In this study, we report the synthesis, antibacterial and anticancer evaluation of 38 novel phenanthridines that were designed as analogs of the benzo[c]phenanthridine alkaloids. The prepared phenanthridines differ from the benzo[c]phenanthridines in the absence of a benzene A-ring. All novel compounds were prepared from 6-bromo-2-hydroxy-3-methoxybenzaldehyde in several synthetic steps through reduction of Schiff bases and accomplished by radical cyclization. Twelve derivatives showed high antibacterial activity against Bacillussubtilis, Micrococcusluteus and/or Mycobacteriumvaccae at single digit micromolar concentrations. Some compounds also displayed cytotoxicity against the K-562 and MCF-7 cancer cell lines at as low as single digit micromolar concentrations and were more potent than chelerythrine and sanguinarine. The active compounds caused cell-cycle arrest in cancer cells, increased levels of p53 protein and caused apoptosis-specific fragmentation of PARP-1. Biological activity was connected especially with the presence of the N-methyl quaternary nitrogen and 7-benzyloxy substitution (compounds 7i, 7j, 7k, and 7l) of phenanthridine.
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- Bacteria účinky léků MeSH
- fenantridiny chemická syntéza chemie farmakologie MeSH
- kontrolní body buněčného cyklu účinky léků MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- techniky syntetické chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The proposed HPLC method using solely or nearly 100% aqueous mobile buffer as mobile phase offers fast determination of dissociation constant for compounds in relatively wide range of lipophilicity (log P from -2.26 to 2.26). The dissociation constant value for simpler chemical compounds can be determined via only 8 chromatographic runs. The number of needed chromatographic separations depends on the structural complexity of the tested compound. Moreover, the proposed method does not require a measurement of Yasuda-Shedlovsky extrapolation that includes several pKa determinations in solutions with different methanol content which speeds up considerably the procedure. The methodology is suitable for evaluation of large series of drug candidates, which can be present as complex mixtures and in small amounts.
2-Aminoquinolin-4(1H)-one was reacted with various primary/secondary amines and paraformaldehyde under Mannich reaction conditions. In the case of secondary amines, the reaction in N,N-dimethylformamide yielded expected Mannich products accompanied with 3,3'-methylenebis(2-aminoquinolin-4(1H)-one). Except these main products, the pyrimido[4,5-b]quinolin-5-one derivative was also identified as co-product. The reaction with primary amines led to the formation of pyrimido[4,5-b]quinolin-5-ones. The Mannich reaction products were thermally unstable and afforded a mixture of bis-(2-aminoquinolin-4(1H)-one) and tris-(2-aminoquinolin-4(1H)-one) derivative, probably via reactive methylene species. This retro-Mannich reaction was tested in reaction with indole and thiophenole as nucleophilles, and appropriate conjugates were formed. The mechanism of above discussed reactions in which 2-aminoquinolinone displays the nucleophilicity on C3 carbon as well as N2 nitrogen is discussed.
- MeSH
- aminochinoliny chemie MeSH
- Mannichovy báze chemie MeSH
- Publikační typ
- časopisecké články MeSH
7-(2-Thienyl)-7-deazaadenosine (AB61) showed nanomolar cytotoxic activities against various cancer cell lines but only mild (micromolar) activities against normal fibroblasts. The selectivity of AB61 was found to be due to inefficient phosphorylation of AB61 in normal fibroblasts. The phosphorylation of AB61 in the leukemic CCRF-CEM cell line proceeds well and it was shown that AB61 is incorporated into both DNA and RNA, preferentially as a ribonucleotide. It was further confirmed that a triphosphate of AB61 is a substrate for both RNA and DNA polymerases in enzymatic assays. Gene expression analysis suggests that AB61 affects DNA damage pathways and protein translation/folding machinery. Indeed, formation of large 53BP1 foci was observed in nuclei of AB61-treated U2OS-GFP-53BP1 cells indicating DNA damage. Random incorporation of AB61 into RNA blocked its translation in an in vitro assay and reduction of reporter protein expression was also observed in mice after 4-hour treatment with AB61. AB61 also significantly reduced tumor volume in mice bearing SK-OV-3, BT-549, and HT-29 xenografts. The results indicate that AB61 is a promising compound with unique mechanism of action and deserves further development as an anticancer agent. Mol Cancer Ther; 15(5); 922-37. ©2016 AACR.
