Thermogravimetric characterization of styrene–divinylbenzene copolymers containing alpha-isopropylaminophosphonic acid groups

A commercial styrene–divinylbenzene copolymer was functionalized by multistep reactions with alpha-isopropylaminophosphonic acid groups. Three different functionalized copolymers were obtained in which the phosphonic groups are in meta (1E), para (2E), and ortho (3E) positions. The thermal behavior was studied using the TG/IR hyphenated technique and kinetic analysis of thermo-oxidation under nonisothermal conditions. The evolved gas analysis confirms the partial thermo-oxidative degradation of polymeric materials, with significant preservation of the aromatic ring. The kinetic analysis was performed by three methods: Friedman, Flynn–Wall–Ozawa, and nonparametric kinetic.     

Quantitative analysis of betulinic acid in mouse,rat and dog plasma using electrospray liquid chromatography/mass spectrometry

Betulinic acid is under development as a therapeutic agent for the treatment of metastatic malignant melanoma. In support of pharmacokinetic and toxicological evaluations, a robust assay based on liquid chromatography/mass spectrometry (LC/MS) was developed for the quantitative analysis of betulinic acid. Sample preparation consisted of deproteinization of the plasma by the addition of three volumes of acetonitrile and one volume of methanol followed by centrifugation. Aliquots of the supernatant were analyzed using an isocratic reversed-phase high-performance liquid chromatography (HPLC) system coupled to a negative ion electrospray mass spectrometer. Deprotonated molecules of betulinic acid and the isomeric internal standard oleanolic acid were detected using selected ion monitoring at m/z 455. The limit of detection of betulinic acid was 0.5 pg (1.1 fM) injected on-column (50 pg/mL, 10 microL injection volume), and the limit of quantitation was 2 pg (4.4 fM, 200 pg/mL, 10 microL injection volume). Betulinic acid was stable in plasma samples at -20 degrees C for at least 3 weeks. The intra-day and inter-day coefficients of variation of the assay were < or =6.4 and < or =9.0%, respectively. The utility of the assay was demonstrated by analyzing betulinic acid spiked into mouse, rat and dog plasma, by determining the extent of binding of betulinic acid to plasma proteins, and by measuring betulinic acid in mouse and rat plasma following intraperitoneal or intravenous administration in vivo. At 15 and 25 microg/mL in mouse, rat or dog plasma, betulinic acid was 99.99% bound to serum proteins, and, at 5 microg/mL, betulinic acid was > or =99.97% bound.     

Design,Synthesis, and Cytotoxicity of Semisynthetic Betulinic Acid-1,2,4-Oxadiazole Amide Derivatives

Biological activity of betulinic acid derivatives containing a 1,2,4-oxadiazole ring prompted us to synthesize betulinic acid-1,2,4-oxadiazole amide derivatives 14–25 starting with the amide coupling reaction of betulinic acid 1 and (3-aryl-1,2,4-oxadiazol-5-yl)methanamines 2–13. The products were tested for cytotoxicity on three human cancer cell lines in vitro. All tested compounds demonstrated high activity. The structures of the synthesized compounds were elucidated from IR, NMR and mass spectra.     

Physico-chemical comparison of betulinic acid, betulin and birch bark extract and in vitro investigation of their cytotoxic effects towards skin epidermoid carcinoma (A431), breast carcinoma (MCF7) and cervix adenocarcinoma (HeLa) cell lines

Betulin and betulinic acid are pentacyclic triterpenes present in the bark of the birch tree and other vegetal sources. Quantitatively, in birch bark betulin is more significant than betulinic acid; therefore, birch can be a large and feasible source of raw material for betulin extraction. Betulin can be used as extracted or, after chemical modification, as a starting compound for its acid, betulinic acid, with both substances possessing various interesting pharmacological properties. The purpose of this study is to analyse the betulin and betulinic acid content of a birch tree bark extract, as well as its cytotoxic activity. The extraction was done using a Soxhlet extractor and chloroform/dichlormethane/methanol (1?:?1?:?1) as solvent. The betulin and betulinic acid content of the extract was estimated using standards of pure betulin and betulinic acid, by thermal analysis as opposed to pure substance (thermogravimetric and differential thermal analysis). The extract and the main compounds were also analysed by NMR. The results indicated a high amount of betulin in the final extract (up to 50%), and an important quantity of betulinic acid: over 3%. The cytotoxic activity indicated a high proliferation inhibition for the birch tree extract but was still comparable with betulinic acid and betulin.     

Chemical Fingerprint and Determination of Triterpenoids in Cultured Cyclocarya paliurus Cells by High-Performance Liquid Chromatography

Cyclocarya paliurus is a medicinal plant containing various bioactive components with significant health benefits. Cell cultures of C. paliurus have been used to produce these bioactive metabolites. A chemical fingerprint was obtained by high-performance liquid chromatography (HPLC) to monitor the synthesis of major triterpenoids in cultured C. paliurus cells and provide a reliable quality assessment for the cell strain screening. The determination of five triterpenoids, namely, maslinic acid, corosolic acid, betulinic acid, oleanic acid, and ursolic acid, was also performed. The HPLC method for the determination of triterpenoids in the cultured cells was accurate, stable, and reliable, and therefore suitable for chemical fingerprint analysis. Sixteen C. paliurus cell strains varied dramatically in their triterpenoid accumulations. The concentrations of the triterpenoids were 0.45–2.19 (maslinic acid), 0.92–5.34 (corosolic acid), 2.58–4.70 (betulinic acid), 4.07–12.47 (oleanic acid), and 12.64–40.98 (ursolic acid) mg/g. A high yield cell strain had a total triterpenoid concentration of 66.34?mg/g. Ten peaks in the HPLC chromatogram with reasonable height and high resolution were assigned as characteristic for fingerprint and analysis. A reference fingerprint was also obtained for cell strain assessment.     

Synthesis and α-Glucosidase Inhibitory Activity of Ursolic Acid,Lupeol, and Betulinic Acid Derivatives

Chemistry of Natural Compounds - Seven synthetic derivatives of ursolic acid, lupeol, and betulinic acid (1a–1b, 2a–2b, and 3a–3c) were synthesized to study their...     

桦木酸及其衍生物的制备与抗肿瘤作用的研究进展

桦木酸是一种羽扇豆烷型的五环三萜类化合物,因具有显著的抗肿瘤和抗HIV病毒特性而受到人们关注。桦木酸存在于多种植物中,可以用提取法得到,但由于桦木酸在植物中含量低,其主要来源是由合成法得到。许多桦木酸衍生物也具有抗肿瘤活性。本文介绍了桦木酸的提取与合成等制备方法,以及几种桦木酸衍生物的合成路线,并对桦木酸及其衍生物的抗肿瘤途径和机理进行了概述。     

Lupane triterpenoids,antioxidant potential and antimicrobial activity of Myrciaria floribunda (H. West ex Willd.) O. Berg.

Chemical composition of the methanol extract of Myrciaria floribunda leaves was investigated. The nor-lupane triterpenoids platanic acid and messagenic I acid were identified, along with other known triterpenoids (betulinic aldehyde, ursolic acid acetate and betulinic acid), a new lupane triterpenoid (2α,6α,30-trihydroxybetulinic acid) and the flavonoids catechin, quercetrin and mirycitrin. The structures were determined by spectroscopic methods (NMR, LC-MS, GC-MS). The major isolated compound was betulinic acid. The methanol extract and 2α,6α,30-trihydroxybetulinic acid were evaluated for their DPPH scavenging potential. The tested triterpenoid was one hundred times more active than betulinic acid, but less active than the extract. Screening for antimicrobial activity showed that the methanol extract was active against Staphylococcus aureus and Escherichia coli, but inactive against Candida albicans and Candida krusei, while 2α,6α,30-trihydroxybetulinic acid was inactive to all tested microorganisms.     

Determination of Pentacyclic Triterpenes from Betula utilis by High-Performance Liquid Chromatography and High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance Spectroscopy

A rapid and reliable method was developed and validated for determining betulin and betulinic acid in bark in Betula utilis by high-resolution magic angle spinning ¹H nuclear magnetic resonance (HR-MAS NMR) spectroscopy. HR-MAS NMR spectroscopy clearly distinguished the resonances of betulin and betulinic acid in the bark of all accessions of B. utilis. The concentrations of betulin and betulinic acid were calculated and added to the spectra. The determination of the targeted metabolites in chloroform extract of bark of each accession of B. utilis was performed by high-performance liquid chromatography (HPLC). Quantitatively, betulin was present at higher concentrations than betulinic acid in all accessions. The HR-MAS NMR and HPLC results showed that betulin and betulinic acid varied significantly among accessions of B. utilis. Principal component analysis of the NMR and HPLC results provided classification into three metabolic groups in which the betulin concentration was high, moderate, or low. The results show that HR-MAS NMR is rapid for fingerprinting of betulin and betulinic acid in the bark of B. utilis, while minimizing the drawbacks associated with solvent extraction.     

A Concise Semi-Synthetic Approach to Betulinic Acid from Betulin

Betulin was convert to betulinic acid using two different synthetic routes. The first approach involved an oxidation of betulin using Jones' reagent to betulonic acid and subsequent NaBH₄ reduction to betulinic acid. The second approach involved steps utilizing different protecting groups on the alcohol functional groups of betulin and Jones' oxidation to circumvent the isomerization of the secondary alcohol of betulinic acid.     

TLC Determination of Betulinic Acid from Nymphodies macrospermum: A New Botanical Source for Tagara

The accepted botanical source of Tagara, an ayurvedic drug is Valeriana jatamansi Jones. In South India, a drug by the name of Granthika Tagara is used as Tagara in several therapeutic preparations. Currently, no analytical procedures appear to be available for quality control purposes. A sensitive, selective and precise thin-layer chromatographic method has been developed and validated for the analysis of betulinic acid in Nymphoides macrospermum. Separation and quantification was achieved by TLC using ternary mobile phase of hexane:ethyl acetate:acetic acid (7:3:0.03, v/v) (R _F 0.60) on precoated silica gel 60F₂₅₄ aluminium plates and densitometric determination was carried out after derivatization with anisaldehyde-sulphuric acid reagent in the reflection/absorption mode at 540 nm. The calibration curve was linear in the concentration range of 100–600 ng spot^?1. The method was validated for precision, repeatability and accuracy. The proposed method was found to be simple, precise, specific, sensitive and accurate for the quantification of betulinic acid. This is the first TLC report for the identification and quantification of betulinic acid in N. macrospermum and may be useful for the routine quality control of Granthika Tagara.     

Synthesis of betulinic acid acyl glucuronide for application in anticancer prodrug monotherapy

The synthesis of 28-O-β-d-glucuronide betulinic acid, an acyl glucuronide derivative, was successfully carried out for the first time using commercially available peracetylated methyl glucuronate bromide under phase-transfer conditions. The target compound could be used in an anticancer prodrug monotherapy (PMT) strategy since it is non-cytotoxic, non-haemolytic, more water soluble than betulinic acid, it possesses a good in vitro stability in phosphate buffer and can be hydrolyzed in the presence of β-d-glucuronidase releasing in vitro betulinic acid, a promising anticancer agent.     

A Review on Preparation of Betulinic Acid and Its Biological Activities

Betulinic acid, a pentacyclic triterpene, is distributed in a variety of plants, such as birch, eucalyptus and plane trees. It shows a wide spectrum of biological and pharmacological properties, such as anti-inflammatory, antibacterial, antiviral, antidiabetic, antimalarial, anti-HIV and antitumor effects. Among them, the antitumor activity of betulinic acid has been extensively studied. However, obtaining betulinic acid from natural resources can no longer meet the needs of medicine and nutrition, so methods such as chemical synthesis and microbial biotransformation have also been used to prepare betulinic acid. At the same time, with the development of synthetic biology and genetic engineering, and the elucidation of the biosynthetic pathways of terpenoid, the biosynthesis of betulinic acid has also been extensively researched. This article reviews the preparation of betulinic acid and its pharmacological activities, in order to provide a reference for the research and utilization of betulinic acid.     

Comparative analysis of the thermal decomposition kinetics of β-cyclodextrin inclusion complexes with anabasine at different heating rates

The results of analysis of the thermal decomposition kinetics of inclusion complexes of β-cyclodextrin with the alkaloid anabasine at different heating rates are presented. The kinetic characteristics of the processes are determined based on the Friedman, Flynn–Wall–Ozawa and nonparametric kinetics methods.     

Efficient synthesis of lupane-type saponins via gold(I)-catalyzed glycosylation with glycosyl ortho-alkynylbenzoates as donors

Glycosylation of the acid labile betulin and betulinic acid derivatives was achieved with glycosyl ortho-hexynylbenzoates as donors under the catalysis of PPh(3)AuNTf(2); this enabled the efficient synthesis of lupane-type saponins, as exemplified by the total synthesis of the proposed betulinic acid trisaccharide from Bersama engleriana.     

