A novel library of human carbonic anhydrase (hCA) inhibitors based on the 2-sulfanilamido[1,2,4]triazolo[1,5-a]pyrimidine skeleton modified at its 7-position was prepared by an efficient convergent procedure. These derivatives were evaluated in vitro for their inhibition properties against a representative panel of hCA isoforms (hCA I, II, IV, IX, and XII). The target tumour-associated isoforms hCA IX and XII were potently inhibited with KIs in the low nanomolar range of 5-96 nM and 4-72 nM, respectively. Compounds 1d, 1j, 1v, and 1x were the most potent hCA IX inhibitors with KIs of 5.1, 8.6, 4.7, and 5.1 nM, respectively. Along with derivatives 1d and 1j, compounds 1r and 1ab potently inhibited hCA XII isoform with KIs in a single-digit nanomolar range of 8.8, 5.4, 4.3, and 9.0 nM, respectively. Compounds 1e, 1m, and 1p exhibited the best selectivity against hCA IX and hCA XII isoforms over off-target hCA II, with selectivity indexes ranging from 5 to 14.

• Klíčová slova
• Carbonic anhydrase inhibitors, [1,2,4]triazolo[15-a]pyrimidine, antiproliferative activity, structure–activity relationship, sulphanilamide,
• MeSH
• antigeny nádorové * MeSH
• inhibitory karboanhydras farmakologie   MeSH
• karboanhydrasa I metabolismus   MeSH
• karboanhydrasa II * metabolismus   MeSH
• karboanhydrasa IX metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• protein - isoformy MeSH
• sulfanilamidy MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny nádorové * MeSH
• inhibitory karboanhydras MeSH
• karboanhydrasa I MeSH
• karboanhydrasa II * MeSH
• karboanhydrasa IX MeSH
• protein - isoformy MeSH
• sulfanilamidy MeSH

Bisphosphonates (BPs) are compounds resembling the pyrophosphate structure. BPs bind the mineral component of bones. During the bone resorption by osteoclasts, nitrogen-containing BPs are released and internalized, causing an inhibition of the mevalonate pathway. As a consequence, osteoclasts are unable to execute their function. Alendronate (ALN) is a bisphosphonate used to treat osteoporosis. Its administration could be associated with adverse effects. The purpose of this study is to evaluate four different ALN concentrations, ranging from 10-6 to 10-10 M, in the presence of different combinations of M-CSF and RANKL, to find out the effect of low ALN concentrations on osteoclastogenesis using rat and human peripheral blood mononuclear cells. The cytotoxic effect of ALN was evaluated based on metabolic activity and DNA concentration measurement. The alteration in osteoclastogenesis was assessed by the activity of carbonic anhydrase II (CA II), tartrate-resistant acid phosphatase staining, and actin ring formation. The ALN concentration of 10-6 M was cytotoxic. Low ALN concentrations of 10-8 and 10-10 M promoted proliferation, osteoclast-like cell formation, and CA II activity. The results indicated the induction of osteoclastogenesis with low ALN concentrations. However, when high doses of ALN were administered, their cytotoxic effect was demonstrated.

• Klíčová slova
• M-CSF, RANKL, alendronate, osteoclastogenesis,
• MeSH
• aktiny metabolismus   MeSH
• alendronát farmakologie   MeSH
• barvení a značení MeSH
• DNA metabolismus   MeSH
• faktor stimulující kolonie makrofágů farmakologie   MeSH
• karboanhydrasa II metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselá fosfatasa rezistentní k tartarátu metabolismus   MeSH
• leukocyty mononukleární účinky léků   metabolismus   MeSH
• lidé MeSH
• ligand RANK farmakologie   MeSH
• osteogeneze účinky léků   MeSH
• osteoklasty účinky léků   enzymologie   metabolismus   MeSH
• proliferace buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aktiny MeSH
• alendronát MeSH
• DNA MeSH
• faktor stimulující kolonie makrofágů MeSH
• karboanhydrasa II MeSH
• kyselá fosfatasa rezistentní k tartarátu MeSH
• ligand RANK MeSH

Simple molecular descriptors of extensive series of 1,3,5-triazinyl sulfonamide derivatives, based on the structure of sulfonamides and their physicochemical properties, were designed and calculated. These descriptors were successfully applied as inputs for artificial neural network (ANN) modelling of the relationship between the structure and biological activity. The optimized ANN architecture was applied to the prediction of the inhibition activity of 1,3,5-triazinyl sulfonamides against human carbonic anhydrase (hCA) II, tumour-associated hCA IX, and their selectivity (hCA II/hCA IX).

