Remote control of the axial chirality of N-(2-t-butylphenyl)succinimides was realized via the vinylogous Michael addition of 3-substituted cyclohexenones to N-(2-t-butylphenyl)maleimides. ...9-Amino(9-deoxy)epi-quinine promoted the enantioselective desymmetrization, leading to atropisomeric succinimides with two adjacent stereocenters.
The ever‐increasing need for enantiomerically pure chiral compounds has greatly expanded the number of enantioselective separation methods available for the precise and accurate measurements of the ...enantiomeric purity. The introduction of chiral stationary phases for liquid chromatography in the last decades has revolutionized the routine methods to determine enantiomeric purity of chiral drugs, agrochemicals, fragrances, and in general of organic and organometallic compounds. In recent years, additional efforts have been placed on faster, enantioselective analytical methods capable to fulfill the high throughput requirements of modern screening procedures. Efforts in this field, capitalizing on improved chromatographic particle technology and dedicated instrumentation, have led to highly efficient separations that are routinely completed on the seconds time scale. An overview of the recent achievements in the field of ultra‐high‐resolution chromatography on column packed with chiral stationary phases, both based on sub‐2 μm fully porous and sub‐3 μm superficially porous particles, will be given, with an emphasis on very recent studies on ultrafast chiral separations.
The atroposelective desymmetrization of N-arylmaleimides was realized by means of a primary amine catalyzed Diels–Alder reaction of enones. The chiral axis as new element of chirality is generated ...under the remote control of the catalyst that selectively drives the formal Diels–Alder reaction through an exclusive stereochemical outcome.
•Novel Pirkle-type Whelk-O1 core–shell chiral stationary phase was prepared.•Difficulty of efficiently packing polar core–shell particles is reported.•Effect of surface coverage on ...adsorption–desorption kinetics is pointed out.•Kinetic characterization of new stationary phase in normal phase mode is described.•Separation of enantiomers in less than 1s was achieved.
Pirkle-type Whelk-O1 chiral stationary phase (CSP) was prepared on 2.6μm superficially porous particles (SPPs). The chromatographic behavior of columns packed with this new CSP was compared with that of columns packed respectively with 1.8 and 2.5μm Whelk-O1 fully porous particles (FPPs). In the comparison, both thermodynamic and kinetic aspects were considered. Contrary to initial expectations, chiral columns packed with 2.6μm SPPs were quasi-comparable to those packed with 2.5μm FPPs, apparently due to larger contributions to band broadening from both eddy dispersion and, especially for the second eluted enantiomer, adsorption–desorption kinetics. These findings raise the question if SPPs, in spite of the undeniable advantages of their morphology to speed up mass transfer, are always the best choice for high-efficient ultrafast chiral separations. The last part of the work focuses on the use of short columns (10mm long) and very high flow rates to realize the separation of the enantiomers of trans-stilbene oxide (TSO) in normal phase mode in less than 1s.
Salivary caffeine in Parkinson's disease Leodori, Giorgio; De Bartolo, Maria Ilenia; Belvisi, Daniele ...
Scientific reports,
05/2021, Volume:
11, Issue:
1
Journal Article
Peer reviewed
Open access
We aimed to investigate salivary caffeine content, caffeine absorption and metabolism in Parkinson's disease (PD) and verify whether salivary caffeine can be used as a biomarker of PD. We enrolled 98 ...PD patients and 92 healthy subjects. Caffeine and its major metabolite, paraxanthine, were measured in saliva samples collected before and 4 h after the oral intake of caffeine (100 mg). We measured caffeine absorption as the normalized increase in caffeine levels, and caffeine metabolism as the paraxanthine/caffeine ratio. The Movement Disorder Society Unified Parkinson's Disease Rating Scale part III, the Hoehn & Yahr, the presence of motor complications, and levodopa equivalent dose (LED) were assessed and correlated with caffeine levels, absorption, and metabolism. The effects of demographic and environmental features possibly influencing caffeine levels were also investigated. Caffeine levels were decreased in patients with moderate/advanced PD, while caffeine levels were normal in patients with early and de-novo PD, unrelated to caffeine intake. Caffeine absorption and metabolism were normal in PD. Decreased salivary caffeine levels in PD were associated with higher disease severity, longer duration, and the presence of motor complications, no significant association was found with LED. Salivary caffeine decrease correlates with PD progression.
