Herein we report the polymer-supported synthesis of 3,4-dihydro-2H-1,4-oxazine-3-carboxylic acid derivatives using immobilized Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu)-OH as the starting materials. After the solid-phase-synthesis of N-alkyl-N-sulfonyl/acyl intermediates, the target dihydrooxazines were obtained using trifluoroacetic acid-mediated cleavage from the resin. This approach was also studied for the preparation of dihydrothiazines from immobilized Fmoc-Cys(Trt)-OH. Inclusion of triethylsilane in the cleavage cocktail resulted in the stereoselective formation of the corresponding morpholine/thiomorpholine-3-carboxylic acids. Stereochemical studies revealed the specific configuration of the newly formed stereocenter and also the formation of stable N-acylmorpholine rotamers.
- MeSH
- Fluorenes chemistry MeSH
- Carboxylic Acids chemical synthesis chemistry MeSH
- Morpholines chemical synthesis chemistry MeSH
- Oxazines chemical synthesis chemistry MeSH
- Polymers chemistry MeSH
- Stereoisomerism MeSH
- Solid-Phase Synthesis Techniques methods MeSH
- Thiazines chemical synthesis chemistry MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
We have synthesized a series of 2-phenyl-3-hydroxy-4(1H)-quinolinone derivatives substituted with one or more fluorine atoms on the quinolone backbone as well as on phenyl ring. The derivatives bearing more fluorine atoms were subjected to modification by nucleophilic substitutions by thiophenol, morpholine, and piperazine derivative. We have tested the prepared compounds in cytotoxic activity assay against cancer cell lines. Four derivatives exhibited micromolar values of IC50 against some of the cancer cell lines, and we have subjected them to cell cycle analysis on CCRF-CEM. Moreover, most active 7-fluoro-3-hydroxy-2-phenyl-6-(phenylthio)quinolin-4(1H)-one inhibits mitosis progression. Cell cycle analysis, in vitro tubulin polymerization assay, and tubulin imaging in cells indicated that the anticancer activity of thiophenol derivative is associated with its ability to inhibit microtubule formation.
- MeSH
- Quinolones chemical synthesis chemistry pharmacology MeSH
- Halogenation MeSH
- HCT116 Cells MeSH
- Humans MeSH
- Tubulin Modulators chemical synthesis chemistry pharmacology MeSH
- Molecular Structure MeSH
- Polymerization drug effects MeSH
- Tubulin metabolism MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
We report the design, synthesis and biological evaluation of 17 novel 8-aryl-2-morpholino-3,4-dihydroquinazoline derivatives based on the standard model of DNA-PK and PI3K inhibitors. Novel compounds are sub-divided into two series where the second series of five derivatives was designed to have a better solubility profile over the first one. A combination of in vitro and in silico techniques suggested a plausible synergistic effect with doxorubicin of the most potent compound 14d on cell proliferation via DNA-PK and poly(ADP-ribose) polymerase-1 (PARP-1) inhibition, while alone having a negligible effect on cell proliferation.
- MeSH
- Apoptosis drug effects MeSH
- HT29 Cells MeSH
- Quinazolinones chemical synthesis pharmacology toxicity MeSH
- Doxorubicin pharmacology MeSH
- Enzyme Inhibitors chemical synthesis pharmacology toxicity MeSH
- Nuclear Proteins antagonists & inhibitors MeSH
- Humans MeSH
- Morpholines chemical synthesis pharmacology toxicity MeSH
- Mice MeSH
- Animals, Outbred Strains MeSH
- Poly (ADP-Ribose) Polymerase-1 antagonists & inhibitors MeSH
- Cell Proliferation drug effects MeSH
- DNA-Activated Protein Kinase antagonists & inhibitors MeSH
- Antineoplastic Agents pharmacology MeSH
- Drug Design MeSH
- Drug Synergism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
N-polyfluoroalkyl derivatives of 6-deoxy-6-ethylamino-1,2;3,4-di-O-isopropylidene-alpha-D-galactopyranose (8-10), 1-deoxy-1-methylamino-D-glucitol (13-15), and 1-amino-1-deoxy-D-glucitol (16-18), all possessing perfluoroalkyl segment, were prepared using nucleophilic epoxide ring opening of 2-[(perfluoroalkyl)methyl]oxiranes 1-3. Co-emulsifying properties and hemolytic activity of the new perfluoroalkylated amphiphiles were tested. Both types of the polyol derivatives 8-10 and 13-18 generally displayed good to excellent co-emulsifying properties on testing on perfluorodecalin/Pluronic F-68 microemulsions. Mono-perfluoroalkylated compounds 8-10 and 13-15 displayed high hemolysis, whereas acyclic bis-perfluoroalkylated compounds 16-18 were non-hemolytic even for short perfluorobutyl segment (16). The properties were generally improving with increasing perfluoroalkyl chain length.