• Klíčová slova
• 1,3,5-triazinyl sulfonamide derivatives, ANN, Carbonic anhydrase, Structural descriptors,
• MeSH
• antigeny nádorové metabolismus   MeSH
• inhibitory karboanhydras chemie   metabolismus   MeSH
• karboanhydrasa II antagonisté a inhibitory   metabolismus   MeSH
• karboanhydrasa IX antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• neuronové sítě * MeSH
• racionální návrh léčiv MeSH
• sulfonamidy chemie   metabolismus   MeSH
• triaziny chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antigeny nádorové MeSH
• CA9 protein, human MeSH Prohlížeč
• inhibitory karboanhydras MeSH
• karboanhydrasa II MeSH
• karboanhydrasa IX MeSH
• sulfonamidy MeSH
• triaziny MeSH

Accurate prediction of protein-ligand binding affinities is essential for hit-to-lead optimization and virtual screening. The reliability of scoring functions can be improved by including quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function by using a challenging set of 10 inhibitors binding to carbonic anhydrase II through Zn2+ in the active site. This new dataset consists of the high-resolution (1.1-1.4 Å) crystal structures and experimentally determined inhibitory constant (Ki ) values. It allows for evaluation of the common approximations, such as representing the solvent implicitly or by using a single target conformation combined with a set of ligand docking poses. SQM/COSMO attained a good correlation of R2 of 0.56-0.77 with the experimental inhibitory activities, benefiting from careful handling of both noncovalent interactions (e.g. charge transfer) and solvation. This proof-of-concept study of SQM/COSMO ranking for metalloprotein-ligand systems demonstrates its potential for hit-to-lead applications.

• Klíčová slova
• binding affinities, crystallography, lead optimization, quantum mechanics, scoring function,
• MeSH
• chemické modely MeSH
• inhibitory karboanhydras chemie   metabolismus   MeSH
• karboanhydrasa II chemie   metabolismus   MeSH
• kvantová teorie MeSH
• ligandy MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• sulfonamidy chemie   metabolismus   MeSH
• vazba proteinů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory karboanhydras MeSH
• karboanhydrasa II MeSH
• ligandy MeSH
• sulfonamidy MeSH

A new series of s-triazine derivatives incorporating sulfanilamide, homosulfanilamide, 4-aminoethyl-benzenesulfonamide and piperazine or aminoalcohol structural motifs is reported. Molecular docking was exploited to select compounds from virtual combinatorial library for synthesis and subsequent biological evaluation. The compounds were prepared by using step by step nucleophilic substitution of chlorine atoms from cyanuric chloride (2,4,6-trichloro-1,3,5-triazine). The compounds were tested as inhibitors of physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms. Specifically, against the cytosolic hCA I, II and tumor-associated hCA IX. These compounds show appreciable inhibition. hCA I was inhibited with KIs in the range of 8.5-2679.1 nM, hCA II with KIs in the range of 4.8-380.5 nM and hCA IX with KIs in the range of 0.4-307.7 nM. As other similar derivatives, some of the compounds showed good or excellent selectivity ratios for inhibiting hCA IX over hCA II, of 3.5-18.5. 4-[({4-Chloro-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)methyl] benzene sulfonamide demonstrated subnanomolar affinity for hCA IX (0.4 nM) and selectivity (18.50) over the cytosolic isoforms. This series of compounds may be of interest for the development of new, unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX.

• Klíčová slova
• 1,3,5-Triazine, Benzene sulfonamides, Carbonic anhydrase, Enzyme inhibition, Isoform selectivity,
• MeSH
• aminoalkoholy chemie   farmakologie   MeSH
• antigeny nádorové metabolismus   MeSH
• inhibitory karboanhydras chemická syntéza   chemie   farmakologie   MeSH
• karboanhydrasa I antagonisté a inhibitory   metabolismus   MeSH
• karboanhydrasa II antagonisté a inhibitory   metabolismus   MeSH
• karboanhydrasa IX antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• piperazin chemie   farmakologie   MeSH
• sulfonamidy chemie   farmakologie   MeSH
• triaziny chemie   farmakologie   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
• Názvy látek
• aminoalkoholy MeSH
• antigeny nádorové MeSH
• CA9 protein, human MeSH Prohlížeč
• inhibitory karboanhydras MeSH
• karboanhydrasa I MeSH
• karboanhydrasa II MeSH
• karboanhydrasa IX MeSH
• piperazin MeSH
• sulfonamidy MeSH
• triaziny MeSH

Effective and controlled drug delivery systems with on-demand release and targeting abilities have received enormous attention for biomedical applications. Here, we describe a novel enzyme-based cap system for mesoporous silica nanoparticles (MSNs) that is directly combined with a targeting ligand via bio-orthogonal click chemistry. The capping system is based on the pH-responsive binding of an aryl-sulfonamide-functionalized MSN and the enzyme carbonic anhydrase (CA). An unnatural amino acid (UAA) containing a norbornene moiety was genetically incorporated into CA. This UAA allowed for the site-specific bio-orthogonal attachment of even very sensitive targeting ligands such as folic acid and anandamide. This leads to specific receptor-mediated cell and stem cell uptake. We demonstrate the successful delivery and release of the chemotherapeutic agent Actinomycin D to KB cells. This novel nanocarrier concept provides a promising platform for the development of precisely controllable and highly modular theranostic systems.

