Because of synergism between tubulin and HDAC inhibitors, we used the pharmacophore fusion strategy to generate potential tubulin-HDAC dual inhibitors. Drug design was based on the introduction of a N-hydroxyacrylamide or a N-hydroxypropiolamide at the 5-position of the 2-aroylbenzo[b]furan skeleton, to produce compounds 6a-i and 11a-h, respectively. Among the synthesized compounds, derivatives 6a, 6c, 6e, 6g, 11a, and 11c showed excellent antiproliferative activity, with IC50 values at single- or double-digit nanomolar levels, against the A549, HT-29, and MCF-7 cells resistant towards the control compound combretastatin A-4 (CA-4). Compounds 11a and 6g were also 10-fold more active than CA-4 against the Hela cell line. When comparing the inhibition of tubulin polymerization versus the HDAC6 inhibitory activity, we found that 6a-g, 6i, 11a, 11c, and 11e, although very potent as inhibitors of tubulin assembly, did not have significant inhibitory activity against HDAC6.

• MeSH
• benzofurany * farmakologie   chemie   chemická syntéza   MeSH
• buňky HT-29 MeSH
• HeLa buňky MeSH
• histondeacetylasa 6 antagonisté a inhibitory   metabolismus   MeSH
• inhibitory histondeacetylas farmakologie   chemická syntéza   chemie   MeSH
• kyseliny hydroxamové * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• modulátory tubulinu * farmakologie   chemická syntéza   chemie   MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• protinádorové látky * farmakologie   chemická syntéza   chemie   MeSH
• screeningové testy protinádorových léčiv MeSH
• tubulin * metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Microtubule dynamic is exceptionally sensitive to modulation by small-molecule ligands. Our previous work presented the preparation of microtubule-targeting estradiol dimer (ED) with anticancer activity. In the present study, we explore the effect of selected linkers on the biological activity of the dimer. The linkers were designed as five-atom chains with carbon, nitrogen or oxygen in their centre. In addition, the central nitrogen was modified by a benzyl group with hydroxy or methoxy substituents and one derivative possessed an extended linker length. Thirteen new dimers were subjected to cytotoxicity assay and cell cycle profiling. Dimers containing linker with benzyl moiety substituted with one or more methoxy groups and longer branched ones were found inactive, whereas other structures had comparable efficacy as the original ED (e.g. D1 with IC50 = 1.53 μM). Cell cycle analysis and immunofluorescence proved the interference of dimers with microtubule assembly and mitosis. The proposed in silico model and calculated binding free energy by the MM-PBSA method were closely correlated with in vitro tubulin assembly assay.

• MeSH
• apoptóza MeSH
• ethinylestradiol * chemie   farmakologie   MeSH
• kontrolní body fáze G2 buněčného cyklu účinky léků   MeSH
• mikrotubuly MeSH
• modulátory tubulinu * chemie   farmakologie   MeSH
• nádorové buněčné linie MeSH
• protinádorové látky * chemie   farmakologie   MeSH
• triazoly * chemie   farmakologie   MeSH
• tubulin * metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Studying the anticancer activity of 5-arylidene-2-(4-hydroxyphenyl)aminothiazol-4(5H)-ones towards cell lines of different cancer types allowed the identification of hit-compounds inhibiting the growth of daunorubicin- (CEM-DNR, IC50 = 0.32-1.28 μM) and paclitaxel-resistant (K562-TAX, IC50 = 0.21-1.23 μM) cell lines, with favorable therapeutic indexes. The studied compounds induced apoptosis and cellular proliferation in treated CCRF-CEM cells. The hit compounds were shown to induce mitotic arrest by interacting with tubulin, inhibiting its polymerization by binding to the colchicine binding site.

• MeSH
• apoptóza MeSH
• modulátory tubulinu * farmakologie   chemie   MeSH
• nádorové buněčné linie MeSH
• proliferace buněk MeSH
• protinádorové látky * farmakologie   chemie   MeSH
• screeningové testy protinádorových léčiv MeSH
• tubulin metabolismus   MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH

Prostate cancer (PC) is a potentially high-risk disease and the most common cancer in American men. It is a leading cause of cancer-related deaths in men in the US, second only to lung and bronchus cancer. Advanced and metastatic PC is initially treated with androgen deprivation therapy (ADT), but nearly all cases eventually progress to castrate-resistant prostate cancer (CRPC). CRPC is incurable in the metastatic stage but can be slowed by some conventional chemotherapeutics and second-generation ADT, such as enzalutamide and abiraterone. Therefore, novel therapeutic strategies are urgently needed. Prostate-specific membrane antigen (PSMA) is overexpressed in almost all aggressive PCs. PSMA is widely used as a target for PC imaging and drug delivery. Anti-PSMA monoclonal antibodies (mAbs) have been developed as bioligands for diagnostic imaging and targeted PC therapy. However, these mAbs are successfully used in PC imaging and only a few have gone beyond phase-I for targeted therapy. The 5D3 mAb is a novel, high-affinity, and fast-internalizing anti-PSMA antibody. Importantly, 5D3 mAb demonstrates a unique pattern of cellular localization to the centrosome after internalization in PSMA(+) PC3-PIP cells. These characteristics make 5D3 mAb an ideal bioligand to deliver tubulin inhibitors, such as mertansine, to the cell centrosome, leading to mitotic arrest and elimination of dividing PC cells. We have successfully developed a 5D3 mAb- and mertansine (DM1)-based antibody-drug conjugate (ADC) and evaluated it in vitro for binding affinity, internalization, and cytotoxicity. The in vivo therapeutic efficacy of 5D3-DM1 ADC was evaluated in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu mouse models of human PC. This therapeutic study has revealed that this new anti-PSMA ADC can successfully control the growth of PSMA(+) tumors without inducing systemic toxicity.

