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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
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
Biodegradable polymer-based therapeutics have recently become essential drug delivery biomaterials for various bioactive compounds. Biodegradable and biocompatible polymer-based biomaterials fulfill the requirements of these therapeutics because they enable to obtain polymer biomaterials with optimized blood circulation, pharmacokinetics, biodegradability, and renal excretion. Herein, we describe an adaptable polymerization platform employed for the synthesis of long-circulating, stimulus-sensitive and biodegradable biomaterials, therapeutics, or theranostics. Four chain transfer agents (CTA) were designed and successfully synthesized for the reversible addition-fragmentation chain transfer polymerization, allowing the straightforward synthesis of hydrolytically biodegradable structures of block copolymers-based biomaterials. The controlled polymerization using the CTAs enables controlling the half-life of the hydrolytic degradation of polymer precursors in a wide range from 5 h to 21 days. Moreover, the antitumor drug pirarubicin (THP) was successfully conjugated to the polymer biomaterials via a pH-sensitive hydrazone bond for in vitro and in vivo experiments. Polymer conjugates demonstrated superior antitumor efficacy compared to basic linear polymer-based conjugates. Notably, the biodegradable systems, even though those with degradation in the order of hours were selected, increased the half-life of THP in the bloodstream almost two-fold. Indeed, the presented platform design enables the main chain-end specific attachment of targeting ligands or diagnostic molecules. The adaptable polymerization platform design allows tuning of the biodegradability rate, stimuli-sensitive drug bonding, and optimized pharmacokinetics to increase the therapy outcome and system targeting, thus allowing the preparation of targeted or theranostic polymer conjugates. STATEMENT OF SIGNIFICANCE: Biodegradable and biocompatible polymer-based biomaterials are recognized as potential future bioactive nanomedicines. To advance the development of such biomaterials, we developed polymerization platforms utilizing tailored chain transfer agents allowing the straightforward synthesis of hydrolytically degradable polymer biomaterials with tuned biodegradability from hours to several days. The platform allows for the synthesis of long-circulating, stimulus-sensitive and biodegradable biomaterial serving as drug carriers or theranostics. The therapeutic potential was validated by preparation of polymer biomaterials containing pirarubicin, anticancer drug, bound via pH sensitive bond and by showing prolonged blood circulation and increased antitumor activity while keeping the drug side effects low. This work paves the way for future development of biodegradable polymer biomaterials with advanced properties in drug delivery.
Cílem práce bylo porovnat účinnost několika typů halogenových a LED polymeračních lamp při vytvrzování různých typů kompozitních materiálů. Sledovány byly halogenové lampy Heliolux DLX1 (Ivoclar Vivadent) a Megalux Fast Cure (Mega Physik), LED lampy zahrnující DioPower (CMS Dental), Translux Power Blue (Heraeus Kulzer), BluePhase C8 (Ivoclar Vivadent) s úzkým emisním spektrem (skupina LED 1) a LED lampy G-Light (GC) a BluePhase G2 (Ivoclar Vivadent) s emisí v širší oblasti světla (skupina LED 2). Hodnocení lamp bylo provedeno měřením tvrdosti horní ozářené a spodní neozářené strany tělísek tloušťky 2 mm, zhotovených z radikálově iniciovaného dimetakrylátového kompozitního materiálu Charisma (Heraeus Kulzer) a epoxidového kompozitu Filtek Silorane (3M ESPE) s kationtovým mechanismem polymerace. U obou materiálů byl pozorován významný vliv polymerační lampy na tvrdost, a tedy i stupeň vytvrzení kompozitního materiálu. Nejvyšší tvrdost pro kompozit Charisma byla nalezena při jeho polymeraci halogenovými lampami a lampou BluePhase G2. V případě epoxidového kompozitu Filtek Silorane bylo nejvyšších hodnot tvrdosti dosaženo s oběma LED 2 lampami a s halogenovými typy lamp. I přes omezený rozsah hodnocených polymeračních lamp se ukázalo, že nejvyšší účinnosti polymerace lze dosáhnout s lampami se širokým emisním spektrem, především výkonnými halogenovými typy a LED lampami s diodami emitujícími světlo i v oblasti kratších vlnových délek.
