Phosphodiester Silybin Dimers Powerful Radical Scavengers: A Antiproliferative Activity on Different Cancer Cell Lines.

Silibinin is the main biologically active component of silymarin extract and consists of a mixture 1:1 of two diastereoisomeric flavonolignans, namely silybin A (1a) and silybin B (1b), which we call here silybins. Despite the high interest in the activity of this flavonolignan, there are still few studies that give due attention to the role of its stereochemistry and, there is still today a strong need to investigate in this area. In this regard, here we report a study concerning the radical scavenger ability and the antiproliferative activity on different cell lines, both of silybins and phosphodiester-linked silybin dimers. An efficient synthetic strategy to obtain silybin dimers in an optical pure form (6aa, 6ab and 6bb) starting from a suitable building block of silybin A and silybin B, obtained by us from natural extract silibinin, was proposed. New dimers show strong antioxidant properties, determined through hydroxyl radical (HO●) scavenging ability, comparable to the value reported for known potent antioxidants such as quercetin. A preliminary screening was performed by treating cells with 10 and 50 µM concentrations for 48 h to identify the most sensitive cell lines. The results show that silibinin compounds were active on Jurkat, A375, WM266, and HeLa, but at the tested concentrations, they did not interfere with the growth of PANC, MCF-7, HDF or U87. In particular, both monomers (1a and 1b) and dimers (6aa, 6ab and 6bb) present selective anti-proliferative activity towards leukemia cells in the mid-micromolar range and are poorly active on normal cells. They exhibit different mechanisms of action in fact all the cells treated with the 1a and 1b go completely into apoptosis, whereas only part of the cells treated with 6aa and 6ab were found to be in apoptosis.

Solid-phase synthesis of curcumin mimics and their anticancer activity against human pancreatic, prostate, and colorectal cancer cell lines.

Curcumin is a bioactive natural compound with a wide range of pharmacological properties, including antitumor activity; however, its clinical application has been limited because of its low solubility, stability, and bioavailability. In this study, a solid phase approach was proposed for the combinatorial synthesis of a mini library of the mimics of curcumin in good purity and yield. The non-effective findings in pancreatic cancer cells switched to strong growth inhibition and cell death efficacy for PC3 prostate cancer cells, and mimic 9, in which tyrosol (TYR) and homovanillyl alcohol (HVA) units were linked by a phosphodiester bond, was quite effective not only in cell growth inhibition but also in causing strong cell death under the study conditions and treatments that were not effective in PANC1 cells. The results got more exciting when we also consider the findings in SW480 human colorectal carcinoma cell line, where the growth inhibitor effects were more in line with that of the PC3 cells, but the lack of cell death effect was more in line with the PANC1 cells.

Investigation on the solid-phase synthesis of silybin prodrugs and their timed-release.

Prodrugs are ingenious derivatives of therapeutic agents designed to improve the pharmacokinetic profile of the drug. Here, we report an efficient and regioselective solid phase approach for obtaining new prodrugs of 9″-silybins conjugated with 3'-ribonucleotide units (uridine and adenosine) as pro-moieties. Uridine and adenosine conjugates were obtained in good yields (41-50%), beginning with silibinin and its diastereomers (silybin A and silybin B), using a NovaSyn® support functionalized with an ad hoc linker, which allowed selective detachment of only the desired products. As expected, the solubility of both uridine and adenosine conjugates was higher than that of the parental natural product (5 mg/mL and 3 mg/mL for uridine and adenosine, respectively). Our investigations revealed that uridine conjugates were quickly cleaved by RNase A, releasing silybin drugs, even at low enzyme concentrations. No toxic effects were found for any ribonucleotide conjugate on differentiated neuroblastoma SH-SY5Y cells when tested at increasing concentrations. All results strongly encourage further investigations of uridine-silybin prodrugs as potential therapeutic agents for both oral and intravenous administration. The present synthetic approach represents a valuable strategy to the future design of new prodrugs with modified nucleoside pro-moieties to modulate the pharmacokinetics of silybins or different natural products with strong pharmacological activities but poor bioavailability.

7-O-tyrosyl Silybin Derivatives as a Novel Set of Anti-Prostate Cancer Compounds.

