α-heteroaryl acetaldehydes have become important building blocks in the synthesis of synthetic nucleosides. Novel organocatalytic cascades have enabled the rapid generation of nucleosides, which are ...valuable building blocks in the development of antisense oligonucleotides or as stand-alone antiviral and anticancer therapies, obviating the need for laborious synthetic routes relying on chiral pool starting materials and inefficient synthetic routes. This manuscript describes a robust and scalable protocol to α-heteroaryl acetaldehydes from readily available building blocks.
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A series of substituted sulfonamide bioisosteres of 8-hydroxyquinoline were evaluated for their antibacterial activity against the common mastitis causative pathogens Streptococcus ...uberis, Staphylococcus aureus and Escherichia coli, both in the presence and absence of supplementary zinc. Compounds 9a-e, 10a-c, 11a-e, 12 and 13 were demonstrated to have MICs of 0.0625 µg/mL against S. uberis in the presence of 50 µM ZnSO4. Against S. aureus compounds 9g (MIC 4 µg/mL) and 11d (MIC 8 µg/mL) showed the greatest activity, whereas all compounds were found to be inactive against E. coli (MIC > 256 µg/mL); again in the presence of 50 µM ZnSO4. All compounds were demonstrated to be significantly less active in the absence of supplementary zinc. Compound 9g was subsequently confirmed to be bactericidal, with an MBC (≥3log10 cfu/mL reduction) of 0.125 µg/mL against S. uberis in the presence of 50 µM ZnSO4. To validate the sanitising activity of compound 9g in the presence of supplementary zinc, a quantitative suspension disinfection (sanitizer) test was performed. In this preliminary test, sanitizing activity (>5log10 reduction of CFU/mL in 5 min) was observed against S. uberis for compound 9g at concentrations as low as 1 mg/mL, validating the potential of this compound to function as a topical sanitizer against the major environmental mastitis-causing microorganism S. uberis.
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A series of C-2 derivatized 8-sulfonamidoquinolines were evaluated for their antibacterial activity against the common mastitis causative pathogens Streptococcus uberis, ...Staphylococcus aureus and Escherichia coli, both in the presence and absence of supplementary zinc (50 µM ZnSO4). The vast majority of compounds tested were demonstrated to be significantly more active against S. uberis when in the presence of supplementary zinc (MICs as low as 0.125 µg/mL were observed in the presence of 50 µM ZnSO4). Compounds 5, 34–36, 39, 58, 79, 82, 94 and 95 were shown to display the greatest antibacterial activity against S. aureus (MIC ≤ 8 µg/mL; both in the presence and absence of supplementary zinc), while compounds 56, 58 and 66 were demonstrated to also exhibit activity against E. coli (MIC ≤ 16 µg/mL; under all conditions). Compounds 56, 58 and 66 were subsequently confirmed to be bactericidal against all three mastitis pathogens studied, with MBCs (≥3log10 CFU/mL reduction) of ≤ 32 µg/mL (in both the presence and absence of 50 µM ZnSO4). To validate the sanitizing activity of compounds 56, 58 and 66, a quantitative suspension disinfection (sanitizer) test was performed. Sanitizing activity (>5log10 CFU/mL reduction in 5 min) was observed against both S. uberis and E. coli at compound concentrations as low as 1 mg/mL (compounds 56, 58 and 66), and against S. aureus at 1 mg/mL (compound 58); thereby validating the potential of compounds 56, 58 and 66 to function as topical sanitizers designed explicitly for use in non-human applications.
Endolides A and B are naturally occurring,
-methylated, cyclic tetrapeptides possessing an unusual 3-(3-furyl)alanine amino acid and outstanding biological profiles. 1-Propanephosphonic anhydride ...(T3P) was used to mediate a solution-phase cyclisation reaction of the linear tetrapeptides, thus achieving the first syntheses of both endolides A and B. The stereoselectivity of the tetrapeptide cyclisation reactions was found to be reagent-controlled, and was independent of the C-terminal configuration of the linear peptide starting materials.
Endolides A and B are naturally occurring,
N
-methylated, cyclic tetrapeptides possessing an unusual 3-(3-furyl)alanine amino acid and outstanding biological profiles. 1-Propanephosphonic anhydride ...(T3P) was used to mediate a solution-phase cyclisation reaction of the linear tetrapeptides, thus achieving the first syntheses of both endolides A and B. The stereoselectivity of the tetrapeptide cyclisation reactions was found to be reagent-controlled, and was independent of the C-terminal configuration of the linear peptide starting materials.
