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
- 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
- protinádorové látky farmakologie terapeutické užití 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 * MeSH
- racionální návrh léčiv MeSH
- sulfonamidy chemie metabolismus MeSH
- triaziny chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
An efficient and simple methodology for Ullmann Cu(I)-catalyzed synthesis of di- and trisubstituted 1,3,5-triazine derivatives from dichlorotriazinyl benzenesulfonamide and corresponding nucleophiles is reported. Cations Cu(I) supported on macroporous and weakly acidic, low-cost industrial resin of polyacrylate type were used as a catalyst. The reaction times and yields were compared with traditional synthetic methods for synthesis of substituted 1,3,5-triazine derivatives via nucleophilic substitution of chlorine atoms in dichlorotriazinyl benzenesulfonamide. It was found that Ullmann-type reactions provide significantly shortened reaction times and, in some cases, also higher yields. Finally, trisubstituted s-triazine derivatives were effectively prepared via Ullmann-type reaction in a one-pot synthetic design. Six new s-triazine derivatives with potential biological activity were prepared and characterized.
- MeSH
- katalýza MeSH
- měď chemie MeSH
- molekulární struktura MeSH
- poréznost MeSH
- triaziny chemická syntéza chemie MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie 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
Vrozená vnímavost k mykobakteriálním onemocněním (Mendelian Susceptibility to Mycobacterial Diseases) je skupina monogenně podmíněných primárních imunodeficitů způsobených defekty v jednotlivých komponentech signalizační kaskády IL12-IL23/IFNγ zajišťující komunikaci mezi fagocyty a Th1 lymfocyty. Onemocnění se projevují selektivně sníženou obranyschopností proti mykobakteriím (především proti oportunně patogenním kmenům) a netyfoidním salmonelám, přičemž ostatní antimikrobiální imunita zůstává intaktní. Závažnost onemocnění se pohybuje od lokálních komplikací v místě inokulace BCG vakcíny až po fatální diseminované infekce. Předkládané kazuistiky popisují první dva pacienty diagnostikované v ČR: děvče s mutací receptoru pro IFNγ a chlapce s loss of function STAT1 mutací.
Mendelian Susceptibility to Mycobacterial Diseases (MSMD) encompasses a newly emerged group of monogenic primary immunodeficiencies caused by defects in IL12-IL23/IFNγ mediated mononuclear phagocyte-Th1 communication pathway. Patients typically display various degree of selective impairment of immunity against mycobacteria (particularly against weakly virulent strains) and nontyphoid salmonellae; other aspects of host defence remain intact. Depending on the specific mutation, the clinical presentation ranges from mild adverse reactions to BCG vaccine to life-threatening disseminated mycobacterial infections and salmonellosis. The following case review reports on first two patients diagnosed with MSMD in the Czech Republic: a girl with IFNγ receptor mutation and a boy with STAT1 loss of function mutation.
- Klíčová slova
- MSMD,
- MeSH
- antibakteriální látky terapeutické užití MeSH
- antituberkulotika terapeutické užití MeSH
- BCG vakcína genetika škodlivé účinky MeSH
- dítě MeSH
- genetická predispozice k nemoci * MeSH
- genetické testování MeSH
- imunologické testy MeSH
- interferon gama MeSH
- interleukin-12 MeSH
- klinické laboratorní techniky MeSH
- kojenec MeSH
- lidé MeSH
- mutace MeSH
- mykobakteriózy * diagnóza farmakoterapie genetika MeSH
- transkripční faktor STAT1 genetika imunologie MeSH
- výsledek terapie MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Závěrečná zpráva o řešení grantu Interní grantové agentury MZ ČR
Přeruš. str. : il., tab. ; 32 cm + 1 příloha (Přílohy)
Význam histochemického průkazu aktivit lysosomálních enzymů a enzymů pericelulární proteolýzy pro diagnózu a prognózu nádorů sliznice děložní, čípku, tlustého střeva, močového měchýře a prostaty.; The significane of the histichem. demonst. of activit. of lysosomal and pericellular proteolysis enzames in the diagnos.and prognos.e of tumors of the mucous membrane of the uterus,cervix,large bowel,urinary bladder and of the prostate will be evaluated.
- MeSH
- enzymy diagnostické užití MeSH
- imunohistochemie metody MeSH
- kolorektální nádory diagnóza MeSH
- nádory dělohy diagnóza MeSH
- nádory močového měchýře diagnóza MeSH
- nádory prostaty diagnóza MeSH
- prognóza MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- onkologie
- chemie, klinická chemie
- biochemie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu IGA MZ ČR