Synthesis of triterpenoid derivatives and their anti-tumor and anti-hepatic fibrosis activities

Abstract

Oleanolic acid (1), ursolic acid (2), hederagenin (3), betulinol (4), betulinic acid (5), and glycyrrhetinic acid (6) are obtained from acorn/licorice industrial wastes with common triterpenoid structure as a model set for esterification. Eight 3,4,5-methoxybenzoyl triterpenoid derivatives (1a–6a), including four new derivatives (1a, 3a–1, 3a–2, and 3a–3), are synthesized by classical procedures. Their antitumor and anti-hepatic fibrosis activities are evaluated on four human tumor cell lines and t-HSC/Cl-6 cells. Derivative 1a shows maximum antiproliferative effects against all cell lines, especially against tumor cells with IC₅₀ values in the range of 5.32–15.23?μM, but does not affect the viability of normal cells. The anti-tumor mechanisms of 1a are also investigated by western blot and docking studies. The 3,4,5-methoxybenzoyl triterpenoids offers an intriguing solution for naturally derived antitumor drugs and may be invaluable for further development of cancer therapy.     

Preparation of <Superscript>131</Superscript>I–betulinic acid and its biodistribution in murine model of hepatocellular tumor

The aim of this study was to examine the radioiodinating condition of betulinic acid and understand the possibility of ¹³¹I–betulinic acid (¹³¹I–BA) as a potential tumor radiotherapy agent through in vitro uptake and in vivo biodistribution studies ¹³¹I–BA was prepared by the reaction of betulinic acid with Na¹³¹I in the presence of hydrogen peroxide, and then purified by HPLC. The labeling yield was about 80%, and the radiochemical purity was greater than 95%. ¹³¹I–BA was found to be stable at 4 °C in saline containing 1% ethanol. In vitro studies showed that ¹³¹I–betulinic acid accumulated in the cancer cell lines (BEL-7402 and NCI-H446) in comparison with free ¹³¹I⁻. In vivo biodistribution study in KM mice bearing HepA tumor showed that ¹³¹I–BA stayed longer time in tumors than free ¹³¹I⁻. A significant differences were seen in tumor/muscle ratio at 4 h postinjection between ¹³¹I–BA and free ¹³¹I⁻. In vivo and in vitro studies showed the higher fraction of ¹³¹I–BA can be utilized for therapy and a higher dose will be delivered per targeting event. ¹³¹I–BA is a promising radiopharmaceutical in nuclear medicine, especially for hepatocellular tumor targeted radionuclide brachytherapy.     

Oxidative transformations of betulinol

Starting from commercially available betulinol by a combination of several selective oxidation procedures betutinal, betulinic acid, betulonal as well as betulonic acid were obtained in high yields on a multi-gram scale.     

Synthesis of combinatorial libraries based on terpenoid scaffolds

Triterpenoid-based scaffolds betulinic acid (1a) and ursolic acid (1b), have been used for the generation of combinatorial libraries in parallel format using solid phase organic synthesis method. These templates have the potential for the synthesis and amplification of triterpenoid-based compounds with one and two-point diversity. This has been demonstrated by the synthesis of two small libraries comprising 18 derivatives each of betulinic acid and ursolic acid with structural diversity at C-3 and C-28 positions. The primary screening of antimalarial activity of these libraries against P. falciparum in vitro led to the identification of four compounds with 5 fold increase in the activity compared to betulinic and ursolic acids.     

Methyl Jasmonate Effect on Betulinic Acid Content and Biological Properties of Extract from Senna obtusifolia Transgenic Hairy Roots

It is known that Senna obtusifolia has been used in medicine since ancient times due to the content of many valuable compounds with a pro-health effect. One of them is betulinic acid, which is a pentacyclic triterpene with antimalarial, antiviral, anti-inflammatory and anticancer properties. In this work, a continuation of our previous research, an attempt was made to increase the level of betulinic acid accumulation by the cultivation of transgenic hairy roots that overexpress the squalene synthase gene in a 10 L sprinkle bioreactor with methyl jasmonate elicitation. We present that the applied strategy allowed us to increase the content of betulinic acid in hairy root cultures to the level of 48 mg/g dry weight. The obtained plant extracts showed a stronger cytotoxic effect on the U87MG glioblastoma cell line than the roots grown without elicitors. Additionally, the induction of apoptosis, reduction of mitochondrial membrane potential, chromosomal DNA fragmentation and activation of caspase cascades are demonstrated. Moreover, the tested extract showed inhibition of topoisomerase I activity.