Triterpenoids are natural compounds with a large variety of biological activities such as anticancer, antiviral, antibacterial, antifungal, antiparazitic, antiinflammatory and others. Despite their low toxicity and simple availability from the natural resources, their clinical use is still severely limited by their higher IC50 and worse pharmacological properties than in the currently used therapeutics. This fact encouraged a number of researchers to develop new terpenic derivatives more suitable for the potential clinical use. This review summarizes a new approach to improve both, the activity and ADME-Tox properties by connecting active terpenes to another modifying molecules using click reactions. Within the past few years, this synthetic approach was well explored yielding a lot of great improvements of the parent compounds along with some less successful attempts. A large quantity of the new compounds presented here are superior in both activity and ADME-Tox properties to their parents. This review should serve the researchers who need to promote their hit triterpenic structures towards their clinical use and it is intended as a guide for the chemical synthesis of better drug candidates.

• MeSH
• antitumorózní látky chemická syntéza   farmakologie   MeSH
• antivirové látky chemická syntéza   farmakologie   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• syntetická chemie okamžité shody * MeSH
• terpeny chemická syntéza   farmakologie   MeSH
• triazoly chemická syntéza   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Two sets of new conjugates obtained from d-mannose derivatives and o-, m-, and p-substituted benzoic acid esters interconnected through a triazole ring were synthesized by Cu(I) catalyzed azide-alkyne cycloaddition. All synthesized compounds were tested for their in vitro cytotoxic activity against seven cancer cell lines with/without multidrug resistance phenotype as well as non-tumor MRC-5 and BJ fibroblasts. Butyl ester of 4-aminobenzoic acid 6c showed the highest activity among all tested compounds, however, it was active only against K562 myeloid leukemia cells. N-Glycosyltriazole conjugates, both acetylated and nonacetylated at mannose moiety, were almost completely inactive. In contrast, some of the acetylated O-glycosyl conjugates showed cytotoxic activity which was cell line dependent and strongly affected by position of benzoic acid substitution as well as a length of its ester alkyl chain; the most potent compound was acetylated mannoside conjugated with octyl ester of m-substituted benzoic acid. However, deacetylation resulting in hydrophilicity increase of the glycosides almost completely abolished their cytotoxic potency.

• MeSH
• aminobenzoáty chemie   MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• buněčné linie MeSH
• fibroblasty účinky léků   MeSH
• lidé MeSH
• mannosa chemická syntéza   chemie   farmakologie   MeSH
• molekulární struktura MeSH
• preklinické hodnocení léčiv MeSH
• proliferace buněk účinky léků   MeSH
• stereoizomerie MeSH
• syntetická chemie okamžité shody MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We present an investigation of the preparation of highly porous hydrogels based on biodegradable synthetic poly(α-amino acid) as potential tissue engineering scaffolds. Covalently cross-linked gels with permanent pores were formed under cryogenic conditions by free-radical copolymerization of poly[N(5)-(2-hydroxyethyl)-L-glutamine-stat-N(5)-(2-methacryloyl-oxy-ethyl)-L-glutamine] (PHEG-MA) with 2-hydrohyethyl methacrylate (HEMA) and, optionally, N-propargyl acrylamide (PrAAm) as minor comonomers. The morphology of the cryogels showed interconnected polyhedral or laminar pores. The volume content of communicating water-filled pores was >90%. The storage moduli of the swollen cryogels were in the range of 1-6 kPa, even when the water content was >95%. The enzymatic degradation of a cryogel corresponded to the decrease in its storage modulus during incubation with papain, a model enzyme with specificity analogous to wound-healing enzymes. It was shown that cryogels with incorporated alkyne groups can easily be modified with short synthetic peptides using azide-alkyne cycloaddition "click" chemistry, thus providing porous hydrogel scaffolds with biomimetic features.

