The study on synthesis and vitro hypolipidemic activity of novel berberine derivatives nitric oxide donors.

Berberine was used as the lead compound in the present study to design and synthesize novel berberine derivatives by splicing bromine bridges of different berberine carbon chain lengths coupled nitric oxide donors, and their lipid lowering activities were assessed in a variety of ways. This experiment synthesized 17 new berberine nitric oxide donor derivatives. Compared with berberine hydrochloride, most of the compounds exhibited certain glycerate inhibitory activity, and compounds 6a, 6b, 6d, 12b and 12d showed higher inhibitory activity than berberine, with 6a, 6b and 6d having significant inhibitory activity. In addition, compound 6a linked to furazolidone nitric oxide donor showed better NO release in experiments; In further mechanistic studies, we screened and got two proteins, PCSK9 and ACLY, and docked two proteins with 17 compounds, and found that most of the compounds bound better with ATP citrate lyase (ACLY), among which there may be a strong interaction between compound 6a and ACLY, and the interaction force was better than the target drug Bempedoic Acid, which meaning that 6a may exert hypolipidemic effects by inhibiting ACLY; moreover, we also found that 6a may had the better performance in gastrointestinal absorption, blood-brain barrier permeability, Egan, Muegge class drug principle model calculation and bioavailability.

The effect of defatted cocoa powder on cholesterol-induced changes of serum lipids in rats / El efecto del polvo de cacao desgrasado en los cambios de colesterol inducidos de los lípidos séricos en ratas

Introduction: Cocoa has been known for many health benefits, but its lipid-lowering activity still remains unresolved. Objectives: To investigate effects of varying amounts of defatted cocoa on serum lipids in cholesterol-fed rats. Methods: Forty-eight male Sprague-Dawley rats were randomly assigned into four cholesterol-free (control) and four cholesterol-supplemented (experimental) diets containing 0, 1, 2 or 3% defatted cocoa (DC) and given ad libitum to the rats for ten weeks. Serum total cholesterol (TC), low- and very low-density lipoprotein cholesterol (LDL-C and VLDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were quantified, atherogenic index (AI) was calculated, and other biological parameters were assessed. Results: Food intake and body weight did not respond to DC. Compared to 0% DC, 3% DC had the most prominent effect on serum lipids inducing significant fall in LDL-C and TG, and rise in TC/TG in cholesterol-deprived rats, and increase in VLDL-C and AI, and decrease in HDL-C in cholesterol-fed rats. Compared to cholesterol-deprived rats, 3% DC caused significant rise in VLDL-C, AI and TC/TG, and fall in TG in cholesterol-fed rats. This lipid-modifying effect was markedly substantiated by corresponding linear trend responses to DC. Differences in lipid variables of rats fed on DC diets were less evident. Conclusions: Results suggest that, in contrast to cholesterol-free situations, defatted cocoa is seemingly incapable of counteracting the atherogenic effect of cholesterol in rats, perhaps in an interaction that is likely to have clinical implications in cardiometabolic conditions (AU)

