Synthesis, Characterization, Antiproliferative Activity of Galloyl Derivatives and Investigation of Cytotoxic Properties in HepG2/C3A Cells.

BACKGROUND: Appropriate substituents in the galloyl group could lead to significant biological properties. OBJECTIVES: Novel galloyl-substituted compounds bearing 2-substituted-1, 3, 4-oxadiazol-5-yl, 5- substituted-1,2,4-triazol-3-yl, and carboxamide groups were synthesized and evaluated for their antiproliferative activity. Additionally, galloyl hydrazide (2) was evaluated by performing cytotoxicity, membrane integrity, cell cycle, and apoptosis assays in HepG2/C3A cells. METHODS: General procedure was used for the synthesis of galloyl-substituted (3-9, 11) and characterized by their spectroscopic data (1H and 13C NMR). The antiproliferative activity of all novel galloyl derivatives was evaluated against nine human tumors and one nontumoral cell line. Three response parameters (GI50, TGI, and LC50) were calculated. The cytotoxicity test was performed for the resazurin assay. The membrane integrity, cell cycle, and apoptosis assays were performed by flow cytometry. RESULTS: The substitution of the methoxy group of the galloyl ring system for a carboxamide group (3, 4, 5, and 6) produced compounds with moderate antitumoral activity, particularly 6, against six human cancer cell lines, K-562, PC-3, NCI-ADR/RES, OVCAR, 786-0 and NCI-H460, with GI50 values ≤ 9.45 µg/mL. Triazole derivatives 7 and 8 exhibited higher antitumoral activity toward OVCAR, MCF-7 and leukemia K-562 cell lines, exhibiting GI50 values less than 10 µg/mL. Compound 11 displayed significant activity against PC-3 (GI50 = 4.31 µg/mL), OVCAR (GI50 = 8.84 µg/mL) and K-562 (GI50 = 8.80 µg/mL) cell lines. Galloyl hydrazide (2) had cytotoxic activity in HepG2/C3A cells (IC50 = 153.7 µg/mL). In membrane permeability, cell count, cell cycle, and apoptosis assays, as determined using the IC50 of compound (2) in HepG2/C3A cells, increased membrane permeability, decreased cell count, altered cell cycle, and initial apoptosis was observed compared to the control group. CONCLUSION: Thus, our results showed for the first time the synthesis, antiproliferative activity, and cytotoxicity of galloyl-substituted compounds. Galloyl-substitution does not have a very strong synergistic effect in the inhibition of cancer cell proliferation compared with galloyl hydrazide (2). Compound 2 demonstrated promising activity in HepG2/C3A hepatocarcinoma cells.

Effects of Bidens gardneri Baker leaves aqueous extract in glucose homeostasis of rats.

Bidens gardneri Baker, popularly known as "picão-vermelho", has been used, traditionally, as a medicinal plant for the treatment of Diabetes mellitus. This study aimed to evaluate antidiabetic effect of leaves from B. gardneri aqueous extract (BGAE). We also evaluated in vitro anti-glycation potential. Chemical composition was analyzed based on a colorimetrics and HPLC methods. The oral glucose tolerance test (OGTT), was performed in rats with different doses (30, 100 and 300 mg/kg). Alloxan-induced diabetic and hypercaloric diet-fed rats were treated with 300 mg/kg of BGAE, orally, for 10 days and then 10 weeks, respectively. The activity of intestinal disaccharidases (maltase, sucrase and lactase) and quantification of muscle and liver glycogen content were also evaluated. On chemical analysis, the extract showed high phenolics content and the chromatogram showed 4-O-caffeoylquinic acid as the major component. The extract presented inhibition in the formation of advanced glycation end products (AGEs) and disaccharidases activity. In OGTT the dose of 300 mg/kg significantly decreased the blood glucose. In diabetic animals, BGAE significantly decreased blood glucose levels, preventing weight loss. In addition, in hypercaloric diet-fed rats, the extract prevented hyperglycemia. Our results suggest that, aqueous extract of B. gardneri has a potential for therapeutic intervention of diabetes.

Aqueous extract from Mangifera indica Linn. (Anacardiaceae) leaves exerts long-term hypoglycemic effect, increases insulin sensitivity and plasma insulin levels on diabetic Wistar rats.

BACKGROUND: Diabetes mellitus is one of the most common todays public health problems. According to a survey by the World Health Organization, this metabolic disorder has reached global epidemic proportions, with a worldwide prevalence of 8.5% in the adult population. OBJECTIVES: The present study aimed to investigate the hypoglycemic effect of aqueous extract of Mangifera indica (EAMI) leaves in streptozotocin-induced diabetic rats. METHODS: Sixty male rats were divided into 2 groups: Normoglycemic and Diabetic. Each group was subdivided into negative control, glibenclamide 3 or 10 mg/kg, EAMI 125, 250, 500, and 1000 mg/kg. Intraperitoneal injection of streptozotocin 100 mg/kg was used to DM induction. The hypoglycemic response was assessed acutely after two and four weeks of treatment. After a 6-hour fasting period, the fasting blood glucose of animals was verified, and 2.5 g/kg glucose solution was orally administered. The insulin tolerance test and plasma insulin levels assessment were performed in the morning after fasting of 12 to 14 hours. RESULTS AND CONCLUSION: The chemical analysis of EAMI showed high levels of phenolic compounds. There was no significant difference in fasting blood glucose between normoglycemic and diabetic groups, and that EAMI did not have an acute effect on diabetes. After two and four weeks of treatment, the extract significantly reduced blood glucose levels, exceeding glibenclamide effects. EAMI was effective in maintaining the long-term hypoglycemic effect, as well as, significantly increased the sensitivity of diabetic animals to insulin and the plasma insulin level.

Preclinical safety evaluation of the aqueous extract from Mangifera indica Linn. (Anacardiaceae): genotoxic, clastogenic and cytotoxic assessment in experimental models of genotoxicity in rats to predict potential human risks.

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants widely used by the population contain significant concentrations of biologically active compounds and, although they have proven pharmacological properties, can cause DNA damage and develop fatal diseases. AIM OF THE STUDY: The present study aimed to evaluate the genotoxic, cytotoxic potential and clastogenic effects of the aqueous extract from Mangifera indica leaves (EAMI) on rats submitted to experimental genotoxicity models and through the SMART test performed in Drosophila melanogaster. MATERIAL AND METHODS: The comet assay and the micronucleus test were performed on peripheral and bone marrow blood, respectively, of Wistar rats, orally treated with EAMI at doses of 125, 250, 500 and 1000 mg/kg/bw for 28 days. In the SMART test, the standard cross between three mutant D. melanogaster strains was used. Larvae were treated with EAMI at different concentrations, and the wings of adult flies were evaluated for the presence/frequency of mutant spots and compared to the negative control group. RESULTS: Phytochemical analysis of EAMI indicated high levels of flavonoids. The tests performed in rats showed that EAMI did not present significant genotoxic or clastogenic effects. The results showed a critical dose-dependent cytoprotective effect exerted by EAMI. This result was attributed to the high content of polyphenols and flavonoids. The biotransformation metabolites of EAMI did not present genotoxic activity, as demonstrated by the SMART test. CONCLUSIONS: These results are relevant since they provide safety information about a plant species of great therapeutic, economical, nutritious and ethnopharmacological value for the population.