macrocyclization
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elektronický časopis
- Konspekt
- Biochemie. Molekulární biologie. Biofyzika
- NLK Obory
- biochemie
- biologie
- NLK Publikační typ
- elektronické časopisy
Anion recognition plays an important role in many areas of the natural world. Macrocyclic anion receptors and their potentials are outlined. Bambusurils, a family of glycoluril-based anion receptors, are described in detail.
Macrocyclic inhibitors have emerged as a privileged scaffold in medicinal chemistry, offering enhanced selectivity, stability, and pharmacokinetic profiles compared to their linear counterparts. Here, we describe a novel, on-resin macrocyclization strategy for the synthesis of potent inhibitors targeting the secreted protease Major Aspartyl Peptidase 1 in Cryptococcus neoformans, a pathogen responsible for life-threatening fungal infections. By employing diverse aliphatic linkers and statine-based transition-state mimics, we constructed a focused library of 624 macrocyclic compounds. Screening identified several subnanomolar inhibitors with desirable pharmacokinetic and antifungal properties. Lead compound 25 exhibited a Ki of 180 pM, significant selectivity against host proteases, and potent antifungal activity in culture. The streamlined synthetic approach not only yielded drug-like macrocycles with potential in antifungal therapy but also provided insights into structure-activity relationships that can inform broader applications of macrocyclization in drug discovery.
- MeSH
- antifungální látky * farmakologie chemie chemická syntéza farmakokinetika MeSH
- Cryptococcus neoformans * účinky léků enzymologie MeSH
- inhibitory proteas * farmakologie chemie chemická syntéza farmakokinetika MeSH
- lidé MeSH
- makrocyklické sloučeniny * farmakologie chemie chemická syntéza farmakokinetika MeSH
- mikrobiální testy citlivosti MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
To find and calibrate a robust and reliable computational protocol for mapping conformational space of medium-sized molecules, exhaustive conformational sampling has been carried out for a series of seven macrocyclic compounds of varying ring size and one acyclic analogue. While five of them were taken from the MD/LLMOD/force field study by Shelley and co-workers ( Watts , K. S. ; Dalal , P. ; Tebben , A. J. ; Cheney , D. L. ; Shelley , J. C. Macrocycle Conformational Sampling with MacroModel . J. Chem. Inf. MODEL: 2014 , 54 , 2680 - 2696 ), three represent potential macrocyclic inhibitors of human cyclophilin A. The free energy values (GDFT/COSMO-RS) for all of the conformers of each compound were obtained by a composite protocol based on in vacuo quantum mechanics (DFT-D3 method in a large basis set), standard gas-phase thermodynamics, and the COSMO-RS solvation model. The GDFT/COSMO-RS values were used as the reference for evaluating the performance of conformational sampling algorithms: standard and extended MD/LLMOD search (simulated-annealing molecular dynamics with low-lying eigenvector following algorithms, employing the OPLS2005 force field plus GBSA solvation) available in MacroModel and plain molecular dynamics (MD) sampling at high temperature (1000 K) using the semiempirical quantum mechanics (SQM) potential SQM(PM6-D3H4/COSMO) followed by energy minimization of the snapshots. It has been shown that the former protocol (MD/LLMOD) may provide a more complete set of initial structures that ultimately leads to the identification of a greater number of low-energy conformers (as assessed by GDFT/COSMO-RS) than the latter (i.e., plain SQM MD). The CPU time needed to fully evaluate one medium-sized compound (∼100 atoms, typically resulting in several hundred or a few thousand conformers generated and treated quantum-mechanically) is approximately 1,000-100,000 CPU hours on today's computers, which transforms to 1-7 days on a small-sized computer cluster with a few hundred CPUs. Finally, our data sets based on the rigorous quantum-chemical approach allow us to formulate a composite conformational sampling protocol with multiple checkpoints and truncation of redundant structural data that offers superior insights at affordable computational cost.