• MeSH
• akrylamidy chemie   MeSH
• aminokyseliny chemie   MeSH
• biokompatibilní materiály chemie   MeSH
• biomimetika MeSH
• kryogely chemie   MeSH
• methakryláty chemie   MeSH
• morfinany chemie   MeSH
• peptidy chemie   MeSH
• polymerizace MeSH
• polymery chemie   MeSH
• poréznost MeSH
• syntetická chemie okamžité shody * MeSH
• tkáňové inženýrství MeSH
• tkáňové podpůrné struktury chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The synthesis and chromatographic evaluation of a series of new Cinchona derived chiral weak anion exchangers is presented. Huisgen Cu(I) mediated alkyne-azide cycloaddition, so-called click chemistry, was used as an immobilization strategy. In this way it was possible to immobilize about 90% of offered selector via 1,2,3-triazole linker, which displays a more efficient way of binding the selector to modified silica compared to common radical mediated thiol-ene addition. Problems associated with potential radical scavenging properties of chiral selectors thereby could be circumvented. The evaluation of the synthesized chiral stationary phases regarding chromatographic behavior was carried out using polar organic mode mobile phase composition and a set of representative chiral organic acids. Different loading densities revealed an optimum selector density of about 310μmol/g chiral stationary phase with respect to resolution and selectivity. A decrease of performance was observed for higher loading, indicating mutual spatial influence of selector units leading to sterical hindrance. In addition, we observed that the effect of free azide groups on retention is negligible and the overall chromatographic behavior is comparable to other Cinchona derived chiral stationary phases.

• MeSH
• alkyny chemie   MeSH
• aminokyseliny chemie   MeSH
• azidy chemie   MeSH
• chinidin analogy a deriváty   chemická syntéza   chemie   MeSH
• chinin analogy a deriváty   chemická syntéza   chemie   MeSH
• chromatografie MeSH
• cykloadiční reakce MeSH
• iontová výměna MeSH
• karbamáty chemická syntéza   chemie   MeSH
• oxid křemičitý MeSH
• stereoizomerie MeSH
• syntetická chemie okamžité shody MeSH
• Publikační typ
• časopisecké články MeSH

To tailor cell-surface interactions, precise and controlled attachment of cell-adhesive motifs is required, while any background non-specific cell and protein adhesion has to be blocked effectively. Herein, a versatile and highly reproducible antifouling surface modification based on "clickable" groups and hierarchically structured diblock copolymer brushes for the controlled attachment of cells is reported. The polymer brush architecture combines an antifouling bottom block of poly(2-hydroxyethyl methacrylate) poly(HEMA) and an ultrathin azide-bearing top block, which can participate in well-established "click" reactions including the highly selective copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction under mild conditions. This straightforward approach allows the rapid conjugation of a cell-adhesive, alkyne-bearing cyclic RGD peptide motif, enabling subsequent specific attachment of NIH 3T3 fibroblasts, their extensive proliferation and confluent cell sheet formation after 48 h of incubation. The generally applicable strategy presented in this report can be employed for surface functionalization with diverse alkyne-bearing biological moieties via CuAAC or copper-free alkyne-azide cycloaddition protocols, making it a versatile functionalization approach and a promising tool for tissue engineering, biomaterial implant design, and other applications that require surfaces supporting highly specific cell attachment.

• MeSH
• alkyny chemie   farmakologie   MeSH
• antiinfekční látky chemická syntéza   farmakologie   MeSH
• azidy chemie   farmakologie   MeSH
• biokompatibilní materiály chemická syntéza   farmakologie   MeSH
• buňky NIH 3T3 MeSH
• cykloadiční reakce MeSH
• katalýza MeSH
• myši MeSH
• oligopeptidy chemie   MeSH
• polyhydroxyethylmethakrylát chemie   MeSH
• proliferace buněk účinky léků   MeSH
• syntetická chemie okamžité shody MeSH
• tkáňové inženýrství MeSH
• tkáňové podpůrné struktury * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Prostate cancer is primarily fatal after it becomes metastatic and castration-resistant despite novel combined hormonal and chemotherapeutic regimens. Hence, new therapeutic concepts and drug delivery strategies are urgently needed for the eradication of this devastating disease. Here we report the highly specific, in situ click chemistry driven pretargeted delivery of cytotoxic drug carriers to PSMA(+) prostate cancer cells. Anti-PSMA 5D3 mAb and its F(ab')2 fragments were functionalized with trans-cyclooctene (TCO), labeled with a fluorophore, and used as pretargeting components. Human serum albumin (ALB) was loaded with the DM1 antitubulin agent, functionalized with PEGylated tetrazine (PEG4-Tz), labeled with a fluorophore, and used as the drug delivery component. The internalization kinetics of components and the therapeutic efficacy of the pretargeted click therapy were studied in PSMA(+) PC3-PIP and PSMA(-) PC3-Flu control cells. The F(ab')2 fragments were internalized faster than 5D3 mAb in PSMA(+) PC3-PIP cells. In the two-component pretargeted imaging study, both components were colocalized in a perinuclear location of the cytoplasm of PC3-PIP cells. Better colocalization was achieved when 5D3 mAb was used as the pretargeting component. Consecutively, the in vitro cell viability study shows a significantly higher therapeutic effect of click therapy in PC3-PIP cells when 5D3 mAb was used for pretargeting, compared to its F(ab')2 derivative. 5D3 mAb has a longer lifetime on the cell surface, when compared to its F(ab')2 analogue, enabling efficient cross-linking with the drug delivery component and increased efficacy. Pretargeting and drug delivery components were cross-linked via multiple bioorthogonal click chemistry reactions on the surface of PSMA(+) PC cells forming nanoclusters, which undergo fast cellular internalization and intracellular transport to perinuclear locations.