• MeSH
• aktivní transport MeSH
• buněčné linie MeSH
• daktinomycin aplikace a dávkování   farmakokinetika   MeSH
• HeLa buňky MeSH
• karboanhydrasa II chemie   genetika   metabolismus   MeSH
• KB buňky MeSH
• lékové transportní systémy * MeSH
• léky s prodlouženým účinkem MeSH
• lidé MeSH
• myši MeSH
• nanočástice * chemie   MeSH
• oxid křemičitý MeSH
• proteinové inženýrství MeSH
• protinádorové látky aplikace a dávkování   farmakokinetika   MeSH
• receptory léků chemie   genetika   metabolismus   MeSH
• uvolňování léčiv MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• daktinomycin MeSH
• karboanhydrasa II MeSH
• léky s prodlouženým účinkem MeSH
• oxid křemičitý MeSH
• protinádorové látky MeSH
• receptory léků MeSH

Isoquinolinesulfonamides inhibit human carbonic anhydrases (hCAs) and display selectivity toward therapeutically relevant isozymes. The crystal structure of hCA II in complex with 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-ylsulfonamide revealed unusual inhibitor binding. Structural analyses allowed for discerning the fine details of the inhibitor binding mode to the active site, thus providing clues for the future design of even more selective inhibitors for druggable isoforms such as the cancer associated hCA IX and neuronal hCA VII.

• MeSH
• inhibitory karboanhydras chemie   metabolismus   farmakologie   MeSH
• isochinoliny chemie   metabolismus   farmakologie   MeSH
• izoenzymy antagonisté a inhibitory   chemie   metabolismus   MeSH
• karboanhydrasa II antagonisté a inhibitory   chemie   metabolismus   MeSH
• konformace proteinů MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární modely MeSH
• substrátová specifita MeSH
• vazba proteinů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory karboanhydras MeSH
• isochinoliny MeSH
• izoenzymy MeSH
• karboanhydrasa II MeSH

Previous data concerning the action of calcium (Ca) on gastric acid secretion (GAS) indicated that calcium ions increase GAS elicited by gastrin released through a vagal mechanism, and also by a direct effect on parietal cells. Our research showed that the stimulating effect of calcium on gastric acid secretion can be antagonized by verapamil administration, which reduces gastric acid secretion . In the present study we followed the effect induced by administration of calcium and Ca-chelating agents (disodium EDTA) on gastric acid secretion and on carbonic anhydrase (CA) activity. We selected two groups of healthy volunteers: Group I (n=21) received a single i.v. dose of CaCl2 (15 mg/kg b.w.), whereas Group II (n=22) received a single i.v. dose of disodium EDTA (5 mg/kg b.w.). We determined blood calcium before and after treatment, gastric acid secretion at 2 hours. erythrocyte CA II activity, and CA IV activity in membrane parietal cells, which were isolated from gastric mucosa obtained by endoscopic biopsy. Assessment of carbonic anhydrase activity was achieved by the stopped-flow method. In Group I calcium administration increased blood calcium, HCl output, CA II and CA IV activity as compared to initial values. In Group II, disodium EDTA reduced blood calcium, HCl output, CA II and CA IV activity as compared to initial values. The results demonstrated that increased blood calcium and GAS values after calcium administration correlated with the increase of erythrocyte CA II and parietal cell CA IV activity, while disodium EDTA induced a reversed process. Our results also show that cytosolic CA II and membrane CA IV values are sensitive to calcium changes and they directly depend on these levels. Our data suggest that intra- and extracellular pH changes induced by carbonic anhydrase might account for the modulation of the physiological and pathological secretory processes in the organism.

• MeSH
• chelátory aplikace a dávkování   MeSH
• dospělí MeSH
• EDTA aplikace a dávkování   MeSH
• erytrocyty enzymologie   MeSH
• karboanhydrasa II metabolismus   MeSH
• karboanhydrasa IV metabolismus   MeSH
• koncentrace vodíkových iontů MeSH
• lidé středního věku MeSH
• lidé MeSH
• nervus vagus fyziologie   MeSH
• vápník aplikace a dávkování   krev   MeSH
• žaludeční kyselina metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• chelátory MeSH
• EDTA MeSH
• karboanhydrasa II MeSH
• karboanhydrasa IV MeSH
• vápník MeSH