The first syntheses of the bioactive cyclic tetrapeptide natural products, endolides A and B, were accomplished using a solution-phase macrocyclisation reaction; the stereoselectivity of which was found to be reagent-controlled.
The first syntheses of the bioactive cyclic tetrapeptide natural products, endolides A and B, were accomplished using a solution-phase macrocyclisation reaction; the stereoselectivity of which was ...found to be reagent-controlled.
Endolides A and B are naturally occurring,
N
-methylated, cyclic tetrapeptides possessing an unusual 3-(3-furyl)alanine amino acid and outstanding biological profiles. 1-Propanephosphonic anhydride (T3P) was used to mediate a solution-phase cyclisation reaction of the linear tetrapeptides, thus achieving the first syntheses of both endolides A and B. The stereoselectivity of the tetrapeptide cyclisation reactions was found to be reagent-controlled, and was independent of the C-terminal configuration of the linear peptide starting materials.
Abstract
Context
More than 3% of adults report vitamin D intakes of 4000 IU/day or more, but the safety of this practice is unknown.
Objective
The objective of this work is to establish whether ...vitamin D doses up to 10 000 IU/day are safe and well tolerated.
Design
The Calgary Vitamin D Study was a 3-year, double-blind, randomized controlled trial.
Setting
A single-center study was conducted at the University of Calgary, Canada.
Participants
Participants included healthy adults (n = 373) ages 55 to 70 years with serum 25-hydroxyvitamin D 30 to 125 nmol/L.
Interventions
Participants were randomly assigned 1:1:1 to vitamin D3 400, 40 000, or 10 000 IU/day. Calcium supplementation was initiated if dietary calcium intake was less than 1200 mg/day.
Main Outcome Measures
In these prespecified secondary analyses, changes in serum 25-hydroxyvitamin D, calcium, creatinine, 24-hour urine calcium excretion, and incidence of adverse events were assessed. Between-group differences in adverse events were examined using incident rate differences and logistic regression.
Results
Of 373 participants (400: 124, 4000: 125, 10 000: 124), 49% were male, mean (SD) age was 64 (4) years, and 25-hydroxyvitamin D 78.0 (19.5) nmol/L. Serum calcium, creatinine, and 24-hour urine calcium excretion did not differ between treatments. Mild hypercalcemia (2.56-2.64 mmol/L) occurred in 15 (4%) participants (400: 0%, 4000: 3%, 10 000: 9%, P = .002); all cases resolved on repeat testing. Hypercalciuria occurred in 87 (23%) participants (400: 17%, 4000: 22%, 10 000: 31%, P = .01). Clinical adverse events were experienced by 365 (97.9%) participants and were balanced across treatment arms.
Conclusions
The safety profile of vitamin D supplementation is similar for doses of 400, 4000, and 10 000 IU/day. Hypercalciuria was common and occurred more frequently with higher doses. Hypercalcemia occurred more frequently with higher doses but was rare, mild, and transient.
Measurement of bone mineral density is the most common method of diagnosing and assessing osteoporosis. We sought to estimate the average rate of change in bone mineral density as a function of age ...among Canadians aged 25-85, stratified by sex and use of antiresorptive agents.
We examined a longitudinal cohort of 9423 participants. We measured the bone mineral density in the lumbar spine, total hip and femoral neck at baseline in 1995-1997, and at 3-year (participants aged 40-60 years only) and 5-year follow-up visits. We used the measurements to compute individual rates of change.
Bone loss in all 3 skeletal sites began among women at age 40-44. Bone loss was particularly rapid in the total hip and was greatest among women aged 50-54 who were transitioning from premenopause to postmenopause, with a change from baseline of -6.8% (95% confidence interval CI -7.5% to -4.9%) over 5 years. The rate of decline, particularly in the total hip, increased again among women older than 70 years. Bone loss in all 3 skeletal sites began at an earlier age (25-39) among men than among women. The rate of decline of bone density in the total hip was nearly constant among men 35 and older and then increased among men older than 65. Use of antiresorptive agents was associated with attenuated bone loss in both sexes among participants aged 50-79.
The period of accelerated loss of bone mineral density in the hip bones occurring among women and men older than 65 may be an important contributor to the increased incidence of hip fracture among patients in that age group. The extent of bone loss that we observed in both sexes indicates that, in the absence of additional risk factors or therapy, repeat testing of bone mineral density to diagnose osteoporosis could be delayed to every 5 years.
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