- MeSH
- algoritmy MeSH
- kalibrace MeSH
- krystalografie MeSH
- kvantová teorie MeSH
- makrocyklické sloučeniny chemie MeSH
- molekulární konformace * MeSH
- rychlé screeningové testy MeSH
- simulace molekulární dynamiky MeSH
- termodynamika MeSH
- vysoká teplota MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
A synthesis procedure for heteroatom-substituted tetra(3,4-pyrido)porphyrazines that absorb light near 800 nm was developed. Based on the observed relationships between the structure and photophysical parameters, a novel highly photodynamically active (IC50 = 0.26 μM) compound was synthesized and biologically characterized.
Sheep farmers in the UK rely on strategic anthelmintic use to treat and control gastrointestinal roundworms in their flocks. However, resistance to these drugs is now widespread and threatens the sustainability of sheep production. The mechanisms underlying resistance to the most commonly used class, the macrocyclic lactones, are not known and sensitive diagnostic tools based on molecular markers are not currently available. This prohibits accurate surveillance of resistance or assessment of strategies aimed at controlling its spread. In this study, we examined four UK field populations of Haemonchus contortus, differing in macrocyclic lactone treatment history, for evidence of selection at 'candidate gene' loci identified as determining macrocyclic lactone resistance in previously published research. Individual worms were genotyped at Hc-lgc-37, Hc-glc-5, Hc-avr-14 and Hc-dyf-7, and four microsatellite loci. High levels of polymorphism were identified at the first three candidate gene loci with remarkably little polymorphism at Hc-dyf-7. While some between-population comparisons of individual farms with and without long-term macrocyclic lactone use identified statistically significant differences in allele frequency and/or fixation index at the Hc-lgc-37, Hc-glc-5 or Hc-avr-14 loci, we found no consistent evidence of selection in other equivalent comparisons. While it is possible that different mechanisms are important in different populations or that resistance may be conferred by small changes at multiple loci, our findings suggest that these are unlikely to be major loci conferring macrocyclic lactone resistance on UK farms or suitable for diagnostic marker development. More powerful approaches, using genome-wide or whole genome sequencing, may be required to define macrocyclic lactone resistance loci in such genetically variable populations.
- MeSH
- frekvence genu MeSH
- genetická variace MeSH
- genotypizační techniky MeSH
- Haemonchus účinky léků genetika MeSH
- hemonchóza farmakoterapie parazitologie veterinární MeSH
- laktony farmakologie terapeutické užití MeSH
- léková rezistence genetika MeSH
- makrocyklické laktamy farmakologie terapeutické užití MeSH
- nemoci ovcí farmakoterapie parazitologie MeSH
- ovce MeSH
- polymorfismus délky restrikčních fragmentů MeSH
- vazebná nerovnováha MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Spojené království MeSH
Cucurbit[n]urils are macrocyclic compounds capable of forming host-guest complexes with different molecules. In this study, we focused on cucurbit[7]uril (CB[7]) safety and pharmacokinetics. We investigated CB[7] cytotocixity in human renal cells ACHN using the xCELLigence system. We also determined maximum tolerated doses (MTD) and no observed adverse effect levels (NOAEL) after intramuscular (i.m.), intraperitoneal (i.p.), and intragastric (i.g.) administration in mice using clinical observation, blood biochemistry, and histopathology. At NOAELs, we studied its pharmacokinetics in plasma and kidneys. Finally, we performed a 7 day repeated-dose toxicity study at 50% of NOAEL after i.p. administration, assaying CB[7] concentration in plasma, brain, kidney, and liver; we also assessed the liver and kidney histopathology. In vitro, CB[7] did not show toxicity up to 0.94 mg/mL. MTDs in vivo were set at 300, 350, and 600 mg/kg, and NOAEL were established at 150, 100, and 300 mg/kg after i.m., i.p., and i.g. administration, respectively. Parenteral administration produced tissue damage mainly to the kidney, while i.g. administration caused only minor liver damage. Parenteral CB[7] administration led to fast elimination from blood, accompanied with kidney accumulation; absorption from the gastrointestinal tract was minimal. Short repeated i.p. administration was well tolerated. After initial CB[7] accumulation in blood and kidney, the concentrations stabilised and decreased during the experiment. Approximately 3.6% of animals showed signs of nephrotoxicity. Although CB[7] appears to be a promising molecule, nephrotoxicity may be the most critical drawback of its parenteral use, because the kidney represents the main organ of its elimination.
