Structure-based design of new KSP-Eg5 inhibitors assisted by a targeted multicomponent reaction.

An integrated multidisciplinary approach that combined structure-based drug design, multicomponent reaction synthetic approaches and functional characterization in enzymatic and cell assays led to the discovery of new kinesin spindle protein (KSP) inhibitors with antiproliferative activity. A focused library of new benzimidazoles obtained by a Ugi+Boc removal/cyclization reaction sequence generated low-micromolar-range KSP inhibitors as promising anticancer prototypes. The design and functional studies of the new chemotypes were assessed by computational modeling and molecular biology techniques. The most active compounds-20 (IC50 =1.49 µM, EC50 =3.63 µM) and 22 (IC50 =1.37 µM, EC50 =6.90 µM)-were synthesized with high efficiency by taking advantage of the multicomponent reactions.

Heart rate recovery normality data recorded in response to a maximal exercise test in physically active men.

BACKGROUND: Despite a growing clinical interest in determining the heart rate recovery (HRR) response to exercise, the limits of a normal HRR have not yet been well established. PURPOSE: This study was designed to examine HRR following a controlled maximal exercise test in healthy, physically active adult men. METHODS: The subjects recruited (n = 789) performed a maximal stress test on a treadmill. HRR indices were calculated by subtracting the first and third minute heart rates (HRs) during recovery from the maximal HR obtained during stress testing and designated these as HRR-1 and HRR-3, respectively. The relative change in HRR was determined as the decrease in HR produced at the time points 1 and 3 min after exercise as a percentage of the peak HR (%HRR-1/HR(peak) and %HRR-3/HR(peak), respectively). Percentile values of HRR-1 and HRR-3 were generated for the study population. RESULTS: Mean HHR-1 and HHR-3 were 15.24 ± 8.36 and 64.58 ± 12.17 bpm, respectively, and %HRR-1/HR(peak) and %HRR-3/HR(peak) were 8.60 ± 4.70 and 36.35 ± 6.79%, respectively. Significant correlation was detected between Peak VO2 and HRR-3 (r = 0.36; p < 0.001) or %HRR-3/HR(peak) (r = 0.23; p < 0.001). CONCLUSIONS: Our study provides normality data for HRR following a maximal Ergometry test obtained in a large population of physically active men.

Molecular basis of the effect of MMP-9 on the prostate bone metastasis: A review.

INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is the second most common cancer in men especially after 50 years old. The metastasis of said cancer involves a rise for morbidity, metastasizing 90% of the occasions on bone. Metalloproteinases (MMPs) are involved in the process of bone formation and they are postulated to be involved in the process of metastasizing, in particular MMP-9. This work is justified taking into account the scientific interest of the subject and the quality of the literature sources used. PCa generates a high morbidity and mortality in men, especially due to the process of metastasis, resulting in effects to health and socioeconomic level. METHODS: This search was performed selecting articles published from 2003 to 2017. Items were selected and valued according to the Cochrane criteria (2011). FINDINGS AND CONCLUSIONS: The selected articles (17) demonstrate the involvement of MMP-9 as a modulator of bone metastatic lesions either of osteoblast, osteoclast or mixed origin as well as the recognition of the major mechanisms or molecules involved in the regulation of expression gene of MMP-9 and finally establishing the MMP-9 as a therapeutic target for possible future drug development. Finally, this study evidences MMP-9 as an essential factor for the activation of the chain of the different MMPs and consequently in the genesis and development of bone metastasis of PCa due to its influence on bone osteoblastic and osteoclastic activity.

Urinary biopyrrins: potential biomarker for monitoring of the response to treatment with anxiolytics.

During periods of psychological stress, excess amounts of free radicals are produced. Bilirubin oxidative metabolites (biopyrrins; BOM) are generated from bilirubin as a result of its scavenging action against free radicals. We investigated whether the urinary excretion of biopyrrins is altered by anxiolytics. In the present study, mice were immobilized for a period of 6 hr. Alprazolam (0.1-1 mg/kg of body-weight) was administered 30 min. before subjecting the animals to acute stress. The BOM concentrations in urine and the corticosterone levels in serum were measured by ELISA with an anti-bilirubin antibody and EIA, respectively. We observed an increase in urinary biopyrrins in stressed mice in comparison with non-stressed mice and a decrease after the treatment of stressed animals with alprazolam. A correlation between urinary BOM and serum corticosterone levels was found. Urinary levels of biopyrrins might be used to assess the response to anxiolytics prescribed during acute stress periods.

Effects of fluoxetine on the oxidative status of peripheral blood leucocytes of restraint-stressed mice.

Emotional stress can be viewed as a cause of adverse circumstances that induces a wide range of biochemical and behavioural changes. Oxidative stress is a critical route of damage in various psychological stress-induced disorders such as depression. Antidepressants are widely prescribed to treat these conditions; however, no animal study has investigated the effect of selective serotonin reuptake inhibitors (SSRIs) on the levels of intracellular reactive oxygen species in peripheral blood leucocytes of stressed mice. In this study, mice were immobilized for a period of 6 hr. Fluoxetine (5 mg/kg of body-weight) was administered 30 min. before subjecting the animals to acute stress. The level of intracellular reactive oxygen species in leucocytes of the peripheral blood of stressed mice was investigated using a 2',7'-dichlorofluorescein diacetate probe, and the antioxidant response of fluoxetine was evaluated by superoxide dismutase, diaphorase, catalase and reduced glutathione. Our results show that restraint stress significantly increases the generation of reactive oxygen species in the peripheral defence cells. Treatment with fluoxetine partially reverses the adverse effects of stress. The improvement in cellular oxidative status may be an important mechanism underlying the protective pharmacological effects of fluoxetine, which are clinically observed in the treatment of depressive disorders.