- MeSH
- Emulsions MeSH
- Erythrocytes drug effects MeSH
- Ethylamines chemistry MeSH
- Fluorocarbons chemistry MeSH
- Hydrocarbons, Fluorinated chemistry MeSH
- Galactose adverse effects analogs & derivatives chemical synthesis MeSH
- Humans MeSH
- Methylamines chemistry MeSH
- Morpholines chemistry MeSH
- Poloxamer chemistry MeSH
- Sorbitol adverse effects analogs & derivatives chemical synthesis MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Tuberkulóza (TB) provází lidstvo po celou jeho historii. Navzdory faktu, že její původce Mycobacterium tuberculosis byl odhalen před více než stoletím a déle než padesát let již máme k dispozici základní řadu léků pro léčbu této nemoci, představuje i nadále celosvětovou hrozbu jak počtem nakažených a nemocných, tak i mortalitou. V současné době je v České republice epidemiologická situace dobrá, incidence a prevalence TB je jednou z nejnižších v celé Evropě. Je to dáno jednak kvalitní léčbou a vyšetřováním kontaktů a jejich sledováním, dobrou politikou chemoprofylaxe a chemoprevence, ale i izolací nemocných po dobu jejich infekčnosti. BCG vakcinace je v ČR od roku 2011 selektivní, což znamená, že jsou očkováni pouze rizikoví novorozenci, navzdory tomu nestoupají počty dětí nemocných TB. Určité změny v epidemiologii TB lze očekávat v Evropě s migračními vlnami ze zemí s vysokým výskytem TB, včetně multirezistentních forem. Čas ukáže, jak se dokážeme s těmito vlivy v našem systému kontroly TB vyrovnat, nicméně vzhledem k nízkému počtu migrantů u nás zřejmě k významným nárůstům počtu nemocných TB nedojde.
Tuberculosis (TB) accompanies humans throughout their entire history. Despite the fact that etiologic agent of TB, Mycobacterium tuberculosis, was described more than one century ago and for more than half of century we have basic line of antituberculous drugs, TB still represents global threat, with respect both to the number of infected individuals and to mortality. The current epidemiologic situation in the Czech Republic is optimistic, with incidence and prevalence values being one of the lowest in Europe. This is due to a quality treatment system and contact tracing and investigation, good policy of chemoprevention and chemoprophylaxis, and also due to isolation of all patients with contagious forms of TB. BCG vaccination in the Czech Republic is selective since 2011, i.e. only newborns at higher risk of TB are vaccinated. Despite this approach, the number of children with TB does not grow. Some changes in epidemiology of TB might be expected due to the migration waves from the countries with higher prevalence of TB, multidrug resistant forms included. Time will show how we can cope with these influences in our system of TB control; however, given the low numbers of migrants in the Czech Republic, changes in TB epidemiology will probably not be significant.
