A series of 1,3,5-triazinyl aminobenzenesulfonamides substituted by aminoalcohol, aminostilbene, and aminochalcone structural motifs was synthesized as potential human carbonic anhydrase (hCA) inhibitors. The compounds were evaluated on their inhibition of tumor-associated hCA IX and hCA XII, hCA VII isoenzyme present in the brain, and physiologically important hCA I and hCA II. While the test compounds had only a negligible effect on physiologically important isoenzymes, many of the studied compounds significantly affected the hCA IX isoenzyme. Several compounds showed activity against hCA XII; (E)-4-{2-[(4-[(2,3-dihydroxypropyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (31) and (E)-4-{2-[(4-[(4-hydroxyphenyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (32) were the most effective inhibitors with KIs = 4.4 and 5.9 nM, respectively. In addition, the compounds were tested against vancomycin-resistant Enterococcus faecalis (VRE) isolates. (E)-4-[2-({4-[(4-cinnamoylphenyl)amino]-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]benzenesulfonamide (21) (MIC = 26.33 μM) and derivative 32 (MIC range 13.80-55.20 μM) demonstrated the highest activity against all tested strains. The most active compounds were evaluated for their cytotoxicity against the Human Colorectal Tumor Cell Line (HCT116 p53 +/+). Only 4,4'-[(6-chloro-1,3,5-triazin-2,4-diyl)bis(iminomethylene)]dibenzenesulfonamide (7) and compound 32 demonstrated an IC50 of ca. 6.5 μM; otherwise, the other selected derivatives did not show toxicity at concentrations up to 50 μM. The molecular modeling and docking of active compounds into various hCA isoenzymes, including bacterial carbonic anhydrase, specifically α-CA present in VRE, was performed to try to outline a possible mechanism of selective anti-VRE activity.
- MeSH
- antibakteriální látky farmakologie MeSH
- antitumorózní látky farmakologie terapeutické užití MeSH
- enterokoky rezistentní vůči vankomycinu účinky léků MeSH
- HCT116 buňky MeSH
- inhibitory karboanhydras farmakologie MeSH
- karboanhydrasa I antagonisté a inhibitory MeSH
- karboanhydrasa II antagonisté a inhibitory MeSH
- karboanhydrasa IX antagonisté a inhibitory MeSH
- karboanhydrasy účinky léků MeSH
- lidé MeSH
- nádory farmakoterapie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- sulfonamidy farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články 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).
- 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 (počítačové) * MeSH
- racionální návrh léčiv MeSH
- sulfonamidy chemie metabolismus MeSH
- triaziny chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články 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.
- 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
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
Survival and capability of cancer cells to form metastases fundamentally depend on interactions with their microenvironment. Secondary tumors originating from prostate carcinomas affect remodeling of bone tissue and can induce both osteolytic and osteocondensing lesions. However, particular molecular mechanisms responsible for selective homing and activity of cancer cells in bone microenvironment have not been clarified yet. Growth/differentiation factor-15 (GDF-15), a distant member of the TGF-beta protein family, has recently been associated with many human cancers, including prostate. We show that both pure GDF-15 and the GDF-15-containing growth medium of 1,25(OH)(2)-vitamin D(3)-treated prostate adenocarcinoma LNCaP cells suppress formation of mature osteoclasts differentiated from RAW264.7 macrophages and bone-marrow precursors by M-CSF/RANKL in a dose-dependent manner. GDF-15 inhibits expression of c-Fos and activity of NFkappaB by delayed degradation of IkappaB. Moreover, GDF-15 inhibits expression of carbonic anhydrase II and cathepsin K, key osteoclast enzymes, and induces changes in SMAD and p38 signaling. The lack of functional osteoclasts can contribute to accumulation of bone matrix by reduction of bone resorption. These results unveil new role of GDF-15 in modulation of osteoclast differentiation and possibly in therapy of bone metastases.
- MeSH
- buněčná diferenciace účinky léků MeSH
- buněčné linie MeSH
- časové faktory MeSH
- faktor stimulující kolonie makrofágů farmakologie MeSH
- femur cytologie MeSH
- inbrední kmeny myší MeSH
- izoenzymy metabolismus MeSH
- kalcitriol farmakologie MeSH
- karboanhydrasa II antagonisté a inhibitory MeSH
- kathepsin K antagonisté a inhibitory genetika MeSH
- kultivační média speciální farmakologie MeSH
- kyselá fosfatasa metabolismus MeSH
- lidé MeSH
- ligand RANK farmakologie MeSH
- makrofágy cytologie MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory prostaty metabolismus MeSH
- NF-kappa B antagonisté a inhibitory MeSH
- osteoklasty metabolismus účinky léků MeSH
- protoonkogenní proteiny c-fos antagonisté a inhibitory MeSH
- růstový diferenciační faktor 15 farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