• MeSH
• albuminy MeSH
• antigeny povrchové imunologie   MeSH
• antitumorózní látky fytogenní terapeutické užití   MeSH
• cyklooktany chemie   MeSH
• fluorbenzeny chemie   MeSH
• glutamátkarboxypeptidasa II imunologie   metabolismus   MeSH
• imunoglobuliny - Fab fragmenty chemie   metabolismus   terapeutické užití   MeSH
• lidé MeSH
• maytansin terapeutické užití   MeSH
• modulátory tubulinu terapeutické užití   MeSH
• monoklonální protilátky chemie   metabolismus   terapeutické užití   MeSH
• nádorové buněčné linie MeSH
• nádory prostaty farmakoterapie   enzymologie   metabolismus   MeSH
• nanomedicína MeSH
• syntetická chemie okamžité shody metody   MeSH
• systémy cílené aplikace léků metody   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví 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

The site-specific chemical modification of proteins through incorporation of noncanonical amino acids enables diverse applications, such as imaging, probing, and expanding protein functions, as well as to precisely engineer therapeutics. Here we report a general strategy that allows the incorporation of noncanonical amino acids into target proteins using the amber suppression method and their efficient secretion in the biotechnological relevant expression host Bacillus subtilis. This facilitates efficient purification of target proteins directly from the supernatant, followed by their functionalization using click chemistry. We used this strategy to site-specifically introduce norbornene lysine into a single chain antibody and functionalize it with fluorophores for the detection of human target proteins.

• MeSH
• Bacillus subtilis genetika   metabolismus   MeSH
• CRISPR-Cas systémy MeSH
• ELISA MeSH
• genetické vektory MeSH
• genetický kód MeSH
• isopropylthiogalaktosid farmakologie   MeSH
• kreatinkinasa, forma MM metabolismus   MeSH
• lidé MeSH
• lysin chemie   MeSH
• norbornany chemie   MeSH
• proteinové inženýrství metody   MeSH
• regulace genové exprese u bakterií účinky léků   MeSH
• rekombinantní proteiny chemie   genetika   izolace a purifikace   metabolismus   MeSH
• syntetická chemie okamžité shody MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Prolaps mitrální chlopně (PMCH) prodělal za 38 let své existence jako klinická jednotka několik fází vývoje. Zásluhou echokardiografie a nekritického hodnocení jejích nálezů se nejprve stal nejčastěji diagnostikovanou srdeční abnormalitou. Spojení PMCH s komplexem nespecifických obtíží vedlo ke vzniku termínu syndrom PMCH. Teprve po vytvoření a přijetí standardních diagnostických kritérií a provedení populačních studií, bylo možné PMCH jako klinickou jednotku zhodnotit realisticky. Prevalence PMCH v populaci je kolem 2,4 %, tedy výrazně nižší, než se dříve předpokládalo. Syndrom PMCH takřka jistě neexistuje. Závažnými komplikacemi (infekční endokarditidou, dysrytmiemi a náhlou smrtí) je ohroženo jen 2-4 % nositelů PMCH se závažnou mitrální insuficiencí. U všech ostatních představuje PMCH naprosto benigní abnormalitu.

