This and the accompanying report (DOI: 10.1021/jm201467r ) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP-434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference , Boston, MA , September 12-15, 2010 , poster F1 - 2157 ), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).

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Background:Bisphenol A (BPA) is an endocrine-disrupting chemical that may contribute to development of obesity and metabolic disorders. Humans are constantly exposed to low concentrations of BPA, and studies support that the developmental period is particularly sensitive.Objectives:The aim was to investigate the effects of low-dose developmental BPA exposure on metabolic parameters in male and female Fischer 344 (F344) rat offspring.Methods:Pregnant F344 rats were exposed to BPA via their drinking water, corresponding to 0.5μg/kg BW/d (BPA0.5; n=21) or 50μg/kg BW/d (BPA50; n=16), from gestational day (GD) 3.5 until postnatal day (PND) 22, and controls were given vehicle (n=26). Body weight (BW), adipose tissue, liver (weight, histology, and gene expression), heart weight, and lipid profile were investigated in the 5-wk-old offspring.Results:Males and females exhibited differential susceptibility to the different doses of BPA. Developmental BPA exposure increased plasma triglyceride levels (0.81±0.10 mmol/L compared with 0.57±0.03 mmol/L, females BPA50 p=0.04; 0.81±0.05 mmol/L compared with 0.61±0.04 mmol/L, males BPA0.5 p=0.005) in F344 rat offspring compared with controls. BPA exposure also increased adipocyte cell density by 122% in inguinal white adipose tissue (iWAT) of female offspring exposed to BPA0.5 compared with controls (68.2±4.4 number of adipocytes/HPF compared with 55.9±1.5 number of adipocytes/HPF; p=0.03) and by 123% in BPA0.5 females compared with BPA50 animals (68.2±4.4 number of adipocytes/high power field (HPF) compared with 55.3±2.9 number of adipocytes/HPF; p=0.04). In iWAT of male offspring, adipocyte cell density was increased by 129% in BPA50-exposed animals compared with BPA0.5-exposed animals (69.9±5.1 number of adipocytes/HPF compared with 54.0±3.4 number of adipocytes/HPF; p=0.03). Furthermore, the expression of genes involved in lipid and adipocyte homeostasis was significantly different between exposed animals and controls depending on the tissue, dose, and sex.Conclusions:Developmental exposure to 0.5μg/kg BW/d of BPA, which is 8–10 times lower than the current preliminary EFSA (European Food Safety Authority) tolerable daily intake (TDI) of 4μg/kg BW/d and is within the range of environmentally relevant levels, was associated with sex-specific differences in the expression of genes in adipose tissue plasma triglyceride levels in males and adipocyte cell density in females when F344 rat offspring of dams exposed to BPA at 0.5μg/kg BW/d were compared with the offspring of unexposed controls. https://doi.org/10.1289/EHP505

BackgroundPhthalates, commonly used to soften plastic goods, are known PPAR-agonists affecting lipid metabolism and adipocytes in the experimental setting. We evaluated if circulating concentrations of phthalates were related to different indices of obesity using data from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Data from both dual-energy X-ray absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI) were used.Methods1,016 subjects aged 70 years were investigated in the PIVUS study. Four phthalate metabolites were detected in the serum of almost all subjects (> 96%) by an API 4000 liquid chromatograph/tandem mass spectrometer. Abdominal MRI was performed in a representative subsample of 287 subjects (28%), and a dual-energy X-ray absorptiometry (DXA)-scan was obtained in 890 (88%) of the subjects two year following the phthalate measurements.ResultsIn women, circulating concentrations of mono-isobutyl phthalate (MiBP) were positively related to waist circumference, total fat mass and trunk fat mass by DXA, as well as to subcutaneous adipose tissue by MRI following adjustment for serum cholesterol and triglycerides, education, smoking and exercise habits (all p < 0.008). Mono-methyl phthalate (MMP) concentrations were related to trunk fat mass and the trunk/leg-ratio by DXA, but less powerful than MiBP. However, no such statistically significant relationships were seen in men.ConclusionsThe present evaluation shows that especially the phthalate metabolite MiBP was related to increased fat amount in the subcutaneous abdominal region in women measured by DXA and MRI two years later.

Process research and development of the first fully synthetic broad spectrum 7-fluorotetracycline in clinical development is described. The process utilizes two key intermediates in a convergent approach. The key transformation is a Michael–Dieckmann reaction between a suitable substituted aromatic moiety and a key cyclohexenone derivative. Subsequent deprotection and acylation provide the desired active pharmaceutical ingredient in good overall yield.

The aim of the present study was to relate brachial artery intima-media thickness (IMT) and the grey scale median of the intima-media complex (IM-GSM) to traditional cardiovascular risk factors and markers of inflammation and oxidative stress. In the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study, a population-based study of 1016 subjects aged 70, brachial artery IMT and IM-GSM, who were evaluated by ultrasound. Lipids, thirteen markers of inflammation and nine markers of oxidative stress were measured. The Framingham risk score was related to IMT (p < 0.0001), but not to the IM-GSM. In univariate analysis, HDL-cholesterol, serum triglycerides, fasting glucose, smoking, HOMA insulin resistance index and oxidized LDL levels were related to IMT. HDL and LDL-cholesterol, triglycerides, VCAM-1, e-selectin, leukocyte count, conjugated diens, baseline conjugated diens (BCD)-LDL, antibodies to oxLDL, the GSSG/GSH glutathione ratio and homocysteine were related to IM-GSM. In multiple regression models, HDL-cholesterol, fasting glucose and oxLDL levels were the independently related to IMT (p = 0.01-0.04), while serum triglycerides, BCD-LDL and the GSSG/GSH ratio were independently related to IM-GSM (p = 0.0001-0.004). In conclusion, in addition to traditional lipid variables, markers of oxidative stress were associated with both thickness and echogenicity of the brachial artery intima-media complex. Thus, both thickness and echogenicity of the brachial artery intima-media complex might be useful biomarkers in the future.

Although no relationships between BPA levels and measures of fat mass were seen, BPA associated strongly with the adipokines adiponectin and leptin and with the gut-hormone ghrelin suggesting that BPA may interfere with hormonal control of hunger and satiety.