Introducción: los beneficios del cacao para la salud se conocen desde hace muchos años, pero su actividad hipolipemiante aún permanece sin resolver. Objetivos: investigar los efectos de cantidades variables de cacao desgrasado en los lípidos séricos en ratas alimentadas con colesterol. Métodos: cuarenta y ocho ratas Sprague-Dawley macho fueron asignadas aleatoriamente en cuatro dietas libres de colesterol (control) y cuatro dietas con suplemento de colesterol (experimentales) que contenían 0, 1, 2 o 3% de cacao desgrasado (CD), suministradas a las ratas ad libitum durante diez semanas. Se cuantificaron el colesterol sérico total (TC), las lipoproteínas de baja o muy baja densidad (LDL-C y VLDL-C), las lipoproteínas de alta densidad (HDL-C) y los triglicéridos (TG), se calculó el índice aterogénico (IA), y se evaluaron otros parámetros biológicos. Resultados: la ingesta de alimentos y el peso corporal no respondieron al CD. En comparación con el 0% de CD, la dieta con un 3% de CD tuvo el efecto más prominente en los lípidos séricos, produciendo una bajada significativa de LDL-C y TG y subida de TC/TG en ratas privadas de colesterol, y un aumento de VLDL-C y IA y descenso del HDL-C en ratas alimentadas con colesterol. En comparación con las ratas privadas de colesterol, la dieta con un 3% de CD causó un aumento significativo de VLDL-C, IA y TC/TG y un descenso de los TG en ratas alimentadas con colesterol. Este efecto modificador de los lípidos estuvo claramente reflejado en respuestas al CD de tendencia lineal. Las diferencias en las variables lipídicas de las ratas alimentadas con dietas con CD fueron menos evidentes. Conclusiones: los resultados sugieren que, en contraste con situaciones libres de colesterol, el cacao desgrasado es aparentemente incapaz de contrarrestar el efecto aterogénico del colesterol en ratas, lo que sugiere una interacción que puede tener implicaciones clínicas en las condiciones cardiometabólicas (AU)

Synthesis and physico-chemical characterization of modified starches from banana (Musa AAB) and its biological activities in diabetic rats.

This study describes a simple method of preparation and physico-chemical properties of modified starches (type-3 resistant starches) from banana (Musa AAB), and the modified starches investigated as functional food with a beneficial effect on type-2 diabetes. RS3 was prepared using a method combined with debranching modification and physical modification; native and modifies starches were characterized by scanning electron microscope (SEM), powder X-ray diffraction (XRD), differential scanning calorimetry (DSC) and rapid visco analyzer (RVA). Use of the enzymatic and physical modification methodology, improved the yield of RS (26.62%) from Musa AAB. A reduced viscosity and swelling power; increased transition temperatures, water absorption capacity and solubility index with B-type crystalline pattern and loss of granular appearance were observed during the debranching modification and physical modification. The modified starches exhibited beneficial health effects in diabetic and HFD rats who consumed it. These results recommend that dietary feeding of RS3 was effective in the regulation of glucose and lipid profile in serum and suppressing the oxidative stress in rats under diabetic and HFD condition. This current study provides new bioactive starches, with potential applications in the food and non-food industries.

[Synthesis and biological evaluation of novel chalcone aromatic oxygen alkyl acids compounds].

Six novel ligustrazine chalcone aromatic oxygen alkyl acids compounds and two pyridine chalcone aromatic oxygen alkyl acids ester compounds were synthesized according to the traditional Chinese medicine theory removing blood stasis. The structures of target compounds were identified by IR, NMR and ESI-MS. The inhibitory activities of platelet aggregation induced by adenosine diphosphate (ADP) and arachidonic acid(AA) were measured by the liver microsomal incubation method in vitro. Hypolipidemic activities of compounds were tested in vivo for better inhibitory activities of platelet aggregation. Preliminary pharmacological results showed that compounds 7c, 8a and 11 a had potent inhibitory activity against platelet aggregation induced by AA, compounds 7c, 7d, 8a and 11 b showed significant inhibitory activity against platelet aggregation induced by ADP. Compounds 7c and 8a exhibited good hypolipidemic activities in high-fat-diet(HFD) induced hyperlipidemia C57/BL6 mice and worthy for further investigation.

Synthesis and antihyperlipidemic activity of piperic acid derivatives.

A series of piperic acid derivatives were designed and synthesized from piperine/piperlonguminine, and their antihyperlipidemic activities evaluated in diet-induced hyperlipidemic rats with respect to simvastatin. Two promising analogues 3 and 10 were discovered and their antihyperlipidemic activities were comparable to or better than those of simvastatin.

Synthesis and pharmacological evaluation of novel unsubstituted indole-anthraquinone carboxamide derivatives as potent antihyperlipidemic agents.