Over the 38 years of existence as a clinical entity, the concept of mitral valve prolapse (MVP) has evolved through several stages. It has been thanks to echocardiography and the non-critical evaluation of its finding that MVP has become the most frequent diagnosed cardiac abnormality. An association of MVP with a complex of non-specific complaints led to the coining of the term, mitral valve prolapse syndrome. It was not until standard diagnostic criteria were formulated and adopted, and population based studies conducted, that we were able to make a realistic assessment of MVP as a clinical entity. The prevalence of MPV in the population is about 2.4 %, markedly lower than originally believed. The existence of the MVP syndrome is not certain. Only 2-4 % of the MVP patients with a hemodynamically severe mitral insufficiency are at risk of serious complications (infectious endocarditis, dysrthythmias, and sudden death). In all others MVP is an absolutely benign abnormality.

• MeSH
• diagnostické techniky kardiovaskulární metody   MeSH
• echokardiografie metody   MeSH
• nemoci srdečních chlopní diagnóza   patologie   terapie   MeSH
• prognóza MeSH
• prolaps mitrální chlopně diagnóza   patologie   terapie   MeSH
• Publikační typ
• přehledy MeSH

To understand which morphological/anatomical parts may be responsible in artiodactyl ungulates for the clicking sound made when moving, this research focuses on the forelimb tendon apparatus where an undescribed opening in the fibrous cuff (manica flexoria), called hereafter for its shape as an "oval window" in the manica flexoria (OWMF), was detected. This oval window was found in 24 of the 25 species of four families (Camelidae, Giraffidae, Cervidae, and Bovidae) evaluated; the exception being in Bos taurus taurus (Domestic cattle). The length and width of the OWMF enabled correct species discrimination between the majority of species, but remained conservative intraspecifically, as it did not differ between the left and right side of the forelimb, third and fourth digits, or between sexes. When evaluating the shape of OWMF in individual species, and measuring its length and width, 18 out of the 24 species investigated had this window as an oval shape, the remaining 25% of species exhibited more oval-oblong shapes with either proximal or distal asymmetry. The function of the OWMF in the thoracic autopodium of most ruminant even-toed ungulates is not yet fully understood. Its most likely function is to help balance the pressure inside the ligament cuff and reduce the friction of the touching surfaces of the muscle tendons-thus facilitating the movement of the digits when walking. None of the absolute or relative OWMF parameters fit exclusively with the occurrence and distribution of knee-clicks produced by some bovids and cervids during movement, so the mechanism responsible for this sound remains cryptic from the present anatomical perspective.

• MeSH
• Artiodactyla * MeSH
• horní končetina MeSH
• lidé MeSH
• ligamenta MeSH
• přední končetina MeSH
• skot MeSH
• šlachy MeSH
• vysoká zvěř * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Series of multivalent α-l-fucoside containing glycoclusters and variously decorated l-fucosides were synthesized to find potential inhibitors of fucose-specific lectins and study the structure-binding affinity relationships. Tri- and tetravalent fucoclusters were built using copper-mediated azide-alkyne click chemistry. Series of fucoside monomers and dimers were synthesized using various methods, namely glycosylation, an azide-alkyne click reaction, photoinduced thiol-en addition, and sulfation. The interactions between compounds with six fucolectins of bacterial or fungal origin were tested using a hemagglutination inhibition assay. As a result, a tetravalent, α-l-fucose presenting glycocluster showed to be a ligand that was orders of magnitude better than a simple monosaccharide for tested lectins in most cases, which can nominate it as a universal ligand for studied lectins. This compound was also able to inhibit the adhesion of Pseudomonas aeruginosa cells to human epithelial bronchial cells. A trivalent fucocluster with a protected amine functional group also seems to be a promising candidate for designing glycoconjugates and chimeras.

• MeSH
• bakteriální proteiny chemie   metabolismus   MeSH
• fukosa chemie   metabolismus   MeSH
• fungální proteiny chemie   metabolismus   MeSH
• hemaglutinace MeSH
• lektiny chemie   metabolismus   MeSH
• lidé MeSH
• testy inhibice hemaglutinace MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH