The Hofmann-Löffler-Freytag (HLF) reaction serves as a late-stage functionalization technique for generating pyrrolidine heterocyclic ring systems. Contemporary HLF protocols utilize in situ ...halogenated sulfonamides as precursors in the radical-mediated rearrangement cycle. Despite its well-established reaction mechanism, experiments toward the detection of radical intermediates using EPR techniques have only recently been attempted. However, the obtained spectra lack the distinct features of the N-centered radicals expected for the employed reactants. This paper presents phenylbutylnitrone spin-trapped C-centered and N-centered radicals, generated via light irradiation from N-halogen-tosyl-sulfonamide derivatives and detected using EPR spectroscopy. NMR spectroscopy and DFT calculations are used to explain the observed regioselectivity of the HLF reaction.
The aim of this study was to evaluate body composition, handgrip strength, quality of life, disease duration and activity and lifestyle habits in patients with rheumatoid arthritis (RA) and to ...evaluate possible associations between all of the abovementioned factors. Seventy-five stable RA patients were included. Data on sociodemographic data, disease activity, quality of life, nutritional risk, body mass composition, anthropometric parameters, and clinical and laboratory parameters were collected for each study participant. The results showed that the mean score of the disease activity score (DAS28) was 5.4, the mean score of the health assessment questionnaire-disability index (HAQ-DI) was 1.19, and the mean disease duration in our population was 13.9 years. Our studied population had a long disease duration and high disease activity. Positive predictors of muscle mass in RA patients were daily caloric intake, fat-free mass, bone mass, basal metabolic rate, total body water, weight, body mass index (BMI), height, and muscle strength. There were no significant negative predictors. Positive predictors of muscle strength in RA patients were daily caloric intake, basal metabolic rate, predicted muscle mass, fat-free mass, bone mass, weight, total body water, metabolic age, hemoglobin, BMI, and number of exercises per week. In contrast, negative predictors of muscle strength were number of comorbidities, number of swollen joints, DAS, number of tender joints, erythrocyte sedimentation rate (ESR), and duration of RA. An association was also found between bone mineral density and both muscle mass and muscle strength. A structured nutritional approach in terms of multidisciplinary collaboration between rheumatologist, dietitian and physical medicine specialist is needed in the Dalmatian RA population.
Thallium (Tl) is a highly toxic heavy metal whose mechanism of toxicity is still not completely understood. The aim of this study was to test Tl cytotoxicity on several cell lines of different tissue ...origin in order to clarify specific Tl toxicity to a particular organ. In addition, possible interference of Tl with cell potassium (K) transport was examined. Human keratinocytes (HaCaT), human hepatocellular carcinoma (HepG2), porcine kidney epithelial cells (PK15), human neuroblastoma (SH-SY5Y) and Chinese hamster lung fibroblast cells (V79) were treated with thallium (I) acetate in a wide concentration range (3.9-500 µg/mL) for 24 h, 48 and 72 h. To assess competitive interaction between Tl and K, the cells were treated with four Tl concentrations close to IC
(15.63, 31.25, 62.50, 125 µg/mL) in combination with/or without potassium (I) acetate (500 µg/mL). The cells' morphology was monitored, and cytotoxic effect was assessed by 3-(4, 5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) test. The most sensitive to Tl exposure were SH-SY5Y cells, while HepG2 were the most resistant. The combined exposure to thallium (I) acetate and potassium (I) acetate for every cell line, except V79 cells, resulted in higher cell viability compared to thallium (I) acetate alone. The results of our study indicate that cell sensitivity to Tl treatment is largely affected by tissue culture origin, its function, and Na
/K
-ATPase activity.
EPR spectroscopy has been used for the study of the free radicals formed in the single crystals of 2-thiothymine (5-methyl-2-thiouracil) γ-irradiated at room temperature (300
K). The radicals formed ...by a net hydrogen-atom addition to C(6) (5-thymyl or 5-yl radicals) and by a net hydrogen abstraction from the methyl group (7-thymyl or 7-yl radicals) has been studied in detail. The hyperfine tensors of proton couplings in these radicals are given together with their g-tensors. It has been shown that the calculated hyperfine proton couplings and relative orientation of the coupling tensors along the pyrimidine ring are similar to those observed earlier in 5-yl and 7-yl radicals in the single crystals of thymine and its derivatives. Although no large differences in hyperfine couplings were found, calculated values of the g-tensor elements of the 5-yl radical are appreciable larger, what is expected due to the presence of sulfur at C(2) in 2-thiothymine. Also, the observed superhyperfine 1:2:2:1 splitting of the resonance lines of the 5-yl radical indicated that the presence of sulfur in 2-thiothymine slightly affects the spin distribution in this radical insomuch that appreciable amount of spin is located on one of N–H fragments of 2-thiothymine.
