New open-chain and water-soluble hypervalent iodine reagents were synthesized and used for the transfer of fluoroalkyl groups to sulfur atoms of cysteine and cysteine-containing peptides under biocompatible conditions. Some of the reagents displayed excellent reactivity despite their limited stability in aqueous media. In reactions with a short cysteine-containing peptide, in addition to the expected S-fluoroalkylated product, a range of side-products were obtained. The amount of side-products depended on the conditions used (type of reagent, concentration, and pH). With highly activated hypervalent iodine reagents, a new reactive mode was observed - reaction with disulfides to form fluoroalkyl thiols.
- MeSH
- alkylace MeSH
- fluorované uhlovodíky chemická syntéza chemie MeSH
- indikátory a reagencie chemická syntéza chemie MeSH
- jod chemie MeSH
- molekulární struktura MeSH
- rozpustnost MeSH
- sulfhydrylové sloučeniny chemie MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We have examined the insertion of carbenes carrying leaving groups into the [nido-B11H13]2- dianion to form the [closo-1-CB11H12]- anion. The best procedure uses CF3SiMe3 and LiCl as the source of CF2. It is simple, convenient and scalable and proceeds with 70-90% yield. Density functional calculations have been used to develop a mechanistic proposal that accounts for the different behavior of CF2, requiring only one equivalent of base for successful conversion of Na[nido-B11H14]- to [closo-1-CB11H12]-, and CCl2 and CBr2, which require more.
We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosis strains, including clinically isolated multidrug-resistant strains. Thorough structure-activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosis H37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosis were found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-β-d-ribofuranose 2'-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.
- MeSH
- alkoholoxidoreduktasy antagonisté a inhibitory metabolismus MeSH
- antituberkulotika chemická syntéza chemie farmakologie MeSH
- bakteriální proteiny antagonisté a inhibitory metabolismus MeSH
- dinitrobenzeny chemická syntéza chemie farmakologie MeSH
- fluorované uhlovodíky chemická syntéza chemie farmakologie MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- Mycobacterium tuberculosis účinky léků enzymologie MeSH
- triazoly chemická syntéza chemie farmakologie MeSH
- vyvíjení léků * MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In this article, we describe the preparation and cytotoxic properties of a small focused library of lupane and 18α-oleanane triterpenoids that contain a combination of two structural motifs known to enhance the biological activities. First, we introduced two fluorine atoms to position 2 of the skeleton. Second, we synthesized a set of hemiester prodrugs, which were intended to increase the solubility and activity. Starting from betulin, we obtained two hydroxyketones (derivatives of dihydrobetulinic acid and allobetulin) and their fluorination using DAST provided 2,2-difluoro-3-oxo-compounds as the main products. Then the 3-oxo group in each derivative was reduced by NaBH4 to obtain 3β-hydroxy compounds suitable for modifying by various hemiesters. We prepared 21 compounds, 11 of them new, their cytotoxicity was tested on T lymphoblastic leukemia CCRF-CEM cells first and the most active derivatives were selected for screening on another six tumor and two non-tumor cell lines. All of them showed selectivity against cancer lines with therapeutic index between 2 and 8. All hemiesters had activity in the same range as the free hydroxyl derivatives and they would be suitable prodrugs for future in vivo experiments. Interestingly, all hemiesters of 2,2-difluorodihydrobetulonic acid had higher activity against p53 knock-out p53-/- cancer cell line than against the non-mutated analog. In active derivatives, the cell cycle was analyzed by flow cytometry and several compounds slowed down cell cycle progression through G0/G1 or S-phase.
- MeSH
- apoptóza účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- fibroblasty účinky léků MeSH
- fluorované uhlovodíky chemická syntéza chemie farmakologie MeSH
- fytogenní protinádorové látky chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární konformace MeSH
- nádorové buňky kultivované MeSH
- proliferace buněk účinky léků MeSH
- screeningové testy protinádorových léčiv MeSH
- triterpeny chemie 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
A series of final six propanoyloxy derivatives of 5β-cholan-24-oic acid (tridecafluoroctylsulfanyl- and tridecafluoroctylsulfinylethoxycarbonylpropanoyloxy derivatives) as potential drug absorption promoters (skin penetration enhancers, intestinal absorption promoters) was generated by multistep synthesis. Structure confirmation of all generated compounds was accomplished by (1)H NMR, (13)C NMR, IR and MS spectroscopy methods. All the prepared compounds were analyzed using RP-TLC, and their lipophilicity (RM) was determined. The hydrophobicity (log P), solubility (logS), polar surface area (PSA) and molar volume (MV) of the studied compounds were also calculated. All the target compounds were tested for their in vitro transdermal penetration effect and as potential intestinal absorption enhancers. The cytotoxicity of all the evaluated compounds was evaluated against normal human skin fibroblast cells. Their anti-proliferative activity was also assessed against human cancer cell lines: T-lymphoblastic leukaemia cell line and breast adenocarcinoma cell line. One compound showed high selective cytotoxicity against human skin fibroblast cells and another compound possessed high cytotoxicity against breast adenocarcinoma cell line and skin fibroblast cells. Only one compound expressed anti-proliferative effect on leukaemia and breast adenocarcinoma cells without affecting the growth of normal cells, which should be promising in potential development of new drugs. Most of the target compounds showed minimal anti-proliferative activity (IC50>37μM), indicating they would have moderate cytotoxicity when administered as chemical absorption modifiers. The relationships between the lipophilicity/polarity and the chemical structure of the studied compounds as well as the relationships between their chemical structure and penetration enhancement effect are discussed in this article.
- MeSH
- fibroblasty účinky léků metabolismus MeSH
- fluorované uhlovodíky chemická syntéza metabolismus toxicita MeSH
- hydrofobní a hydrofilní interakce MeSH
- intestinální absorpce MeSH
- kožní absorpce MeSH
- kyseliny cholové chemie MeSH
- lidé MeSH
- membrány umělé MeSH
- MFC-7 buňky MeSH
- permeabilita MeSH
- pomocné látky chemická syntéza metabolismus toxicita MeSH
- proliferace buněk účinky léků MeSH
- propionáty chemická syntéza metabolismus toxicita MeSH
- rozpustnost MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