Five novel derivatives of N-(9,10-dihydro-9,10-dioxoanthracenyl)-1H-indole-2-carboxamide were synthesized and their lipid-lowering effects studied in hyperlipidemic rats. Fusion of the anthraquinone derivatives at high temperature with 5-indole-2-carbonyl chloride, followed by recrystallization from chloroform/methanol gave the desired compounds in excellent yields. Compounds 1 to 5 at a non-toxic dose (1 ml of 57 microM solutions) and bezafibrate as positive control were administered to rats that were hyperlipidemic due to treatment with Triton WR-1339. A decrease in the plasma levels of triglyceride (TG) and low-density lipoprotein-cholesterol (LDL-C) and an increase in the plasma level of high-density lipoprotein-cholesterol (HDL-C) were observed with compounds 1, 3, 4, and 5. Compounds 1, 4, and 5 significantly reduced total cholesterol (TC) levels as well. These compounds may provide agents for targeting dyslipidemia and cardiovascular disease.

Synthesis of new andrographolide derivatives and evaluation of their antidyslipidemic, LDL-oxidation and antioxidant activity.

Andrographis paniculata, native to Taiwan, Mainland China and India, is a medicinal herb, which possesses various biological activities including anti-atherosclerosis. Andrographolide (1) has been identified as one of the active constituents against atherosclerosis. In continuation of our drug discovery program we synthesized few novel derivatives of 1 to improve their antidyslipidemic, LDL-oxidation and antioxidant activity. The tosylated derivative 7 has been turned out to be more potent than the parent compound and comparable activity with marketed antidyslipidemic drugs.

Hypolipidemic applications of microcrystalline cellulose composite synthesized from different agricultural residues.

Microcrystalline cellulose was prepared from bean hull, rice straw and rice hull. The use of rice hull and rice straw pulp in different proportions as a source of silica to prepare silicified microcrystalline cellulose was investigated. Preparations of microcrystalline cellulose-potato starch composites with different potato starch concentrations were performed. All samples were characterized through various techniques. Physical and mechanical properties of the prepared tablets were tested. The biological activities of one composite was tested in a hyperlipidemic rat model and compared to orlistat to assess its antilipidemic potential. This composite exhibited remarkable antilipidemic effect with decreased insulin sensitivity.

Indole-based fibrates as potential hypolipidemic and antiobesity agents.

Hypolipidemic and antiobesity effects of the newly synthesized indole-based fibrates were evaluated in Triton WR-1339 and high fat diet (HFD)-induced hyperlipidemic rats. Preliminary screening of all the synthesized compounds was done by using an acute model (Triton model), in which compounds 3f and 3l showed significant antidyslipidemic activity. Furthermore, these compounds 3f and 3l were found to induce significant weight loss in the visceral fat mass of HFD-fed hyperlipidemic rats without affecting the normal feeding behavior. Histological examination of the liver of rats supplemented with 3f and 3l revealed a significant decrease in steatosis when compared to the effect of the standard drug fenofibrate. Additional effects such as an increase in lecithin cholesterol acyl-transferase (LCAT) enzyme level and increased receptor mediated catabolism of I(131)-low density lipoproteins (LDL) confirm and reinforce the efficacy of both of these compounds as a new class of dual-acting hypolipidemic and antiobesity agents.

Discovery and identification of 2-phenylethyl 2,6-dihydroxybenzoate as a natural lipid-lowering lead.

Guided by lipid-lowering assays, a new compound (1, 2-phenylethyl 2,6-dihydroxybenzoate) was isolated from the ethanolic extract of Geophila herbacea. The structure of 1 was determined unambiguously by spectral data interpretation and confirmed by X-ray crystallographic analysis. Preliminary dose-dependency of 1 verified its lipid-lowering bioactivity in vitro. A facile chemical synthesis for 1 was performed to provide a practical approach for further studies on structure-activity relationship.

Ursolic acid is a PPAR-α agonist that regulates hepatic lipid metabolism.

