Estrogen receptor alpha (ER) is a key biomarker for breast cancer, and the presence or absence of ER in breast and other hormone-dependent cancers decides treatment regimens and patient prognosis. ER is activated after ligand binding - typically by steroid. 2682 steroid compounds were used in a molecular docking study to identify novel ligands for ER and to predict compounds that may show anticancer activity. The effect of the most promising compounds was determined by a novel luciferase reporter assay. Two compounds, 7 and 12, showing ER inhibitory activity comparable to clinical inhibitors such as tamoxifen or fulvestrant were selected. We propose that the inhibitory effect of compounds 7 and 12 on ER is related to the presence of a double bond in their D-ring, which may protect against ER activation by reducing the electron density of the keto group, or may undergo metabolism leading to an active compound. Western blotting revealed that compound 12 decreased the level of ER in the breast cancer cell line MCF7, which was associated with reduced expression of both isoforms of the progesterone receptor, a well-known downstream target of ER. However, compound 12 has a different mechanism of action from fulvestrant. Furthermore, we found that compound 12 interferes with mitochondrial functions, probably by disrupting the electron transport chain, leading to induction of the intrinsic apoptotic pathway even in ER-negative breast cancer cells. In conclusion, the combination of computational and experimental methods shown here represents a rapid approach to determine the activity of compounds towards ER. Our data will not only contribute to research focused on the regulation of ER activity but may also be useful for the further development of novel steroid receptor-targeted drugs applicable in clinical practice.

• MeSH
• alfa receptor estrogenů genetika   metabolismus   MeSH
• estradiol farmakologie   terapeutické užití   MeSH
• estron * farmakologie   MeSH
• fulvestrant farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prsu * farmakoterapie   metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• simulace molekulového dockingu MeSH
• tamoxifen farmakologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

In this work, we studied indolium and benzothiazolium pentamethine salts 1-3 as novel type of receptors for the recognition of sulphated signalling molecules (sulphated steroids: oestrone, pregnenolone and cholesterol sulphate). A recognition study was performed in an aqueous medium (1mM phosphate buffer (H2O:MeOH; 99:1 (v/v))) at pH 7.34. The tested salts displayed a high affinity for these sulphated analytes, mainly for cholesterol sulphate. However, no interaction between the salts and control, non-sulphated sterol analytes (cholesterol and bile acid) was observed. The highest affinity for the sulphated steroids was observed for benzothiazole salt 1. This salt also displayed different spectral behaviour from that observed for carbocyanine salts 2 and 3. In this presence of cholesterol sulphate, benzothiazole salt 1 displayed significant spectral changes depending on the medium used: a blue shift in the aqueous medium and a red shift in the methanolic one (H2O:MeOH; 2:1 (v/v)). Subsequently preliminary in vivo study showed that, salt 1 significantly inhibits a growth of breast carcinoma on Nu/nu mice model.

• MeSH
• benzothiazoly chemie   MeSH
• estery cholesterolu chemie   farmakologie   MeSH
• estron analogy a deriváty   chemie   farmakologie   MeSH
• heterocyklické sloučeniny chemie   farmakologie   MeSH
• karbocyaniny chemie   MeSH
• myši nahé MeSH
• nádory prsu farmakoterapie   MeSH
• pregnenolon chemie   farmakologie   MeSH
• protinádorové látky farmakologie   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Sixteen platinum(II) complexes of estrone and estradiol were synthesized in this work to evaluate their cytotoxic activity against several cancer cell lines including estrogen dependent and independent ones. The synthesis of all the complexes was done in three steps. The reaction of steroids with dibromoalkanes was followed by a reaction of the bromoalkyl steroids with 2-(aminomethyl)pyridine or 2-(2-aminoethyl)pyridine. The last step was a reaction of steroidal diamino ligands with potassium tetrachloroplatinate to obtain the desired platinum(II) complexes. Cytotoxicity assays showed that most of the complexes prepared are active against the cancer cell lines used-CEM, U-2 OS, MCF7, MCF7 AL, MDA-MB-468, BT-474, BT-549, and BJ fibroblasts. The six-membered platinum complexes are more active than five-membered ones.

• MeSH
• estradiol analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• estron analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• komplexní sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• MFC-7 buňky MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

New hybrid molecules of estrone were synthesized as compounds indicating promising biological activity (antibacterial, antimycobacterial, antifungal, and antiproliferative). The prepared molecules contained various heterocyclic units (pyridine, benzylsulfanyl derivatives of pyridine or derivatives of tetrazole) linked to estrone by n-heptyl bridges. The compounds with charge on molecule (the hybrid pyridinium or benzylsulfanylpyridinium salts) exhibited significant biological activity (antibacterial, antimycobacterial, antifungal, and antiproliferative). On the other hand, the compounds not in the form of salts (omega-(1-phenyl-5-tetrazolylthio)heptylethers of estrone) were inactive. The antimycobacterial activities of three different series of tetrazole derivatives (i.e., the hybrid molecules with estrone, tetrazole-5-thiols, and 5-benzylsulfanyl-1-phenyltetrazoles) with the same substituents on phenyl ring were compared. Amongst them, the 5-benzylsulfanyl-1-phenyltetrazoles were the most potent.

• MeSH
• antibakteriální látky farmakologie   chemická syntéza   MeSH
• antifungální látky farmakologie   chemická syntéza   MeSH
• antituberkulotika farmakologie   chemická syntéza   MeSH
• Bacteria účinky léků   MeSH
• chromatografie na tenké vrstvě MeSH
• estron analogy a deriváty   farmakologie   chemická syntéza   MeSH
• financování organizované MeSH
• heterocyklické sloučeniny farmakologie   chemická syntéza   MeSH
• houby účinky léků   MeSH
• indikátory a reagencie MeSH
• lidé MeSH
• magnetická rezonanční spektroskopie MeSH
• mikrobiální testy citlivosti MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky farmakologie   chemická syntéza   MeSH
• spektrofotometrie infračervená MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH