Search

Veratrum alkaloids are a group of steroidal alkaloids with penta-, hexa-, or heptacyclic C-nor-D-homosteroidal or regular hexacycliccholestane skeleton. Activation of the Hedgehog (Hh) pathway aberrantly associated with numerous malignancies. Cyclopamine blocked Hh pathway by directly binding Smo and slows down the growth of these tumors in various animal models. To less extent, jervine and the veratrane Veratrum alkaloid veratramine were also reported as possible Hh signaling inhibitors. This encouraged the study of our small library of natural, biocatalytic, and semisynthetic jervane and veratrane alkaloids’ ability to inhibit the growth, proliferation, and migration of the prostate metastatic cancer cell line PC-3 to establish a preliminary structure–activity relationship. Alkaloids possessing C-3-keto functionality with ∆4,5 or ∆1,2 and ∆4,5 exhibited significant enhancement of antiproliferative and antimigratory activities. A common feature pharmacophore model of active Veratrum alkaloids was built and validated using receiver-operating characteristic curve analyses.

Prostrate cancer constitutes the second leading cause of cancer deaths in men in United States. In the process of discovery of new antiproliferative and anti-metastatic agents against prostate cancer, marine-derived phenylmethylene hydantoin (PMH) derivatives were identified with activity level range between 50 and 200 μM. 3D-QSAR CoMFA model was used in virtual screening of commercially available derivatives of PMH. PMH derivatives with manifold increase in anti-migratory and anti-invasive activities were discovered using wound-healing and Cultrex invasion assays. Benzene ring replacement with other heterocyclic rings did not significantly improve the methylene hydantoins activities. Multivariate analysis performed on the whole series of methylene hydantoins, which further supported the findings of CoMFA model. Predictive QSAR model with conventional r 2 and cross-validated coefficient ( q 2 ) values up to 0.982 and 0.803 were established. The molecular volume (MV) and the log P were identified as critical parameters for methylene hydatoins migration inhibitory activity. PMH is a novel anti-metastatic lead class with potential therapeutic activity against prostate cancer.

Objective: Obesity and its complications including metabolic syndrome (MetS) have been increased in children and adolescents recently. Leptin is known to play an important role in the pathogenesis of obesity. The objective of this study was to evaluate the relationship between Leptin, Ghrelin and Insulin resistance in the development of metabolic syndrome in obese persons. Methods: this study was carried out on fifty obese persons. All patients have BMI ≥ 30 Kg/m2. Twenty of them have metabolic syndrome. Body Mass Index (BMI), Waist Circumference (WC), and blood pressure were measured. Fasting Plasma Glucose (FBG), two hours Post Prandial Blood Glucose (PPBG), Glycated hamoglobin A1C (HbA1c), triglyceride (TG), Total Cholesterol (TC), high and low density lipoprotein cholesterol (HDL-C and LDL-C), serum Leptin, Ghrelin and Insulin were done. HOMA-IR and HOMA- β were calculated. Results: SBP, DBP, FBS, PPBG, HbA1c, HOMA-IR and HOMA-β were significantly increased in obese and MetS groups compared to control group. There was a significant increase in insulin and Leptin, serum TG, TC and LDL-C with a significant decrease in HDL cholesterol and Ghrelin in obese and MetS groups. A significant negative correlation between plasma Ghrelin and BMI, WC, SBP, DBP, and FBS, PPBG, serum TG, TC, LDL-C, HbA1c, and HOMA-B was observed while leptin showed a significant positive correlation with them and a negative correlation with HOMA-IR. Plasma Ghrelin was positively correlated with HDL-C while Leptin was positively correlated with it in obese and MetS groups. There was a significant negative correlation between plasma Ghrelin, Insulin and leptin with significant positive correlation between plasma insulin and leptin in obese and MS groups. Conclusion: There are hormonal changes associated with clusters of metabolic abnormalities and elevation of blood pressure that may have a role in the development of MetS in obese persons and are major CHD risk factors. Insulin has stimulatory trophic effect on leptin secretion, but the effect of leptin on insulin is controversial as leptin may modulate insulin action and participates in the development of insulin resistance. As regard Ghrelin secretion, there are many suppressive factors: insulin, Leptin and glucose. Our study produces a preliminary result, thus further studies with large number of patients are required.