• MeSH
• androsteny farmakologie   MeSH
• antagonisté androgenů farmakologie   MeSH
• antigeny povrchové metabolismus   MeSH
• benzamidy farmakologie   MeSH
• buňky PC-3 MeSH
• centrozom metabolismus   MeSH
• fenylthiohydantoin farmakologie   MeSH
• glutamátkarboxypeptidasa II metabolismus   MeSH
• imunokonjugáty farmakologie   MeSH
• lidé MeSH
• modulátory tubulinu farmakologie   MeSH
• monoklonální protilátky farmakologie   MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory prostaty rezistentní na kastraci farmakoterapie   metabolismus   MeSH
• nitrily farmakologie   MeSH
• xenogenní modely - testy protinádorové aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

We have synthesized a series of 2-phenyl-3-hydroxy-4(1H)-quinolinone derivatives substituted with one or more fluorine atoms on the quinolone backbone as well as on phenyl ring. The derivatives bearing more fluorine atoms were subjected to modification by nucleophilic substitutions by thiophenol, morpholine, and piperazine derivative. We have tested the prepared compounds in cytotoxic activity assay against cancer cell lines. Four derivatives exhibited micromolar values of IC50 against some of the cancer cell lines, and we have subjected them to cell cycle analysis on CCRF-CEM. Moreover, most active 7-fluoro-3-hydroxy-2-phenyl-6-(phenylthio)quinolin-4(1H)-one inhibits mitosis progression. Cell cycle analysis, in vitro tubulin polymerization assay, and tubulin imaging in cells indicated that the anticancer activity of thiophenol derivative is associated with its ability to inhibit microtubule formation.

• MeSH
• chinolony chemická syntéza   chemie   farmakologie   MeSH
• halogenace MeSH
• HCT116 buňky MeSH
• lidé MeSH
• modulátory tubulinu chemická syntéza   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• polymerizace účinky léků   MeSH
• tubulin metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall activity of the drug candidates. Herein, we report the preparation of cis-restrained carbocyclic analogs of CA-4. The compounds, which differ by the size and hybridization of the carbocyclic ring have been evaluated for their cytotoxic properties and their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified cyclobutenyl and cyclobutyl derivatives of the natural product as highly promising drug candidates.

• MeSH
• kontrolní body fáze G2 buněčného cyklu účinky léků   MeSH
• lidé MeSH
• modulátory tubulinu chemická syntéza   metabolismus   farmakologie   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• protinádorové látky chemická syntéza   metabolismus   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• simulace molekulového dockingu MeSH
• stilbeny chemická syntéza   metabolismus   farmakologie   MeSH
• tubulin metabolismus   MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The substitution inert platinum agent [Pt(1 S,2 S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]2+ (56MeSS, 5) is a potent cytotoxic metallodrug. In contrast to conventional cisplatin or oxaliplatin, the mechanism of action (MoA) of 5 is fundamentally different. However, details of the mechanism by which the 5,6-dimethyl-1,10-phenanthroline ligand contributes to the cytotoxicity of 5 and its derivatives have not been sufficiently clarified so far. Here, we show that 5 and its Pt(IV) derivatives exhibit an intriguing potency in the triple-negative breast cancer cells MDA-MB-231. Moreover, we show that the Pt(IV) derivatives of 5 act by multimodal MoA resulting in the global biological effects, that is, they damage nuclear DNA, reduce the mitochondrial membrane potential, induce the epigenetic processes, and last but not least, the data provide evidence that changes in the organization of cytoskeleton networks are functionally important for 5 and its derivatives, in contrast to clinically used platinum cytostatics, to kill cancer cells.