The objective was to compare efficacy of several types of halogen and LED polymerization lamps in curing restorative composite materials. Halogen lamps Heliolux DLX1 (Ivoclar Vivadent) and Megalux Fast Cure (MegaPhysik) and LED lamps DioPower (CMS Dental), Translux Power Blue (Heraeus Kulzer), BluePhase C8 (Ivoclar Vivadent) of a narrow spectral emission (group LED 1) and G-Light (GC, USA) and BluePhase G2 (Ivoclar Vivadent) of a broad spectral emission (group LED 2) were used. Curing efficacy was evaluated by measuring the composite hardness on the top irradiated and bottom not-irradiated surfaces of 2 mm thick specimens prepared from radically initiated dimethacrylate-based composite material Charisma (Heraeus Kulzer) and epoxy-based cationically polymerized composite material Filtek Silorane (3M ESPE). In curing of both composite materials a significant effect of the polymerization lamp on composite hardness and hence, polymerization degree was observed. The highest hardness of the composite material Charisma was found after polymerization with the halogen lamps and also BluePhase G2 of a broad spectral emission. With the epoxy-based Filtek Silorane the highest surface hardness was reached with both LED 2 and halogen lamps. In spite of limited number of polymerization lamps tested it seems obvious that the highest polymerization degree can be reached with polymerization lamps of broad spectral emission, such as high-power halogen lamps or LED lamps equipped with diodes emitting light in a short wavelength range.
Among the class of zwitterionic polymers poly(carboxybetaine)s (poly(CB)s) are unique, emerging as the only ultra-low fouling materials known allowing the preparation of biosensors, fouling resistant nanoparticles, and non-adhesive surfaces for bacteria. Poly(carboxybetaine methacrylate) and poly(carboxybetaine acrylamide) have been prepared via atom transfer radical polymerization (ATRP), however a polymerization with living characteristics has not been achieved yet. Herein, the first successful living/controlled reversible addition fragmentation transfer (RAFT) polymerization of (3-methacryloylamino-propyl)-(2-carboxy-ethyl)-dimethyl-ammonium (carboxybetaine methacrylamide) (CBMAA-3) in acetate buffer (pH 5.2) at 70 and 37 °C is reported. The polymerization afforded very high molecular weight polymers (determined by absolute size exclusion chromatography, close to 250,000 g·mol(-1) in less than 6 h) with low PDI (<1.3) at 70 °C. The polymerization was additionally carried out at 37 °C allowing to achieve yet lower PDIs (1.06 ≤ PDI ≤ 1.15) even at 90% conversion, demonstrating the suitability of the polymerization conditions for bioconjugate grafting. The living character of the polymerization is additionally evidenced by chain extending poly(CBMAA-3) at 70 and 37 °C. Block copolymerization from biologically relevant poly[N-(2-hydroxypropyl)methacrylamide] macroCTAs was additionally performed.
The ability to tailor mechanical properties and architecture is crucial in creating macroporous hydrogel scaffolds for tissue engineering. In the present work, a technique for the modification of the pore size and stiffness of acrylamide-based cryogels is demonstrated via the regulation of an electron beam irradiation dose. The samples were characterized by equilibrium swelling measurements, light and scanning electron microscopy, mercury porosimetry, Brunauer-Emmett-Teller surface area analysis, and stiffness measurements. Their properties were compared to cryogels prepared by a standard redox-initiated radical polymerization. A (125)I radiolabeled azidopentanoyl-GGGRGDSGGGY-NH2 peptide was bound to the surface to determine the concentration of the adhesive sites available for biomimetic modification. The functionality of the prepared substrates was evaluated by in vitro cultivation of adipose-derived stem cells. Moreover, the feasibility of preparing layered cryogels was demonstrated. This may be the key to the future preparation of complex hydrogel-based scaffolds to mimic the extracellular microenvironment in a wide range of applications.
- MeSH
- elektrony MeSH
- kryogely chemická syntéza farmakologie MeSH
- lidé MeSH
- polymerizace * MeSH
- poréznost * MeSH
- tukové buňky účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The polysaccharide inulin has great importance in the food and pharmaceutical industries. The degree of polymerization (DP) of inulin influences important properties, such as, solubility, thermal stability, sweetness power and prebiotic activity. Molecules with a high degree of polymerization are obtained through physical techniques for enrichment of the inulin chains because they are not commonly obtained from plants extract. Gas chromatography/Mass Spectrometry and (1)H Nuclear Magnetic Resonance analysis showed that inulin from Stevia rebaudiana roots has a degree of polymerization (DPn 28) higher than the value of DPn 12-15 for inulins from other plant species. Furthermore, the methodology of freeze/thaw to enrich the chains allowed us to increase the DP, similarly to other methodologies used for the enrichment of inulin chains. The prebiotic assays confirm that inulin from S. rebaudiana has a high DP. The combined use of these molecules with low degree of polymerization fructans seems to be advantageous to prolong the prebiotic effect in the colon. Our results suggest that S. rebaudiana roots are a promising source of high degree polymerization inulins.