- Keywords
- bedaquilin, delamanid,
- MeSH
- Antitubercular Agents * administration & dosage adverse effects therapeutic use MeSH
- BCG Vaccine adverse effects therapeutic use MeSH
- Diarylquinolines administration & dosage adverse effects MeSH
- Ethambutol administration & dosage adverse effects MeSH
- Isoniazid administration & dosage adverse effects MeSH
- Drug Therapy, Combination * methods MeSH
- Drug Resistance MeSH
- Humans MeSH
- Nimorazole administration & dosage adverse effects MeSH
- Oxazoles administration & dosage adverse effects MeSH
- Pyrazinamide administration & dosage adverse effects MeSH
- Rifampin administration & dosage adverse effects MeSH
- Streptomycin administration & dosage adverse effects MeSH
- Tuberculosis * diagnosis epidemiology drug therapy prevention & control MeSH
- Vaccination MeSH
- Check Tag
- Humans MeSH
Skin penetration enhancers are used in the formulation of transdermal delivery systems for drugs that are otherwise not sufficiently skin-permeable. We generated two series of esters by multi-step synthesis with substituted 6-aminohexanoic acid as potential transdermal penetration enhancers by multi-step synthesis. The synthesis of all newly prepared compounds is presented here. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy. All the prepared compounds were analyzed using RP-HPLC and their lipophilicity (logk) was determined. The hydrophobicity (logP/ClogP) of the studied compounds was also calculated using two commercially available programs and 3D structures of the selected compounds were investigated by means of ab initio calculations of geometry and molecular dynamic simulations. All the synthesized esters were tested for their in vitro transdermal penetration-enhancing activity and showed higher enhancement ratios than oleic acid. The highest enhancement ratios were exhibited by compound 5f (C((2)) substituted with piperidine-2-one, C(11) ester chain) and 5a (C((2)) substituted with piperidine-2-one, C(6) ester chain). The series with a ω-lactam ring (piperidin-2-one; 5a-g), showed slightly higher activities than those with morpholine (6a-6g). All of the agents showed minimal anti-proliferative activity (IC(50) >6.25μM), indicating they would have low cytotoxicity when administered as chemical penetration enhancers. The relationships between the lipophilicity and the chemical structure of the studied compounds, as well as the correlation between their chemical structure and transdermal penetration-enhancing activity, are discussed.
- MeSH
- Administration, Cutaneous MeSH
- Hydrophobic and Hydrophilic Interactions MeSH
- Caproates chemistry pharmacology MeSH
- Skin Absorption drug effects MeSH
- Molecular Structure MeSH
- Drug Carriers chemistry MeSH
- Molecular Dynamics Simulation MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Quinazolines - 1,3-benzodiazines are biological active compounds, which are used in the phamaceutical industry, in agriculture and in the medicine. As documented in the literature, many derivatives demonstrated anticancer activity and they act as multitarget agents. 3-(5-Nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c] quinazoline (NTCHMTQ) - a new synthetically prepared quinazoline derivative was the most effective derivative in our primary cytotoxic screening. In this study, we evaluated cytotoxic/antiproliferative activity of NTCHMTQ using human tumor cell line HeLa. Possible interaction of 3-(5-nitro-2-thienyl)-9-chloro-5-morpholin-4-yl[1,2,4]triazolo[4,3-c] quinazoline with calf thymus DNA was tested by the DNA - modified screen - printed electrode. Quinazoline derivative acted cytotoxically on tumor cell line HeLa. The IC(100) value was 10 microg/ml. The IC(50) values was found to be less than 4 microg/ml, a limit put forward by the National Cancer Institute (NCI) for classification of he compound as a potential anticancer drug. Quinazoline at micromolar concentrations induced morphological changes and necrosis of HeLa cells. Using the DNA based electrochemical biosensor, we have not found damage to DNA under in vitro conditions at an incubation of the biosensor in mixture with quinazoline.
- MeSH
- Quinazolines pharmacology MeSH
- HeLa Cells MeSH
- Humans MeSH
- DNA Damage drug effects MeSH
- Antineoplastic Agents pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Cattle MeSH
- Triazoles pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Cattle MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Keywords
- Rivaroxaban, Apixaban a Dabigatran letexilát, Antidota a sledování nových antitrombotik,
- MeSH
- Ambulatory Care methods utilization MeSH
- Anticoagulants * administration & dosage adverse effects therapeutic use MeSH
- Heparin pharmacokinetics adverse effects therapeutic use MeSH
- Clinical Laboratory Techniques methods utilization MeSH
- Hemorrhage * drug therapy complications prevention & control MeSH
- Coumarins pharmacokinetics adverse effects therapeutic use MeSH
- Humans MeSH
- Morpholines MeSH
- Statistics as Topic MeSH
- Thiophenes MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