- MeSH
- analýza přežití MeSH
- antitumorózní látky chemie metabolismus farmakologie MeSH
- DNA genetika metabolismus MeSH
- fibroblasty MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie genetika metabolismus patologie MeSH
- permeabilita buněčné membrány účinky léků MeSH
- poškození DNA účinky léků MeSH
- proliferace buněk účinky léků MeSH
- proteosyntéza účinky léků MeSH
- regulace genové exprese u nádorů MeSH
- sbalování proteinů účinky léků MeSH
- tubercidin analogy a deriváty chemie metabolismus farmakologie MeSH
- výsledek terapie MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The fluorescence properties of selected benzo[c]phenanthridines (BPs) were examined. The effect of structure, pH and solvent on the fluorescence properties has been investigated. It was found out that the presence of charged iminium nitrogen significantly decreased the fluorescence of the compounds. The fluorescence (intensity as well as emission spectra shape) of the investigated compounds was significantly dependent on pH as well as used solvent. The utilization in epigenetic modification mechanisms studies as demethylase probe and as possible pH indicator was suggested.
- MeSH
- benzofenantridiny chemická syntéza chemie MeSH
- fluorescence * MeSH
- fluorescenční barviva chemická syntéza chemie MeSH
- fluorescenční spektrometrie MeSH
- koncentrace vodíkových iontů MeSH
- molekulární struktura MeSH
- průtoková cytometrie MeSH
- rozpouštědla chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The fluorescence properties of bisheterocyclic compounds that contain purine and the 3-hydroxyquinolin-4(1H)-one skeleton connected with an aliphatic spacer of a different length/structure (3HQP) were examined. It was found that the introducing of the spacer-purine scaffold led in the comparison to 3HQs themselves to (1) the possibility of the effectual excitation in the wider range of excitation wavelengths, moreover, some derivatives can be excited at relatively high wavelengths around 400 nm, (2) the lowering of the quantum yield and (3) the slight longer wavelength shift of the dual emission spectra. Tested organic solvents did not affect significantly the 3HQP fluorescence properties. The characters of emission spectra as well as the quantum yields of 3HQPs were notably influenced by the ratio of water and DMSO in their composed mixture applied as a solvent. With increasing water content in the mixture both I(1)/I(2) and the quantum yield decreased.
The comparison of theoretical approaches describing the collection of analyte in the cylindrical wet effluent diffusion denuder (CWEDD) with experimental data is presented. Various absorption liquids were tested for the collection of formaldehyde (distilled-deionized water, H(2)SO(4) solution), acetaldehyde (distilled-deionized water) and nitrous acid (distilled-deionized water, sodium carbonate and sodium bicarbonate solutions of various concentrations and sodium phosphate pH 6-8) in CWEDD. pH of absorption liquids significantly influences the collection of formaldehyde as well as nitrous acid. The collection efficiency of formaldehyde for 0.05 M H(2)SO(4) as absorption liquid was generally higher than for distilled-deionized water. Absorption liquid pH markedly affected the collection efficiency of HONO too (with increasing pH the collection efficiency increase). Data derived by Gormley-Kennedy equation for all investigated compounds were overestimated especially for higher flow rates of air, data calculated with respect to Henry constant are not in good agreement with experimental data and are considerably depended on a determination of the Henry constant value. The CWEDD can be alternative tool for the determination of uptake coefficient. Obtained uptake coefficients were in good agreement with data found in other literature.
- Publikační typ
- časopisecké články MeSH
