due to their unique fat-solubilizing ability. However, the toxicity of bile salts increases with improving fat-solubilizing capability and so an optimal combination of efficient solubilization and low toxicity is necessary. To improve hydrophilicity (and decrease toxicity), we substituted hydroxyl groups of several natural bile acid (BA) molecules for oxogroups and studied their intrinsic molecular association behavior. Here we present the comparative Langmuir trough study of the two-dimensional (2D) association behavior of eight natural BAs and four oxoderivatives (traditionally called keto-derivatives) floated on an aqueous subphase. The series of BAs and derivatives showed systematic changes in the shape of the compression isotherms. Two types of association could be distinguished: the first transition was assigned to the formation of dimers through H-bonding and the second to the hydrophobic aggregation of BA dimers. Hydrophobic association of BA molecules in the films is linked to the ability of forming H-bonded dimers. Both H-bond formation and hydrophobic association weakened with increasing number of hydroxyl groups, decreasing distance between hydroxyl groups, and increasing oxosubstitution. The results also show that the Langmuir trough method is extremely useful in selecting appropriate BA molecules to design drug delivery systems.


Assuntos
Ácidos e Sais Biliares/química , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Oxirredução
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