A series of 11-substituted 9-hydroxy-3,5,10,11-tetrahydro-2H-benzo[6,7]thiochromeno[2,3-d][1,3]thiazole-2,5,10-triones 3.1-3.13 were synthesized via hetero-Diels-Alder reaction of 5-ene-4-thioxo-2-thiazolidinones and 5-hydroxy-1,4-naphthoquinone (juglone). The structure of newly synthesized compounds was established by means of spectral data and a single-crystal X-ray diffraction analysis. The synthesized compounds were tested on a panel of cell lines representing different types of cancer as well as normal and pseudonormal cells and peripheral human blood lymphocytes. Compound 3.10 was found to be the most active derivative, exhibiting a cytotoxic effect similar to doxorubicin's one (IC50 ranged from 0.6 to 5.98 μM), but less toxic to normal and pseudonormal cells. All synthesized compounds were able to interact with DNA, although their anticancer activity did not correlate with the potency of interaction with DNA. The status of p53 in colorectal cancer cells correlated with the activity of the synthesized derivatives 3.1, 3.7, and 3.10. Compound 3.10 did not have an acute toxic effect on the body of С57BL/6 mice, unlike the well-known anticancer drug doxorubicin, which was used as a positive control. The injection of 3.10 (20 mg/kg) to mice had no effect on the counts of leukocytes, erythrocytes, platelets and hemoglobin level in their blood, in contrast to doxorubicin, which caused anemia and leukopenia, indicating bio-tolerance of 3.10in vivo.
- MeSH
- antitumorózní látky * chemie MeSH
- doxorubicin farmakologie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- molekulární struktura MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- naftochinony * farmakologie MeSH
- proliferace buněk MeSH
- simulace molekulového dockingu MeSH
- thiazoly chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
There are numerous studies supporting the contribution of oxidative stress to the pathogenesis of epilepsy. Prolonged oxidative stress is associated with the overexpression of ATP-binding cassette transporters, which results in antiepileptic drugs resistance. During our studies, three 1,2,4-triazole-3-thione derivatives were evaluated for the antioxidant activity and anticonvulsant effect in the 6 Hz model of pharmacoresistant epilepsy. The investigated compounds exhibited 2-3 times more potent anticonvulsant activity than valproic acid in 6 Hz test in mice, which is well-established preclinical model of pharmacoresistant epilepsy. The antioxidant/ROS scavenging activity was confirmed in both single-electron transfer-based methods (DPPH and CUPRAC) and during flow cytometric analysis of total ROS activity in U-87 MG cells. Based on the enzymatic studies on human carbonic anhydrases (CAs), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), one can assume that the herein investigated drug candidates will not impair the cognitive processes mediated by CAs and will have minimal off-target cholinergic effects.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antikonvulziva chemická syntéza chemie farmakologie MeSH
- antioxidancia chemická syntéza chemie farmakologie MeSH
- bifenylové sloučeniny antagonisté a inhibitory MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- epilepsie farmakoterapie metabolismus MeSH
- inhibitory karboanhydras chemická syntéza chemie farmakologie MeSH
- karboanhydrasy metabolismus MeSH
- lidé MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- oxidační stres účinky léků MeSH
- pikráty antagonisté a inhibitory MeSH
- reaktivní formy kyslíku metabolismus MeSH
- triazoly chemická syntéza chemie farmakologie MeSH
- viabilita buněk účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