One measure of protein glycosylation (GlycA) has been reported to predict higher cardiovascular risk by reflecting inflammatory pathways.
The main objective of this study is to assess the role of a ...comprehensive panel of IgG glycosylation traits on traditional risk factors for cardiovascular disease and on presence of subclinical atherosclerosis in addition to GlycA.
We measured 76 IgG glycosylation traits in 2970 women (age range, 40-79 years) from the TwinsUK cohort and correlated it to their estimated 10-year atherosclerotic cardiovascular disease risk score and their carotid and femoral plaque measured by ultrasound imaging. Eight IgG glycan traits are associated with the 10-year atherosclerotic cardiovascular disease risk score after adjusting for multiple tests and for individual risk factors-5 with increased risk and 3 with decreased risk. These glycans replicated in 967 women from ORCADES cohort (Orkney Complex Disease Study), and 6 of them were also associated in 845 men. A linear combination of IgG glycans and GlycA is also associated with presence of carotid (odds ratio, 1.55; 95% confidence interval, 1.25-1.93;
=7.5×10
) and femoral (odds ratio, 1.32; 95% confidence interval, 1.06-1.64;
=0.01) plaque in a subset of women with atherosclerosis data after adjustment for traditional risk factors. One specific glycosylation trait, GP18-the percentage of FA2BG2S1 glycan in total IgG glycans, was negatively correlated with very-low-density lipoprotein and triglyceride levels in serum and with presence of carotid plaque (odds ratio, 0.60; 95% confidence interval, 0.50-0.71;
=5×10
).
We find molecular pathways linking IgG to arterial lesion formation. Glycosylation traits are independently associated with subclinical atherosclerosis. One specific trait related to the sialylated N-glycan is negatively correlated with cardiovascular disease risk, very-low-density lipoprotein and triglyceride serum levels, and presence of carotid plaque.
In addition to several well-known drug delivery strategies developed to facilitate effective chemotherapy with anticancer agents, some new approaches have been recently established, based on specific ...effects arising from the applications of ultrasound, magnetic and electric fields on drug delivery systems. This paper gives an overview of newly developed methods of drug delivery to tumors and of the related anticancer therapies based on the combined use of different physical methods and specific drug carriers. The conventional strategies and new approaches have been put into perspective to revisit the existing and to propose new directions to overcome the threatening problem of cancer diseases.
Osim dobro poznatih metoda prijenosa lijekova u kemoterapijskom pristupu liječenja tumora, nedavno su otkriveni novi načini prijenosa koji se zasnivaju na specifičnim mehanizmima uzrokovanim upotrebom ultrazvuka, magnetskih i električnih polja. U članku se daje prikaz fizikalnih mehanizama na kojima se temelje te nove metode, pregled novootkrivenih prijenosnika lijekova (Pluronske micele, magnetoliposomi, magnetski fluidi), novih načina terapije tumora (magnetska hipertermija, elektrokemoterapija) i najnovijih istraživanja temeljenih na fizikalnom pristupu ovoj problematici.
Single crystals of 2-thiothymine (5-methyl-2-thiouracil) were γ-irradiated at 77
K and studied using EPR spectroscopy. In addition to previously observed sulfur σ radical, another sulfur-centered ...radical of π type was formed and analyzed at 100
K. The large values and the directions of the g-tensor principal elements undoubtedly confirmed the assignment. The observed isotropic 1:3:3:1 quartet structure of the EPR spectra, attributed to the couplings with methyl group protons, indicates the large delocalization of the spin along the 2-thiothymine molecule. Doublet splitting of the 1:3:3:1 quartets observed in some crystal orientations supports the idea that the pristine radical is an anion, formed by the capture of an electron at S(2) and subsequently neutralized by addition of a proton to S(2). From the crystal structure data it is concluded that the captured proton is the H′(3) of neighboring molecule, participating in the formation of the N′(3)–S(2) hydrogen bonding between two adjacent 2-thiothymine molecules in the unit cell.
