Advances in Research on Hepatoprotective Activity and Synthesis of Oleanolic Acid Derivatives
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Oleanolic acid (3b-hydroxyolean-12-en-28-oic acid) is a pentacyclic triterpenoid compound with a wide spread occurrence throughout the plant kingdom. During the last decade many research articles associated with oleanolic acid have been published. Particularly its hepatoprotective activity has been studied for many years. However, the clinical application of oleanolic acid has been limited by its poor solubility. In order to overcome this disadvantage, various approaches have been sought and many derivatives of oleanolic acid have been designed and synthesized. And some of these analogues show improved pharmacokinetic and pharmacodynamic properties, indicating that it may be promising candidates for the treatment of human liver diseasesCite
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Oleanolic acid(OA),a naturally occurring pentacyclic triterpenoid,is a biologically active marker compound commonly present in Chinese herbs,such as Fructus Ligustri Lucidi,Fructus Forsythiae and Radix Ginseng etc.Oleanolic acid has been successfully used as an OTC oral drug to treat human liver disorders in China due to its hepatoprotective effect.In addition,it exerts anti-inflammatory,antitumor and anti-hyperlipidemic effects.Up to now,the commonly used formulations of OA in the market are tablets,capsules,and pills.However,being hydrophobic,OA exhibits poor aqueous solubility and low bioavailability in vivo.The present review covers its physicochemical properties,dosage form development and pharmacokinetics studies.The difference between the application of these dosage forms,as well as the effectiveness of their improvements in OA's dissolution and oral bioavailability,are especially discussed.
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Abstract Review: (201 refs.
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Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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We describe a novel disulfide reaction via UV/DMAP methodology for efficient construction of simple disulfides and structurally complex peptides.
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Oleanane-type triterpenes and their glycosides are a structurally and biologically diverse class of metabolites that are widely distributed in terrestrial plants and some marine organisms.Many of these compounds bear functional groups and modifications on the D and/or E rings of the triterpenes.These triterpenes compounds are of growing interest for drug research as they are active constituents of folk medicines and provide valuable pharmacological profiles.For their limited availability and accessibility, chemical synthesis provides a realistic way to determine the availability of homogenous natural products and their derivatives.Here, we report the selective dehydrogenation on the D or E rings of oleanoic acid by palladium promoted C-H activation with 8-aminoquinoline amide (substrate 12) and 2-aminomethylpyridine amide (substrate 16) as the directing groups.Thus, upon treatment with thionyl chloride, the 28-COOH of oleanoic acid was converted into 28-COCl, which coupled with the corresponding amines to provide the substrates readily for dehydrogenation.Notably, treatment of 12 with optimized conditions (1.0 equiv.Pd(OAc) 2 , 1.5 equiv.Oxone ® , 1,2-dichloroethane, 80 ℃, 24 h) led to the dehydrogenated products 13 [double bond at C(15)-C( 16)] and 14 [double bond at C(20)-C(21)] in 55% and 2% yields respectively.Treatment of 16 with optimized conditions (1.0 equiv.Pd(OAc) 2 , 2.0 equiv.Oxone ® , 1,2-dichloroethane, microwave 85 ℃, 50 min) provided 17 [double bond at C(20)-C(21)] and 18 [double bond at C(15)-C( 16)] in 42% and 20% yields respectively.Moreover, the distribution of the products varied in different solvents.It is worth mentioning that the N,N-bidentate ligands (two nitrogen atoms as the coordination sites in 12 and 16) are crucial for the palladium promoted olefination.
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Abstract 1,3‐Dicyclohexylcarbodiimide (DCC) has been exploited as an activating agent for nucleoside‐H‐phosphonates in the solution as well as solid phase synthesis of oligonucleotide and is effective in terms of speed and coupling efficiency.
Phosphonate
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Tuberculosis a major cause of death worldwide, is an infectious disease caused by Mycobacterium tuberculosis. An increase in drug-resistant tuberculosis cases and the emergence of additional resistant strains and coinfections with HIV has stimulated the search for and development of new anti-TB drugs [1]. The wide variety of natural products chemical structures plays a major role on the development of new antimycobacterial drugs generations. Duroia macrophylla is an endemic plant of the Amazon Forest [2]. To the best of our knowledge, no chemical or biological investigations other than ours [3,4] have been carried out on this species as of yet. Hence this work aims to evaluate the antimycobacterial activity of their extracts and isolate and identify the substances present in D. macrophylla active extracts.
Antimycobacterial
Ursolic acid
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The pharmacokinetics of oleanolic acid was evaluated in vitro and in vivo. From Caco-2 cell permeation studies, oleanolic acid was a low permeability compound with no directional effects, suggesting a low in vivo absorption mediated by a passive diffusion. Oleanolic acid was metabolically unstable following incubation with rat liver microsomes in the presence of NADPH. After intravenous injection at doses of 0.5, 1 and 2 mg/kg doses, oleanolic acid showed dose-linear pharmacokinetics as evidenced by unaltered CL (28.6-33.0 ml/min/kg), Vss (437-583 ml/kg), dose-normalized AUC (16.0-17.9 microg min/ml based on 1 mg/kg) and t1/2 (41.9-52.7 min). Following oral administration of oleanolic acid at doses of 10, 25 and 50 mg/kg, Tmax, t1/2, dose-normalized Cmax (66-74 ng/ml based on 25 mg/kg) and dose-normalized AUC (5.4-5.9 microg min/ml based on 25 mg/kg) were comparable between 25 and 50 mg/kg dose, but the plasma concentrations at 10 mg/kg dose were not measurable as they were below the limit of quantitation (2 ng/ml). The absolute oral bioavailability was 0.7% for oral doses of 25 and 50 mg/kg. The extent of urinary excretion was minimal for both i.v. and oral doses. The very low oral bioavailability of oleanolic acid could be due to a poor absorption and extensive metabolic clearance.
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Abstract Durch Diazotierung von (I) in wäßriger Tetrafluorborsäure entstehen die Diazoniumfluorborate (II), die bei der thermischen Zersetzung in Paraffinöl in die 5‐Fluorpyrimidine (III) übergehen.
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