V prehľadnom referáte sa popisujú vlastnosti vankomycínu, teikoplanínu a ristocetínu A, makrocyklických antibiotík, ktoré sa dajú využiť ako stacionárne fázy na separáciu enantiomérov liečivobsahujúcich stereogénne centrum. Analyzujú sa výsledky, ktoré sa dosiahli pri separácii aminokyselín, ich derivátov, loxiglumidu, clenbuterolu, practololu, carnitínu levodopy, metyldopy, ceftazidí-nu, derivátov kyseliny alkoxyfenylkarbámovej, dichlorpropu, ketoprofenu, warfarinu, námelovýchalkaloidov metódou vysokoúčinnej kvapalinovej chromatografie (HPLC).
The present review paper describes the properties of the macrocyclic antibiotics vancomycin,teikoplanin, and ristocetin A, which can be used as stationary phases for separation of theenantiomers of drugs containing a stereogenic centre. It analyzes the results obtained in theseparation of amino acids, its derivatives, loxiglumide, clenbuterol, practolol, carnitine, levodopa,methyldopa, ceftazidine, alkoxyphenylcarbamic acid derivatives, dichloroprop, ketoprofen, warfarin, and ergot alkaloids by means of high-performance liquid chromatography (HPLC).
Bifunctional derivatives of bis(phosphinate)-bearing cyclam (BPC) chelators bearing a carboxylate, amine, isothiocyanate, azide, or cyclooctyne in the BP side chain were synthesized. Conjugations required no protection of phosphinate or ring secondary amine groups. The ring amines were not reactive (proton protected) at pH < ∼8. For isothiocyanate coupling, oligopeptide N-terminal α-amines were more suitable than alkyl amines, e.g., Lys ω-amine (p Ka ∼7.5-8.5 and ∼10-11, respectively) due to lower basicity. The Cu-64 labeling was efficient at room temperature (specific activity ∼100 GBq/μmol; 25 °C, pH 6.2, ∼100 ligand equiv, 10 min). A representative Cu-64-BPC was tested in vivo showing fast clearance and no nonspecific radioactivity deposition. The monoclonal anti-PSCA antibody 7F5 conjugates with thiocyanate BPC derivative or NODAGA were radiolabeled and studied in PC3-PSCA tumor bearing mice by PET. The radiolabeled BPC conjugate was accumulated in the prostate tumor with a low off-target uptake, unlike Cu-64-labeled NODAGA-antibody conjugate. The BPC chelators have a great potential for theranostic applications of the Cu-64/Cu-67 matched pair.
- MeSH
- chelátory chemie farmakokinetika MeSH
- imunokonjugáty chemie farmakokinetika MeSH
- izotopové značení MeSH
- kyseliny fosfinové chemie MeSH
- ligandy MeSH
- makrocyklické laktamy chemie farmakokinetika MeSH
- monoklonální protilátky chemie farmakokinetika MeSH
- myši MeSH
- nádorové buňky kultivované MeSH
- nádory prostaty diagnóza diagnostické zobrazování metabolismus MeSH
- potkani nazí MeSH
- potkani Wistar MeSH
- pozitronová emisní tomografie MeSH
- radiofarmaka chemie farmakokinetika MeSH
- radioizotopy mědi chemie farmakokinetika MeSH
- stabilita léku MeSH
- tkáňová distribuce MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cyclodextrins are macrocyclic molecules able to form host-guest complexes due to their hydrophobic cavity. Because of their carbohydrate nature they do not absorb light in the UV-vis region (200-800nm), but they can be converted into spectroscopically active compounds via modification with a chromophore unit. Among the chromophores, the group of fluorophores can provide high sensitivity in analytical applications (chemosensing) and low detection limit in optical imaging methods (fluorescent microscopy). Fluorophore-tagged cyclodextrins therefore combine interesting spectroscopic properties with promising supramolecular features which make these conjugates widely applicable in various pharmaceutical fields. The aim of this work is to review the various types of fluorophores which have been used for cyclodextrin tagging, to discuss the synthetic strategies used for the conjugation and to summarize the pharmaceutical applications of these 'visualized' macrocycles including their use in photodynamic therapy. The recent achievements in studying how the fluorophore-appended cyclodextrin derivatives cross biological barriers are also reviewed.
