A novel bioresponsive self-immolative spacer based on aza-quinone methide reactivity for the controlled release of thiols, phenols, amines, sulfonamides or amides.

A stimuli-sensitive linker is one of the indispensable components of prodrugs for cancer therapy as it covalently binds the drug and releases it upon external stimulation at the tumour site. Quinone methide elimination has been widely used as the key transformation to release drugs based on their nucleofugacity. The usual approach is to bind the drug to the linker as a carbamate and release it as a free amine after a self-immolative 1,6-elimination. Although this approach is very efficient, it is limited to amines (as carbamates), alcohols or phenols (as carbonates) or other acidic functional groups. We report here a self-immolative spacer capable of directly linking and releasing amines, phenols, thiols, sulfonamides and carboxyamides after a reductive stimulus. The spacer is based on the structure of (5-nitro-2-pyrrolyl)methanol (NPYM-OH), which was used for the direct alkylation of the functional groups mentioned above. The spacer is metabolically stable and has three indispensable sites for bioconjugation: the bioresponsive trigger, the conjugated 1,6 self-immolative system and a third arm suitable for conjugation with a carrier or other modifiers. Release was achieved by selective reduction of the nitro group over Fe/Pd nanoparticles (NPs) in a micellar aqueous environment (H2O/TPGS-750-M), or by NADH mediated nitroreductase activation. A DFT study demonstrates that, during the 1,6 elimination, the transition state formed from 5-aminopyrrole has a lower activation energy compared to other 5-membered heterocycles or p-aminobenzyl derivatives. The NPYM scaffold was validated by late-stage functionalisation of approved drugs such as celecoxib, colchicine, vorinostat or ciprofloxacin. A hypoxia-activated NPYM-based prodrug (HAP) derived from HDAC inhibitor ST7612AA1 was also produced, which was active in cancer cells under hypoxic conditions.

Lewis Base-Catalysed Enantioselective Radical Conjugate Addition for the Synthesis of Enantioenriched Pyrrolidinones.

We report a catalytic asymmetric protocol for the preparation of chiral pyrrolidinones proceeding via a radical pathway. The chemistry exploits the combination of photoredox catalysis and Lewis base catalysis to realise the first example of asymmetric radical conjugate addition to α,ß-unsaturated anhydrides and esters. The reaction is initiated by photoredox activation of N-arylglycines to generate, upon decarboxylation, α-amino radicals. These radicals are then intercepted stereoselectively by α,ß-unsaturated acyl ammonium intermediates, whose formation is mastered by a chiral isothiourea organocatalyst. Cyclisation leads to catalyst turnover and formation of enantioenriched pyrrolidinones. The utility of the protocol was demonstrated with application to the synthesis of biologically-active γ-amino butyric acids.

Antibody drug conjugates with hydroxamic acid cargos for histone deacetylase (HDAC) inhibition.

Antitumor hydroxamates SAHA and Dacinostat have been linked to cetuximab and trastuzumab through a non-cleavable linker based on the p-mercaptobenzyl alcohol structure. These antibody drug conjugates (ADCs) were able to inhibit HDAC in several tumour cell lines. The cetuximab based ADCs block human lung adenocarcinoma cell proliferation, demonstrating that bioconjugation with antibodies is a suitable approach for targeted therapy based on hydroxamic acid-containing drugs. This work also shows that ADC-based delivery might be used to overcome the classical pharmacokinetic problems of hydroxamic acids.

Gender differences in barriers to physical activity among adolescents.

BACKGROUND AND AIMS: Great attention is now being paid to effective policies and programs to promote physical activity among adolescents, girls consistently found to be less active than boys. The aim of this study was to assess gender differences in perceived barriers for physical activity practice and their relationship with physical activity levels and physical condition among adolescents. METHODS AND RESULTS: A cross-sectional study was conducted in February-April 2017 among students (n = 368) in the last year of two state high schools in Florence (Italy). Participants underwent the measurements of anthropometric parameters (height, weight, waist, and hip circumferences), blood pressure and administration of 3 standardized questionnaires (International Physical Activity Questionnaire, Mediterranean Diet Score Quiz, and Barriers to Being Active Quiz). Gender differences were assessed using a multivariate logistic regression model (adjusted for age and body mass index). The prevalence of participants who reached recommended levels was lower among girls compared to boys (OR 0.27; 95% CI 0.17-0.43). The number of perceived barriers to physical activity was higher among girls than among boys (OR 1.52; 95% CI 1.29-1.79), lack of energy for exercise and lack of willpower being the two barriers most frequently reported by girls. At multivariable adjusted logistic regression analysis, gender (female), and positivity of at least one perceived barrier (score ≥ 5) were independently selected as the main determinants of non-compliance with WHO criteria for physical activity. CONCLUSIONS: Exercise professionals should be aware of the barriers that young girls can face during exercise prescription and be able to contrast them with useful individual strategies.

