Article

Synthesis of Boswellic Acid Derivatives and Primary Research on their Activities

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Abstract

In order to search for new potent anti-cancer agents, a series of boswellic acid derivatives were designed and synthesized. Six of them were identified by IR, NMR and MS as new compounds and biologic assay of anti-cancer is underway. Boswellic acid and its acetates, isolated from the gummy exudates of Boswellia serrata Roxb and Boswellia carterri Birdw, belong to the ursane-type pentacyclic triterpene class of compounds 1 . It has been found that acetyl-11-keto-β-boswellic acid (AKBA, 3-acetyl-11-oxo-ursa-12-en-24-oic acid) is an inhibitor of topoisomerase I and 5-lipoxygenase, and induces apoptosis in human leukemia, colon, hepatoma, and other malignant cell lines also 2-7 . Recently, it was found that α-and β-boswellic acid acetates without the 11-keto group can induce apoptosis in several leukemia cell lines also 8 . These data suggested that a group existing both in AKBA and boswellic acid acetates is required for its apoptosis induction ability. In this paper, AKBA was utilized as the parent compound from which six novel boswellic acid derivatives were designed and synthesized with substitutions at the positions 3 and 24, in order to find new anti-cancer drugs with novel action-mechanism and low toxicity. The synthetic route is outlined in Scheme 1. The apoptosis-induced ability of these compounds was evaluated in human NB4 leukemia cells.