Hydroxyurea (HU) effectively reduces vanadium(V) into vanadium(IV) species (hereafter V
V and V
IV species, respectively) in acidic aqueous solution via the formation of a transient complex followed ...by an electron transfer process that includes the formation and subsequent fading out of a free radical, U
(U
≡
H
2N–C(=O)N(H)O
). The electron paramagnetic resonance (EPR) spectra of U
in H
2O/D
2O solutions suggest that the unpaired electron is located predominantly on the hydroxamate hydroxyl-oxygen atom. Visible and V
IV–EPR spectroscopic data reveal HU as a two-electron donor, whereas formation of U
, which reduces a second V
V, indicates that electron transfer occurs in two successive one-electron steps. At the molarity ratio V
V/HU
=
2, the studied reaction can be formulated as: 2 V
V
+
HU
→
2 V
IV
+
0.98 CO
2
+
0.44 N
2O
+
1.1 NH
3
+
0.1 NH
2OH. Lack of evidence for the formation of NO is suggested to be a consequence of the slow oxidation of HNO due to the too low reduction potential of the V
V/V
IV couple under the experimental conditions used.
The nuclear magnetic resonance (
51V-NMR) spectral data indicate protonation of
(
H
2
O
)
4
V
V
O
2
+
, and the protonation equilibrium constant was determined to be
K
=
0.7 M
−1. Spectrophotometric titration data for the V
V–HU system reveal formation of (H
2O)
2V
VO(OH)U
+ and (H
2O)
3V
VOU
2+. Their stability constants were calculated as
K
110
=
5 M
−1 and
K
111
=
22 M
−2, where the subscript digits refer to
(
H
2
O
)
4
V
V
O
2
+
, HU and H
+, respectively.
The transformation of free radicals derived from
N-methylhydroxyurea on reaction with
VO
2
+
is described.
Unlike the oxidation of hydroxyurea with dioxovanadium(V) ions, which proceeds through the ...formation of a single free radical, oxidation of
N-methylhydroxyurea is characterized by consecutive formation of two oxygen-based free radicals, as recorded by EPR spectroscopy. Although the consumption of overall five V(V) ions per
N-methylhydroxyurea molecule has been determined, the formation of NO,
NO
2
-
or
NO
3
-
was not observed. These results are in accordance with a previous suggestion that nitric oxide transfer requires an unsubstituted acylhydroxylamine group.
Kinetics and mechanisms of the oxidation of methoxyurea and N-methylhydroxyurea were studied in neutral and basic aqueous solutions. The obtained pH dependences of the oxidation rates indicate that ...for both hydroxyureas the reactive species are the deprotonated ones. The second order rate constants, the activation enthalpies and the activation entropies for the reactions of methoxyurea (O-methylhydroxyurea) and N-methylhydroxyurea anions with Fe(CN)^sub 6^^sup 3-^ at 25 °C, I = 2 mol dm^sup -3^ (NaClO^sub 4^) were determined as (5.06 ± 0.01) × 10^sup 2^ mol^sup -1^ dm^sup 3^ s^sup -1^, (1.92 ± 0.02) × 10^sup 4^ mol^sup -1^ dm^sup 3^ s^sup -1^, 27 ± 1 kJ mol^sup -1^, 16 ± 1 kJ mol^sup -1^, -101 ± 2 J mol^sup -1^ K^sup -1^, and -107 ± 4 J mol^sup -1^ K^sup -1^, respectively. The pK^sub a^ value of methoxyurea at 25 °C and 2 mol dm^sup -3^ ionic strength was determined kinetically as 12.7 ± 0.1 and the thermodynamic parameters for the deprotonation reaction were determined as Δ^sub a^H = 43 ± 1 kJ mol^sup -1^, and Δ^sub a^S = -96 ± 4 J mol^sup -1^ K^sup -1^. When the kinetic results are compared with the data reported for hydroxyurea, an inverse dependence of the rate constants on the pK^sub a^ of the hydroxyurea derivatives at 25 °C is observed. Such unexpected behaviour has been explained by the ab initio calculations and NBO analysis of HOMOs for all three hydroxyureates. PUBLICATION ABSTRACT
PDF