Levels of physical activity, nutrition and body composition in the workplace: reports from a distribution company.

INTRODUCTION: Lifestyle factors, as eating habits and physical activity, are associated with health and productivity of workers. The aim of this study is an assessment of lifestyle of the employees of an international company of household items. METHODS: 291 (170 female, 121 male) employees underwent body composition assessment and completed two questionnaires (International Physical Activity Questionnaire and National Institute for Research of the Food and Nutrition). RESULTS: The weight status of the sample is at the upper limits of normal weight. Products based on cereals are consumed about once a day, fresh meat 3.0 (0.0-12.0) per week, fresh fruit (5.0, 0.0-25.0) and vegetables (6.0, 0.0-14.0) less than one serving a day. No vigorous physical activity is performed (0.0, 0.0-240.0 min/week), moderate is performed 30.0 (0.0-450.0) min/week and only 106 subjects were aware of the number of daily steps. CONCLUSIONS: Job duties can have an influence on the daily habits. Workplaces have great potential to change personal lifestyle choices and a preliminary assessment should be performed in order to propose a tailored intervention.

Eating Habits and Body Composition of International Elite Soccer Referees.

Soccer referees are a specific group of the athletes' population whose careers peak from 30 to 45 years old. An athlete's performance is not only determined by physical training but also by a lifestyle, e.g. eating habits. The purpose of this study was to verify current eating habits and resulting body composition of a group of elite international soccer referees. At an international FIFA seminar 60 elite international soccer referees (aged 39.2 ± 4.2 years) were enrolled. A body composition assessment was performed with skinfold thickness and bio impedance analysis, while eating habits were evaluated with a multi-pass 24-hour dietary recall. The body composition showed a normal weight condition with a fat content of 11.4 ± 2.5%. Macronutrients showed a low level of carbohydrates (43.6 ± 5.4%) and a high level of fat (40.0 ± 4.5%). Micronutrients showed a low level of calcium, potassium, zinc, magnesium, iodine, vitamin B12 and vitamin B9. Even though their body composition was within the normal range, the current eating habits of elite international soccer referees did not appear to follow the nutrition guidelines. Therefore, it would be advisable to provide knowledge on nutrition for this particular category of sports subjects, an individualized nutritional plan would be advisable, in order to achieve and maintain better performance and appropriate body composition for their role.

Adjuvant Therapy Reduces Fat Mass Loss during Exercise Prescription in Breast Cancer Survivors.

Improvements in cancer care over the years have increased the numbers of cancer survivors. Therefore, quality of life, fat mass management and physical activity are growing areas of interest in these people. After the surgical removal of a breast cancer, adjuvant therapy remains anyway a common strategy. The aim of this study was to assess how adjuvant therapy can affect the effectiveness of an unsupervised exercise program. Forty-two women were enrolled (52.0 ± 10.1 years). Assessments performed at baseline and after six months of exercise prescription were body composition, health-related quality of life, aerobic capacity by Six-Minute Walk Test, limbs strength by hand grip and chair test and flexibility by sit and reach. Statistical analyses were conducted by ANOVA tests and multiple regression. Improvements in body composition, physical fitness and quality of life (physical functioning, general health, social functioning and mental health items) were found. The percentage change in fat mass has been associated with adjuvant cancer therapy (intercept = -0.016; b = 8.629; p < 0.05). An unsupervised exercise prescription program improves body composition, physical fitness and health-related quality of life in breast cancer survivors. Adjuvant therapy in cancer slows down the effectiveness of an exercise program in the loss of fat mass.

Overweight in Young Athletes: New Predictive Model of Overfat Condition.

The aim of the study is to establish a simple and low-cost method that, associated with Body Mass Index (BMI), differentiates overweight conditions due to a prevalence of lean mass compared to an excess of fat mass during the evaluation of young athletes. 1046 young athletes (620 male, 426 female) aged between eight and 18 were enrolled. Body composition assessments were performed with anthropometry, circumferences, skinfold, and bioimpedance. Overweight was established with BMI, while overfat was established with the percentage of fat mass: 3.5% were underweight, 72.8% were normal weight, 20.1% were overweight, and 3.5% were obese according to BMI; according to the fat mass, 9.5% were under fat, 63.6% were normal fat, 16.2% were overfat, and 10.8% were obese. Differences in overfat prediction were found using BMI alone or with the addition of the triceps fold (area under the receiver operating characteristics curve (AUC) for BMI = 0.867 vs. AUC for BMI + TRICEPS = 0.955, p < 0.001). These results allowed the creation of a model factoring in age, sex, BMI, and triceps fold that could provide the probability that a young overweight athlete is also in an overfat condition. The calculated probability could reduce the risk of error in establishing the correct weight status of young athletes.