In this study, we confirmed that ursolic acid, a plant triterpenoid, activates peroxisome proliferator-activated receptor (PPAR)-α in vitro. Surface plasmon resonance and time-resolved fluorescence resonance energy transfer analyses do not show direct binding of ursolic acid to the ligand-binding domain of PPAR-α; however, ursolic acid enhances the binding of PPAR-α to the peroxisome proliferator response element in PPAR-α-responsive genes, alters the expression of key genes in lipid metabolism, significantly reducing intracellular triglyceride and cholesterol concentrations in hepatocytes. Thus, ursolic acid is a PPAR-α agonist that regulates the expression of lipid metabolism genes, but it is not a direct ligand of PPAR-α.

Synthesis and biological evaluation of some novel cyclic-imides as hypoglycaemic, anti-hyperlipidemic agents.

Certain new halogenated cyclic-imides related to N-substituted phthalimide moiety were synthesized. Spacers of one or two carbon atom distances were inserted to connect the N-terminus of the cyclic-imide nuclei to the used heteroaryl groups to evaluate the effect of such alteration on biological activity. The synthesized compounds were subjected to hypoglycaemic and anti-hyperlipidemic evaluation. Some of the tested compounds proved to be more potent than the reference drugs glibenclamide and clofibrate. Compound 5e remarkably reduced serum glucose level by 55%; while 5c, 5e, 7d and 8e reduced total serum cholesterol by 58, 56, 54 and 53%, respectively. Those new cyclic-imides could be considered as useful template for future development to obtain more potent hypoglycaemic and anti-hyperlipidemic agents.

In-situ absorption, protein binding and pharmacokinetic studies of S002-853, a novel antidiabetic and antidyslipidaemic flavone derivative in rats.

OBJECTIVES: The aim of the study was to investigate the in-situ absorption kinetics, plasma protein binding and pharmacokinetic characteristics of a novel synthetic flavone derivative, S002-853, which shows pronounced antidiabetic and antidyslipidaemic activity. METHODS: Quantification of S002-853 in plasma was performed by the LC-MS/MS method and in-situ sample analysis was carried out by the HPLC-UV method. KEY FINDINGS: The absorption rate constant was 0.274/h in a mild alkaline environment, which S002-853 experiences in the intestine following oral dose administration. Plasma protein binding was found to be 26.37 +/- 2.58% at a concentration of 1 microg/ml. The pharmacokinetic parameters were determined in male rats after administration of a single 40 mg/kg oral dose and 10 mg/kg intravenous dose. The peak plasma concentration (C(max)) was found to be 60.93 ng/ml at 8 h after oral administration. Irregular concentration-time profiles with secondary peaks were observed after oral dose administration. The elimination half-life of the compound was 19.56 h and 16.30 h after oral and intravenous doses, respectively. Comparison of the AUC after oral and intravenous dosing of S002-853 indicates that only about 29.48% (bioavailability) of the oral dose reaches the systemic circulation. CONCLUSIONS: In-situ study of S002-853 shows slow absorption from the gastrointestinal tract. S002-853 also shows low plasma protein binding. The pharmacokinetic parameters after oral and intravenous dose reveal low oral bioavailability and high mean residence time.

Chemical synthesis of 9(Z)-octadecenamide and its hypolipidemic effect: a bioactive agent found in the essential oil of mountain celery seeds.

The unusual hypolipidemic activity of the methanolic fractionate of the essential oil (EOM) obtained from the mountain celery seed was previously reported. The most enriched 9(Z)-octadecenamide (oleamide) was speculated to be responsible for the relevant bioactivity. Chemically syntheized oleamide (CSO) yielded 85.1% with a purity of 98.6% when identified by RP-HPLC, FTIR, HREIMS, (1)H NMR, and (13)C NMR. CSO was tested for its antioxidative and hypolipidemic bioactivities. Results indicated CSO was potently hypolipidemic with regard to serum TG, TC, LDL-C, LDL-C/HDL-C, and hepatic TG (p < 0.05), but not for serum HDL-C and hepatic TC. In addition, CSO exhibited only poor antioxidative activity, implicating the possibility that the hypolipidemic and antioxidative bioactivity of original EOM was due to another coexisting constituent, probably gamma-selinene. Conclusively, oleamide is a potent hypolipidemic agent as regarding its effects on decreasing serum TG, TC, LDL-C and hepatic TG.