Silybin is a natural compound extensively studied for its hepatoprotective, neuroprotective and anticancer properties. Envisioning the enhancement of silybin potential by suitable modifications in its chemical structure, here, a series of new 7-O-alkyl silybins derivatives were synthesized by the Mitsunobu reaction starting from the silybins and tyrosol-based phenols, such as tyrosol (TYR, 3), 3-methoxytyrosol (MTYR, 4), and 3-hydroxytyrosol (HTYR, 5). This research sought to explore the antioxidant and anticancer properties of eighteen new derivatives and their mechanisms. In particular, the antioxidant properties of new derivatives outlined by the DPPH assay showed a very pronounced activity depending on the tyrosyl moiety (HTYR > MTYR >> TYR). A significant contribution of the HTYR moiety was observed for silybins and 2,3-dehydro-silybin-based derivatives. According to the very potent antioxidant activity, 2,3-dehydro-silybin derivatives 15ab, 15a, and 15b exerted the most potent anticancer activity in human prostate cancer PC-3 cells. Furthermore, flow cytometric analysis for cell cycle and apoptosis revealed that 15ab, 15a, and 15b induce strong G1 phase arrest and increase late apoptotic population in PC-3 cells. Additionally, Western blotting for apoptotic marker cleaved caspase-3 confirmed apoptosis induction by these silybin derivatives in PC-3 cells. These findings hold significant importance in the investigation of anticancer properties of silybin derivatives and strongly encourage swift investigation in pre-clinical models and clinical trials.

Effectiveness of active versus passive recovery strategies after futsal games.

This study aimed to investigate the effects of immediate postgame recovery interventions (seated rest, supine electrostimulation, low-intensity land exercises, and water exercises) on anaerobic performance (countermovement jump [CMJ], bounce jumping, 10-m sprint), hormones (salivary cortisol, urinary catecholamines), and subjective ratings (rate of perceived exertion [RPE], leg muscle pain, Questionnaire of Recovery Stress for Athletes [RestQ Sport], 10-point Likert scale), and hours of sleep of futsal players. Heart rate (HR), blood lactate, and RPE were used to evaluate the intensity of 4 futsal games in 10 players using a crossover design (P < 0.05), randomly allocating athletes to 1 of the 4 recovery interventions at the end of each game. No significant difference emerged between HR, blood lactate, RPE, and level of hydration of the games. A significant difference (P < 0.001) between games emerged for total urinary catecholamines, with an increase from the first to the second game and a gradual reduction up to the fourth game. After the game, significant reductions in CMJ (P < 0.001) and 10-m sprints (P < 0.05) emerged. No significant difference was found between recovery interventions for anaerobic performances, hormones, muscle pain, and RestQ Sport. Even though a well-balanced diet, rehydration, and controlled lifestyle might represent a sufficient recovery intervention in young elite athletes, the players perceived significantly increased benefit (P < 0.01) from the electrostimulation (7.8 +/- 1.4 points) and water exercises (7.6 +/- 2.1 points) compared to dry exercises (6.6 +/- 1.8 points) and seated rest (5.2 +/- 0.8 points.), which might improve their attitude toward playing. To induce progressive hormonal adaptation to the high exercise load of multiple games, in the last 2 weeks of the preseason, coaches should organize friendly games at a level similar to that of the competitive season.

Aerobic and anaerobic profiles, heart rate and match analysis in older soccer players.

The aim of the present study was to provide aerobic (maximal oxygen consumption--VO2max) and anaerobic [jump tests: counter-movement jump (CMJ) and bounce jump (BJ); and running tests: 10 m sprint and 10 m dribbling the ball (10 mDB)] profiles of older soccer players (n = 12), and heart rate (HR), blood lactate accumulation (La) and match analysis (individual motor activity and team behaviour) aspects of a soccer match. The maximal aerobic test values were: HRmax, 154 +/- 14 beat min(-1); maximal power, 160 +/- 24 W; VO2peak, 36.3 +/- 11.3 ml kg(-1) min(-1); peak La, 8.2 +/- 1.8 mM. Jump test values were: CMJ, 21.2 +/- 4.5 cm; BJ, 17.3 +/- 4.8 cm. Running performances were: 10 m sprint, 2.06 +/- 0.36 s; 10 mDB, 2.17 +/- 0.21 s. Running showed similar values in the two halves (first half, 82%; second half, 88%), while walking lasted longer during the second half. Regarding the technical aspects of the match, 42% of the consecutive passes made in possession of the ball exceeded three passes, indicating that their play was structured in a cooperative manner. Older soccer players succeeded in maintaining good aerobic and anaerobic physical capability.