Design and synthesis of pyrazolo[3,4-d]pyrimidinone derivatives: Discovery of selective phosphodiesterase-5 inhibitors.

A novel series of 1,6-disubstituted pyrazolo[3,4-d]pyrimidin-7-one derivatives, 2a-h, 4a-d, 5 and 6, were successfully synthesized, which showed promising, and potent inhibition of phosphodiesterase 5 (PDE5). The inhibitory activities of 5, 4b, 2a, 2d, 2f, 4d and 4a against PDE5 were similar to that of sildenafil (100%). These compounds exhibited potent relaxant effects on isolated rat cavernosum tissue with pEC50 values ranging from 8.31 to 5.16 µM. Pyrazolo[3,4-d]pyrimidin-7-one scaffolds have been rationally designed via consecutive molecular modelling studies prior to their synthesis and biological evaluation. In addition, the results of the pharmacophore-based virtual screening revealed that 1v0p_PVB might have promising activity as a PDE-5 inhibitor.

Serum serotonin as unexpected potential marker for staging of experimental hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the primary cancer of the liver. The present study aimed to assess the potential role of the endogenous regulators of angiogenesis like neurotransmitters, as possible HCC biomarkers. Five groups of rats were used in this study (8 rats per each): control healthy group (I), four intoxicated groups (II, III, IV, and V) used for induction of HCC with a single IP dose of diethylnitrosamine (DENA), 200mg/kg. Groups II, III, IV, and V were sacrificed after 8, 16, 24, and 32 weeks of DENA injection respectively. Serum levels of epinephrine, nor-epinephrine, serotonin, and dopamine of all animals were estimated using high performance liquid chromatography technique coupled with fluorescence detector (HPLC-FLD). Development of HCC was confirmed histopathologically. Our results showed a significant increase in 3 neurotransmitters (epinephrine, nor-epinephrine, and serotonin) in DENA intoxicated HCC rat model. Only serotonin exhibited a significant increase in early histological stage HCC development (16 weeks post DENA injection) in comparison to alpha-fetoprotein (AFP), (24 weeks post DENA injection). These results suggest that neurotransmitters (Epinephrine and Norepinephrine) may have a role as a biomarker for late histological stage HCC. Like AFP, while serotonin may be used for early stage HCC.

Hesperidin alleviates doxorubicin-induced cardiotoxicity in rats.

BACKGROUND: Doxorubicin (DOX) is a potent chemotherapeutic agent used in the treatment of several tumors but its cardiac toxicity prevents its use at a maximum dose, representing an important problem. Increased reactive oxygen species (ROS) and imbalance in nitric oxide (NO) production have been implicated in the cardiotoxicity of doxorubicin. Hesperidin is a citrus bioflavonoid that possesses a potent antioxidant and NO modulating activities. OBJECTIVES: Therefore, the aim of this study was to investigate the possible protective role of hesperidin against doxorubicin-induced cardiac toxicity. METHODS: Four groups of animals were used in this study. First group served as a control and injected with the vehicle. Second group was given 200 mg/kg of hesperidin orally for seven consecutive days. The third group was injected with a single dose (20 mg/kg) of doxorubicin intraperitoneally and was sacrificed after 48 h. The fourth group was treated with hesperidin for seven days but on day five, 1-hour after hesperidin treatment, rats were injected with the single dose of doxorubicin. On day seven, the rats were scarified by decapitation. Blood was collected and processed for determination of serum lactate dehydrogenase (LDH), creatine kinase (CK) and NO. The hearts were removed and processed for both histopathological examination and determination of oxidative stress parameters like reduced glutathione (GSH), lipid peroxide (TBARS) levels and superoxide dismutase (SOD) activity. RESULTS: Our results showed that doxorubicin produced severe cardiotoxicity as indicated from increase in serum LDH, CK activities and NO level. Histopathological examination of DOX-treated rats revealed degenerative changes in heart tissues. The significant decrease in GSH levels, SOD activity and increase in TBARS levels, indicated that DOX-induced cardiotoxicity was mediated through ROS generation. On the other hand, pretreatment of rats with hesperidin protected cardiac tissues against the cardiotoxic effects of doxorubicin as evidenced from amelioration of histopathological changes and normalization of cardiac biochemical parameters. CONCLUSION: Hesperidin may have a protective effect against DOX-induced cardiotoxicity.