Syntheses and evaluation of glucosyl aryl thiosemicarbazide and glucosyl thiosemicarbazone derivatives as antioxidant and anti-dyslipidemic agents.

A series of N-per-O-acetyl-glucosyl arylthiosemicarbazide and thiosemicarbazone derivatives have been synthesized and evaluated for their in vivo anti-dyslipidemic and in vitro antioxidant activities. Among 16 compounds tested, 3 compounds showed potent anti-dyslipidemic activity and 6 compounds showed potent antioxidant and scavenger of oxygen free radicals activity.

Synthesis and antiplatelet activity of thioaryloxyacids analogues of clofibric acid.

The thiophene-, benzothiazole- and pyridine-thioaryloxyacids analogues of clofibric acid were synthesized and their antiplatelet activity was screened. Some compounds exhibited antiaggregating properties. The platelet-related haemostasis was measured on a PFA-100 analyzer using bull blood.

(2R)-2-methylchromane-2-carboxylic acids: discovery of selective PPARalpha agonists as hypolipidemic agents.

A SAR study was conducted on chromane-2-carboxylic acid toward selective PPARalpha agonisim. As a result, highly potent, and selective PPARalpha agonists were discovered. The optimized compound 43 exhibited robust lowering of total cholesterol levels in hamster and dog animal models.

Molecular design, synthesis, and hypoglycemic and hypolipidemic activities of novel pyrimidine derivatives having thiazolidinedione.

We previously reported the synthesis and biological activity of novel substituted pyridines and purines having thiazolidinedione with hypoglycemic and hypolipidemic activities. We now report the synthesis and antidiabetic activity of novel substituted pyrimidines having thiazolidinedione moiety. These compounds (entry No. 5a-i, 10a-d and 16) were evaluated for their glucose and lipid lowering activity in KKA(y) mice. From the results, novel compounds, 5c and 5g, exhibited considerably more potent biological activity than that of the reference compounds, pioglitazone and rosiglitazone, respectively.

Lipid-lowering properties of 6-benzoyl-2(3H)-benzothiazolone and structurally related compounds.

Fifteen compounds derived from the 2(3H)-benzothiazolone template with an acyl side-chain in position-6 were evaluated for their lipid-lowering action in mice. Among these compounds, 6-benzoyl-2(3H)-benzothiazolone was found to be the most potent one both in mice models receiving a hypercholesterolemic diet (for 15 days) or a standard diet (for 21 days). 6-Benzoyl-2(3H)-benzothiazolone compares favorably with fenofibrate, the standard drug, both in terms of HDL-C/Chol (High Density Lipoprotein-Cholesterol/Total Cholesterol) ratio and absence of liver hepatomegaly.

[Establishment of a drug screening model for identifying up-regulator of human high density lipoprotein receptor].

OBJECTIVE: To establish a new drug screening model based on transcriptional regulation of human high density lipoprotein (HDL) receptor gene CD36 and LIMPII analogous-1 (CLA-1) for discovering up-regulator of this receptor. METHODS: The upstream regulatory sequence of CLA-1 was obtained by polymerase chain reaction. A recombinant reporter plasmid pGL3-CLAP was constructed by inserting the regulatory sequence upstream of luciferase gene of pGL3-Basic. Human hepatoma cell line BEL-7402 was transfected with pGL3-CLAP. Samples were detected by testing luciferase activity of transfected BEL-7402 cells in microtiter wells. RESULTS: The drug screening model was established and optimized. Significant difference was present between pGL3-CLAP and pGL3-Basic transfected BEL-7402 cells (P< 0.001), and coefficient of variation was less than 10%. After primary and secondary screening, 1 compounds and 3 fermentation extracts had up-regulating activities. CONCLUSION: This new drug screening model may be efficiently used to screen up-regulators of human HDL receptor expression, which might become lead compounds for new anti-atherosclerosis drugs.