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... Natural Product boswellic acid is a pentacyclic triterpenes and its derivatives are effective for human leukemia HL-60 cell culture inhibited DNA synthesis in HL-60 cells in a dose-dependent manner with IC 50 values ranging from 0.6 to 7.1 μM. The results indicate that β-boswellic acid and its derivatives (the major constituents of Boswellin) have anti-carcinogenic, anti-tumor, and anti-hyperlipidemic activities [12]. ...
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Cyclin dependent kinases are critical molecules that control cell cycle progression from one phase to the other. However, mutational changes in these molecules lead to the purturbed cell cycle leading to uncontrolled cellular proliferation or cell death. In humans, mutations in cyclin dependent kinase 2 (1GII) is responsible for nearly 50% of cancers. In this paper preliminary in-silico screening were performed of natural polytriterpene phytochemical that are thought to have potential to inhibit mutated 1GII. Out of the two triterpenes boswellic acid and ursolic acid, boswellic acid shows inhibition activity with 1GII. From this study we propose that boswellic acid is promising towards oral cancer than ursolic acid.
... Boswellic acids are a series of pentacyclic triterpene molecules, Like many other te rpe ne s, bo swe ll ic ac id s appe ar i n the re sin o f the plant. It is estimated that they make up 30% of the resin of Boswellia serrata 8 .Boswellic acids also exhibit antiinflammatory behaviour by inhibiting leukotriene synthesis 9 .It inhibits, activity of the enzyme 5lipoxygenase through a non-redox reaction 10 . ...
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The present study involves prepration and evaluation of floating microspheres using boswellic (BA) as model drug for prolongation of the gastric retention time. BA is a lipophillic drug hence it is absorbed rapidly from the stomach and having the half life of 6 Hrs. So it is suitable candatate to formulate GRDDS.The microspheres were prepared by the solvant evaporation method using polymers hydroxypropylmethylcellulose (HPMC) in fixed ratio and Ethylcellulose in varrient ratios.The shape and surface morphology of prepared microspheres were characterized by optical and scanning electron microscopy, respectively. Drug polymer compatibility syudy was done by TLC and IR spectroscopy.The Percentage yield, Particle size distribution, Buoyancy percentage, Entrapment Efficiency and In vitro drug release studies were performed and drug release kinetics was evaluated using the linear regression method. The prepared microspheres exhibited prolonged drug release (18h) and remained buoyant for > 12 h. The mean particle size increased and the drug release rate decreased at higher polymer concentration. In vitro studies demonstrated diffusion- controlled drug release from the microspheres.
... Boswellic acids are a series of pentacyclic triterpene molecules, Like many other te rpe ne s, bo swe ll ic ac id s appe ar i n the re sin o f the plant. It is estimated that they make up 30% of the resin of Boswellia serrata 8 .Boswellic acids also exhibit antiinflammatory behaviour by inhibiting leukotriene synthesis 9 .It inhibits, activity of the enzyme 5lipoxygenase through a non-redox reaction 10 . ...
Article
Full-text available
The present study involves prepration and evaluation of floating microspheres using boswellic (BA) as model drug for prolongation of the gastric retention time. BA is a lipophillic drug hence it is absorbed rapidly from the stomach and having the half life of 6 Hrs. So it is suitable candatate to formulate GRDDS.The microspheres were prepared by the solvant evaporation method using polymers hydroxypropylmethylcellulose (HPMC) in fixed ratio and Ethylcellulose in varrient ratios.The shape and surface morphology of prepared microspheres were characterized by optical and scanning electron microscopy, respectively. Drug polymer compatibility syudy was done by TLC and IR spectroscopy.The Percentage yield ,Particle size distribution, Buoyancy percentage, Entrapment Efficiency and In vitro drug release studies were performed and drug release kinetics was evaluated using the linear regression method. The prepared microspheres exhibited prolonged drug release (18h) and remained buoyant for > 12 h. The mean particle size increased and the drug release rate decreased at higher polymer concentration. In vitro studies demonstrated diffusion-controlled drug release from the microspheres.
... The solvent was removed, and the residue was subjected to column chromatography (silica gel, hexane/ethyl acetate/HOAc, 70:30:1) to afford 16 (quant.) as a colorless solid; mp ¼ 198e201 C (lit.: 196e200 C [79]); [a] D ¼ 53.4 (c ¼ 3.02; CHCl 3 ). ...
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Boswellic acids are the effective components of gum resin of Boswellia serrata, which has anti-inflammatory properties. Recent studies on brain tumors and leukemic cells indicate that boswellic acids may have antiproliferative and apoptotic effects with the mechanisms being not studied in detail. We studied their antiproliferative and apoptotic effects on colon cancer cells and the pathway leading to apoptosis. HT-29 cells were treated with beta-boswellic acid (BA), keto-beta-boswellic acid (K-BA) and acetyl-keto-beta-boswellic acid (AK-BA), respectively. Apoptosis was determined by flow cytometry, by cytoplasmic DNA-histone complex and the activity of caspase-3. The cleavage of poly-(ADP-ribose)-polymerase (PARP) and expression of Fas were examined by western blot. Specific caspase inhibitors, polyclonal Fas antibody, and antagonistic Fas antibody ZB4 were employed to elucidate apoptotic pathways. DNA synthesis and cell viability were examined. Both K-BA and AK-BA increased cytoplasmic DNA-histone complex dose-dependently and increased pre-G(1) peak in flow cytometer analysis, with the effects of AK-BA being stronger than K-BA. BA only increased the formation of DNA-histone complex at a high concentration. K-BA and AK-BA increased caspase-8, caspase-9 and caspase-3 activities accompanied by cleavage of PARP. The effects of AK-BA on formation of cytoplasmic DNA histone and on caspase-3 activation were 3.7- and 3.4-fold, respectively, more effective than those induced by camptothecin. The apoptosis induced by AK-BA was inhibited completely by caspase-3 or caspase-8 inhibitor and partially by caspase-9 inhibitor. ZB4 blocked exogenous Fas ligand-induced apoptosis, but had no effect on AK-BA-induced apoptosis. AK-BA had no significant effect on expression of Fas. Apart from apoptotic effect, these acids also inhibited [(3)H]thymidine incorporation and cell viability to different extent. In conclusion, boswellic acids, particularly AK-BA and K-BA have antiproliferative and apoptotic effects in human HT-29 cells. The apoptotic effect is mediated via a pathway dependent on caspase-8 activation but independent of Fas/FasL interaction.
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Boswellic acid acetate (BC-4), a compound isolated from the herb Boswellia carterii Birdw., can induce differentiation and apoptosis of leukemia cells. Based on cell morphology and NBT reduction, BC-4 induced monocytic differentiation of myeloid leukemia HL-60, U937 and ML-1 cells at a dose under 12.5 microg/ml (24.2 microM). BC-4 was a potent inducer, with 90% of the cells showing morphologic changes and 80-90% of the cells showing NBT reduction. Specific and non-specific esterase were also increased by BC-4. Based on benzidine staining assay, BC-4 failed to induce erythroid leukemia DS-19 and K562 cells differentiation. In contrast to its selective differentiation effect, BC-4 strongly inhibited growth of all cell lines tested. The growth inhibition effect was dose- and time-dependent. In HL-60 cells, 20 microg/ml (38.8 microM) of BC-4 decreased viable cell number by 60% at 24 h, whereas at 3 days there was virtually no viable cells. Morphologic and DNA fragmentation analysis proved that BC-4 induced cell apoptosis. The dual apoptotic and differentiation effects of BC-4 suggest that it may be a powerful agent in the treatment of leukemia.
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A rapid and simple high-performance thin layer chromatographic (HPTLC) method was developed for the simultaneous quantitative estimation of the biologically active triterpenoids beta-boswellic acid, 3-O-acetyl-beta-boswellic acid, 11-keto-beta-boswellic acid and 3-O-acetyl-11-keto-beta-boswellic acid from the gum resin of Boswellia serrata. The assay combines the isolation and separation of boswellic acid derivatives on silica gel 60F254-HPTLC plates with spot visualisation and scanning at 250 nm. Methanol was found to be the most appropriate solvent for the exhaustive extraction of boswellic acid derivatives.
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