The dynamic scenario of di-aryls-pyrano-chromenes was investigated using DFT calculations. The symmetry of the chromene scaffold and the presence of two
-substituted aryls substituents can generate ...two
/
diastereoisomers and conformational enantiomers with different rotational barriers. The relative conformations and configurations were derived using NOESY-1D experiments. Depending on the energies related to the conformational exchange, the experimental energy barriers were determined through Dynamic NMR, Dynamic HPLC or kinetic studies. The atropisomeric pairs were resolved in the latter scenario, and their absolute configuration was assigned using the ECD/TD-DFT method.
•The conformational enantiomers of diazepam were resolved by cryo-HPLC on Whelk-O1.•Prazepam, tetrazepam and flunitrazepam were also resolved on the Whelk-O1 CSP.•Dynamic HPLC and computer simulation ...gave the enantiomerization energy barriers.•The energy barriers measured by DHPLC are between 15.54 and 18.73kcal/mol.
Diazepam and the structurally related 1,4-benzodiazepin-2-ones tetrazepam, prazepam and flunitrazepam are chiral molecules because they adopt a ground state conformation featuring a non-planar seven membered ring devoid of any reflection-symmetry element. The two conformational enantiomers of this class of benzodiazepines interconvert rapidly at room temperature by a simple ring flipping process. Low temperature HPLC on the Whelk-O1 chiral stationary phase allowed us to separate the conformational enantiomers of diazepam and of the related 1,4-benzodiazepin-2-ones, under conditions where the interconversion rate is sufficiently low, compared to the chromatographic separation rate. Diazepam, tetrazepam and prazepam showed temperature dependent dynamic HPLC profiles with interconversion plateaus indicative of on-column enantiomer interconversion (enantiomerization) in the temperature range between −10°C and −35°C, whereas for flunitrazepam on-column interconversion was observed at temperatures between −40°C and −66°C. Simulation of exchange-deformed HPLC profiles using a computer program based on the stochastic model yielded the apparent rate constants for the on-column enantiomerization and the corresponding free energy activation barriers. At −20°C the enantiomerization barriers, ΔG≠, for diazepam, prazepam and tetrazepam were determined to be in the range 17.6–18.7kcal/mol. At −55°C ΔG≠ for flunitrazepam was determined to be in the 15.6–15.7kcal/mol range. The experimental dynamic chromatograms and the corresponding interconversion barriers reported in this paper call for a reinterpretation of previously published results on the HPLC behavior of diazepam on chiral stationary phases.
The presence of stereogenic elements is a common feature in pharmaceutical compounds, and affording optically pure stereoisomers is a frequent issue in drug design. In this context, the study of the ...chiral molecular recognition mechanism fundamentally supports the understanding and optimization of chromatographic separations with chiral stationary phases. We investigated, with molecular docking, the interactions between the chiral HPLC selector Whelk-O1 and the stereoisomers of two bioactive compounds, the antiviral Nevirapine and the anticonvulsant Oxcarbazepine, both characterized by two stereolabile conformational enantiomers. The presence of fast-exchange enantiomers and the rate of the interconversion process were studied using low temperature enantioselective HPLC and VT-NMR with Whelk-O1 applied as chiral solvating agent. The values of the energetic barriers of interconversion indicate, for the single enantiomers of both compounds, half-lives sufficiently long enough to allow their separation only at critically sub-ambient temperatures. The chiral selector Whelk-O1 performed as a strongly selective discriminating agent both when applied as a chiral stationary phase (CSP) in HPLC and as CSA in NMR spectroscopy.
Human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms IX and XII are overexpressed in solid hypoxic tumors, and they are considered as prognostic tools and therapeutic targets for cancer. Based on a ...molecular simplification of the well-known coumarin scaffold, we developed a new series of derivatives of the pyran-2-one core. The new compounds are endowed with potent and selective inhibitory activity against the tumor-related hCA isoforms IX and XII, in the low nanomolar range, whereas they are inactive against the two cytosolic off-targets hCA I and II. The compounds exhibiting the best hCA inhibition were further investigated against the breast adenocarcinoma cell line (MCF7) in hypoxic conditions, evaluating their ability to eventually synergize with doxorubicin. The compounds’ biocompatibility on healthy cells was also tested and confirmed on Human Gingival Fibroblasts (HGFs). Furthermore, the possible binding mode of all compounds to the active site of the tumor-associated human CA IX was investigated by computational techniques which predicted the binding conformations and the persistency of binding poses within the active site of the enzyme, furnishing relevant data for the design of tight binding inhibitors.
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