• MeSH
• aktiny antagonisté a inhibitory   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• cytoskelet účinky léků   MeSH
• DNA nádorová účinky léků   MeSH
• epigeneze genetická účinky léků   MeSH
• křečci praví MeSH
• lidé MeSH
• ligandy MeSH
• mikrotubuly účinky léků   MeSH
• modulátory tubulinu farmakologie   MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemická syntéza   metabolismus   farmakologie   MeSH
• protinádorové látky chemická syntéza   metabolismus   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• triple-negativní karcinom prsu farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Microtubule dynamics is one of the major targets for new chemotherapeutic agents. This communication presents the synthesis and biological profiling of steroidal dimers based on estradiol, testosterone and pregnenolone bridged by 2,6-bis(azidomethyl)pyridine between D rings. The biological profiling revealed unique properties of the estradiol dimer including cytotoxic activities on a panel of 11 human cell lines, ability to arrest in the G2/M phase of the cell cycle accompanied with the attenuation of DNA/RNA synthesis. Thorough investigation precluded a genomic mechanism of action and revealed that the estradiol dimer acts at the cytoskeletal level by inhibiting tubulin polymerization. Further studies showed that estradiol dimer, but none of the other structurally related dimeric steroids, inhibited assembly of purified tubulin (IC50, 3.6 μM). The estradiol dimer was more potent than 2-methoxyestradiol, an endogenous metabolite of 17β-estradiol and well-studied microtubule polymerization inhibitor with antitumor effects that was evaluated in clinical trials. Further, it was equipotent to nocodazole (IC50, 1.5 μM), an antimitotic small molecule of natural origin. Both estradiol dimer and nocodazole completely and reversibly depolymerized microtubules in interphase U2OS cells at 2.5 μM concentration. At lower concentrations (50 nM), estradiol dimer decreased the microtubule dynamics and growth life-time and produced comparable effect to nocodazole on the microtubule dynamicity. In silico modeling predicted that estradiol dimer binds to the colchicine-binding site in the tubulin dimer. Finally, dimerization of the steroids abolished their ability to induce transactivation by estrogen receptor α and androgen receptors. Although other steroids were reported to interact with microtubules, the estradiol dimer represents a new structural type of steroid inhibitor of tubulin polymerization and microtubule dynamics, bearing antimitotic and cytotoxic activity in cancer cell lines.

• MeSH
• buněčný cyklus MeSH
• estradiol chemie   farmakologie   MeSH
• estrogeny chemie   farmakologie   MeSH
• lidé MeSH
• mikrotubuly účinky léků   fyziologie   MeSH
• modulátory tubulinu chemie   farmakologie   MeSH
• nádorové buňky kultivované MeSH
• nádory farmakoterapie   metabolismus   patologie   MeSH
• polymerizace MeSH
• proliferace buněk MeSH
• tubulin chemie   účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Klíčová slova
• Vargatef, ninetedanib, studie LUME-Lung 1, studie LUME-Lung 2,
• MeSH
• analýza přežití MeSH
• docetaxel MeSH
• indoly farmakologie   terapeutické užití   MeSH
• inhibitory enzymů farmakologie   terapeutické užití   MeSH
• klinické zkoušky, fáze II jako téma MeSH
• klinické zkoušky, fáze III jako téma MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• metastázy nádorů MeSH
• modulátory tubulinu farmakologie   terapeutické užití   MeSH
• nádory plic * farmakoterapie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   MeSH
• nežádoucí účinky léčiv MeSH
• protinádorové látky * farmakokinetika   farmakologie   kontraindikace   terapeutické užití   MeSH
• randomizované kontrolované studie jako téma MeSH
• schvalování léčiv MeSH
• taxoidy farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

V současné době jsme svědky překotného rozvoje biologické léčby u HER2-pozitivního karcinomu prsu. Z dřívějšího zabijáka se stalo díky novým molekulám onemocnění, které je velmi dobře léčitelné a vyléčitelné. Trastuzumab emtansin je příkladem nového typu cílené terapie, kde prostřednictvím účinné protilátky je do cílové nádorové buňky vneseno velmi účinné cytostatikum, které zneškodní jen tuto nádorovou buňku. Přesvědčivé výsledky studií od fáze I do fáze III ukazují nezaměnitelnost této nové revoluční molekuly spojující přesnost protilátky, její blokádu proliferace a účinnost velmi silného cytostatika, které cílovou buňku usmrtí. Právě tato kombinace zvyšuje efektivitu léčby a snižuje rizika toxicity.

Currently, we are witnessing a rapid development of biological therapy in HER2-positive breast cancer. Thanks to new molecules, the formerly fatal disease has become a very well treatable and curable disease. Trastuzumab emtansine is an example of a new type of targeted therapy. Using an effective antibody, the cytostatic drug is transported only into the target tumour cell and kills it. Convincing results of studies with phase I-III show the uniqueness of this new revolutionarry molecule that links the accuracy of the antibody, proliferation blockade, and the effectiveness of a very strong cytostatic drug. This combination increaeases the effectiveness of treatment and reduces the risk of toxicity.

• Klíčová slova
• trastuzumab emtansin,
• MeSH
• analýza přežití MeSH
• hodnocení léčiv * statistika a číselné údaje   MeSH
• humanizované monoklonální protilátky farmakologie   škodlivé účinky   terapeutické užití   MeSH
• karcinom farmakoterapie   MeSH
• lidé MeSH
• maytansin analogy a deriváty   MeSH
• modulátory tubulinu farmakologie   škodlivé účinky   terapeutické užití   MeSH
• nádory prsu * farmakoterapie   MeSH
• protinádorové látky farmakologie   škodlivé účinky   terapeutické užití   MeSH
• receptor erbB-2 antagonisté a inhibitory   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH