- Formulation development and antitumor activity of a filter-sterilizable emulsion of paclitaxel
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Purpose. Paclitaxel is currently administered i.v. as a slow infusion of a solution of the drug in an ethanol:surfactant:saline admixture. However, poor solubilization and toxicity are associated with this drug therapy. Alternative drug delivery systems, including parenteral emulsions, are under development in recent years to reduce drug toxicity, improve efficacy and eliminate premedication. Methods. Paclitaxel emulsions were prepared by high- shear homogenization. The particle size of the emulsions was measured by dynamic light scattering. Drug concentration was quantified by HPLC and in vitro drug release was monitored by membrane dialysis. The physical stability of emulsions was monitored by particle size changes in both the mean droplet diameter and 99% cumulative distribution. Paclitaxel potency and changes in the concentration of known degradants were used as chemical stability indicators. Single dose acute toxicity studies were conducted in healthy mice and efficacy studies in B 16 melanoma tumor-bearing mice. Results. QW8184, a physically and chemically stable sub-micron oil-in-water (o/w) emulsion of paclitaxel, can be prepared at high drug loading (8-10 mg/mL) having a mean droplet diameter of a 3-fold increase in the maximum-tolerated-dose (MTD) over the current marketed drug formulation. Using the B16 mouse melanoma model, a significant improvement in drug efficacy was observed with QW8184 over Taxol. Conclusions. QW8184, a stable sub-micron o/w emulsion of paclitaxel has been developed that can be filter-sterilized and administered i.v. as a bolus dose. When compared to Taxol, this emulsion exhibited reduced toxicity and improved efficacy most likely due to the composition and dependent physicochemical characteristics of the emulsion.
- Constantinides, Panayiotis P.,Lambert, Karel J.,Tustian, Alex K.,Schneider, Brian,Lalji, Salima,Ma, Wenwen,Wentzel, Bryan,Kessler, Dean,Worah, Dilip,Quay, Steven C.
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Read Online
- Cloning and characterization of the β-xylosidase from Dictyoglomus turgidum for high efficient biotransformation of 10-deacetyl-7-xylosltaxol
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With the aim of finding an extracellular biocatalyst that can efficiently remove the C-7 xylose group from 10-deacetyl-7-xylosltaxol, a Dictyoglomus turgidum β-xylosidase was cloned and expressed in Escherichia coli BL21 (DE3). The molecular mass of purified Dt-Xyl3 was approximately 84 kDa. The recombinant Dt-Xyl3 was most active at pH 5.0 and 75 °C, retaining 88% activity at 65 °C for 1 h, and displaying excellent stability over pH 4.0–7.5 for 24 h. In terms of kinetic parameters, the Km and Vmax values for pNPX were 0.8316 mM and 5.0178 μmol/mL·min, respectively. Moreover, Dt-Xyl3 was activated by Mn2+ and Ba2+ and inhibited by Cu2+, Ni+ and Al3+. In particular, it displayed high tolerance to salts with 60.8% activity in 20% (w/v) NaCl. Ethanol and methanol at 5–15% showed little effect on the enzymatic activity. Dt-Xyl3 demonstrated multifunctional activities followed by pNPX, pNPAraf and pNPG and had a high selectivity for cleaving the outer xylose moieties of 10-deacetyl-7-xylosltaxol with Kcat/Km 110.87 s?1/mM, which produced 10-deacetyl-taxol to semi-synthesize paclitaxel. Under the optimized conditions (60 °C, pH 4.5, enzyme dosage of 0.5 U/mL), 1 g of 10-deacetyl-7-xylosltaxol was transformed to its corresponding aglycone 10-deacetyl-taxol within 30 min, with a molar conversion of 98%. This is the first report that Dictyoglomus turgidum can produce extracellular GH3 β-xylosidase with highly specific activity for 10-deacetyl-7-xylosltaxol biotransformation, thus leading to the application of β-xylosidase Dt-Xyl3 as a biocatalyst in biopharmaceutics.
- Li, Qi,Jiang, Yujie,Tong, Xinyi,Pei, Jianjun,Xiao, Wei,Wang, Zhenzhong,Zhao, Linguo
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- Glycosyl hydrolase with beta-xylosidase and beta-glucosidase activities and uses thereof
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A novel glycosyl hydrolase with activities of beta-xylosidase and beta-glucosidase is provided. Said glycosyl hydrolase can convert 7-xylosyltaxane compounds to 7-hydroxyltaxane compounds.
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Paragraph 18
(2015/12/26)
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- Microbial hydrolysis of 7-xylosyl-10-deacetyltaxol to 10-deacetyltaxol
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Enterobacter sp. CGMCC 2487, a bacterial strain isolated from the soil around a Taxus cuspidata Sieb. et Zucc. plant, was able to remove the xylosyl group from 7-xylosyltaxanes. The xylosidase of this strain was an inducible enzyme. In the bioconversion of 7-xylosyl-10-deacetyltaxol (7-XDT) to 10-deacetyltaxol (10-DT), for the purpose of enhancing the conversion efficiency, the effects of NH4+, oat xylan, temperature, pH value, cell density and substrate concentration on the bioconversion have been systematically investigated. 3.0 mM NH4+, 0.6% oat xylan in the media could enhance the yield of 10-DT; the optimum biocatalytic temperature was 26 °C and optimum pH value was 6.0. The highest conversion rate and yield of 10-DT from 7-XDT reached 92% and 764 mg/L, respectively. In addition, the biocatalytic capacity of the cell cultures remained 66.1% after continuous three batches. These results indicate that converting 7-XDT to 10-DT, a useful intermediate for the semisynthesis of paclitaxel or other taxane-based anticancer drugs by a novel bacterial strain, Enterobacter sp. CGMCC 2487, would be an alternative for the practical application in the future.
- Wang, Kang,Wang, Tingting,Li, Jianhua,Zou, Jianhua,Chen, Yongqin,Dai, Jungui
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experimental part
p. 250 - 255
(2011/10/12)
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- METHOD FOR THE PREPARATION OF SYNTHESIZED TAXANOIDS
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The present invention relates to a process for the preparation of synthetic taxanes, which protects C(7)-OH with lanthanon compounds. Its advantages are simple process and firm & reliable binding. Moreover, no C(7)-acylated taxanes are produced in the subsequent steps, and hydrolysis of C(2')-ester groups in acylated products becomes readily controllable. In the process for the preparation of synthetic taxanes, tetrahydrofuran is used in the present invention as a medium for acylation, which not only achieves the same effects as pyridine, but also avoids odor, so as to solve the problem regarding the extremely high requirements for the place of production. The present invention can be used for the preparation of not only semi-synthetic taxane using natural taxanes as raw material, but also full-synthetic taxane.
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Page/Page column 5
(2010/02/17)
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- Biological degradation of taxol by action of cultured cells on 7-acetyltaxol-2″-yl glucoside
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Biodegradation pathways of taxol in cultured cells of Synechocystis sp. PCC 6803, Synechococcus sp. PCC 7942, Marchantia polymorpha, Nicotiana tabacum, and Glycine max were investigated using a water-soluble taxol derivative, 7-ace-tyltaxol-2″-yl glucoside, as the substrate. Although cyanobacteria, Synechocystis sp. PCC 6803 and Synechococcus sp. PCC 7942, and a lower plant, M. polymorpha, catalyzed the epimerization at 7-position of taxol skeleton, no epimerization occurred with higher plants, N. tabacum and G. max. On the other hand, Synechocystis sp. PCC 6803, Synechococcus sp. PCC 7942, M. polymorpha, and N. tabacum catalyzed hydrolysis at 13-position of taxol to give baccatin III and 10-deacetyl baccatin III. Both cyanobacteria cells also deacetylated 7-epi-baccatin III at its 10-position. M. polymorpha and G. max deacetylated at 10-position of taxol. Copyright
- Shimoda, Kei,Mikuni, Katsuhiko,Nakajima, Kiyoshi,Hamada, Hatsuyuki,Hamada, Hiroki
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p. 362 - 363
(2008/09/20)
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- Process for the Preparation of Synthetic Taxanes
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The present invention relates to a process for the preparation of synthetic taxanes, which protects C(7)-OH with lanthanon compounds. Its advantages are simple process and firm & reliable binding. Moreover, no C(7)-acylated taxanes are produced in the subsequent steps, and hydrolysis of C(2′)-ester groups in acylated products becomes readily controllable. In the process for the preparation of synthetic taxanes, tetrahydrofuran is used in the present invention as a medium for acylation, which not only achieves the same effects as pyridine, but also avoids odor, so as to solve the problem regarding the extremely high requirements for the place of production. The present invention can be used for the preparation of not only semi-synthetic taxane using natural taxanes as raw material, but also full-synthetic taxane.
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Page/Page column 3
(2008/12/09)
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- METHOD FOR THE PRODUCTION OF TAXOL AND/OR TAXANES FROM CULTURES OF HAZEL CELLS
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Method for the production of taxol and/or taxanes, comprising the steps of: a) inducing the formation of callus from a plant tissue explant, through in vitro culturing in a suitable nutritient medium, b) cultivating the callus in a liquid medium to obtain a cell suspension culture capable of producing taxol and/or taxanes, c) recovering the taxol and/or the taxanes from the cells and/or from the culture medium of the cell suspension obtained from the callus in which the tissue explant is obtained from a plant of the genus Corylus, in particular Corylus avellana.
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- Trifluoroacetic acid-mediated cleavage of a triethylsilyl protecting group: Application in the final step of the semisynthetic route to paclitaxel (Taxol)
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The final step of the semisynthetic route to paclitaxel involves cleavage of the triethylsilyl (TES) protecting group from the C-7 hydroxyl group. Paclitaxel is an extremely complex molecule, and standard deprotection conditions led to formation of several impurities. Trifluoroacetic acid in aqueous acetic acid was found to be very effective in the cleavage of the TES group without compromising the quality of the product.
- Singh, Ambarish K.,Weaver, Raymond E.,Powers, Gerald L.,Rosso, Victor W.,Wei, Chenkou,Lust, David A.,Kotnis, Atul S.,Comezoglu, F. Taha,Liu, Mark,Bembenek, Kenneth S.,Phan, Bich D.,Vanyo, Dale J.,Davies, Merrill L.,Mathew, Rachel,Palaniswamy, Venkatapuram A.,Li, Wen-Sen,Gadamsetti, Kumar,Spagnuolo, Ciro J.,Winter, William J.
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- Mechanistic considerations pertaining to the solvolysis of paclitaxel analogs bearing ester groups at the C2′ position
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Dilute solutions of paclitaxel-related derivatives having chloroacetyl esters in the C2′ position undergo ready methanolysis according to pseudo first-order kinetics while more concentrated solutions appear to be stabilized, possibly by the formation of h
- Klis, Wieslaw A.,Sarver, Jeffrey G.,Erhardt, Paul W.
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p. 7747 - 7750
(2007/10/03)
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- Scandium trifluoromethanesulfonate-catalyzed cleavage of esters bearing a coordinative group at a vicinal position
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Scandium trifluoromethanesulfonate is found to be a Lewis acid catalyst for selective cleavage of esters containing a coordinative group adjacent to an ester moiety. The reaction proceeds under weak acidic conditions at room temperature; the catalyst can be recovered and reused. Even α-acyloxy ketones are deacetylated without racemization. Selective monodeacetylation at C-10 of paclitaxel has been achieved.
- Kajiro, Hiroshi,Mitamura, Shuichi,Mori, Atsunori,Hiyama, Tamejiro
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p. 1553 - 1560
(2007/10/03)
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- Selective process for the deacylation and deacetylation of taxol and taxanes
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The present invention relates to a highly selective method for the deacetylation and deacylation of taxol and taxanes compounds. Specifically, the present invention relates to a one step process wherein acyl groups located at the carbon 2', 10, and 7 positions of taxol and other taxane compounds may be selectively removed.
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- Semi-synthesis of paclitaxel from naturally occurring glycosidic precursors
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Paclitaxel, an antitumor drug effective on ovarian and breast carcinomas, is currently being produced both by direct isolation from the bark of Taxus brevifolia and by semi-synthesis from a natural precursor, 10-deacetyl baccatin III. Although other potential precursors such as 10-deacetyl paclitaxel-7-xyloside were known since 1984, their conversion to paclitaxel could not be achieved because of the lack of suitable methodology for hydrolyzing the xylose residue, compatible with the stability of the compound. A method is described here using periodate, followed by phenylhydrazine, to effect deglycosidation of 10-deacetyl paclitaxel-7-xyloside to form 10-deacetyl paclitaxel. In addition, by including an intermediate acetylation step before the reaction with phenylhydrazine, 'direct' conversion of this xyloside to paclitaxel itself, is described. Because 10-deacetyl paclitaxel-7-xyloside occurs at >0.1% in the bark of Taxus brevifolia, its successful hydrolytic conversion to paclitaxel represents an extremely important reaction for the enhanced availability of this drug.
- Rao, Koppaka V.
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p. 675 - 680
(2007/10/03)
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- Method for the isolation and purification of taxane derivatives
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An improved method for isolating certain clinically important taxane derivatives from the crude extract of a naturally occurring Taxus species comprising treating the extract by reverse phase liquid chromatography on an adsorbent; causing the taxane derivatives to be adsorbed on the adsorbent; and recovering the taxane derivatives from the adsorbent by elution with an elutant. The taxane derivatives thus isolated in pure form are taxol, taxol-7-xyloside, 10-deacetyitaxol, 10-deacetyltaxol-7-xyloside, cephalomannine, cephalomannine-7-xyloside, 10-deactylcephalomannine-7-xyloside, baccatin III, 10-deacetylbaccatin III, baccatin VI, and brevitaxane A.
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- Method for the isolation and purification of taxol and its natural analogues
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An improved method for isolating taxol and certain clinically important analogues of taxol from a crude extract of a naturally occuring Taxus species comprising treating the extract by reverse phase liquid chromatography on an adsorbent, causing the taxol and the taxol analogues to be absorbed on the adsorbent, and recovering taxol and the natural analogues of taxol from the adsorbent by elution with an elutant. The compounds thus isolated in pure form are taxol, taxol-7- xyloside, 10-deacetyltaxol, 10-deacetyltaxol-7-xyloside, cephalomannine, cephalomannine-7-xyloside, 10-deacetylcephalomannine-7-xyloside, baccatin III, 10-deacetylbaccatin III, baccatin VI, brevitaxane A, and taxiflorine.
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- Taxol Structure-Activity Relationships: Synthesis and Biological Evaluation of 10-Deoxytaxol
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10-Deoxytaxol 2 was prepared from taxol (1) in four steps via the intermediate dienone 5b; the key reaction in the sequence is a Yarovenko reagent-mediated dehydration at the C-10 hydroxyl group.Compound 2 was found to possess comparable antitumor activity with respect to taxol.This confirms that the functional group at C-10 in taxol is not involved in receptor binding.
- Chen, Shu-Hui,Fairchild, Craig,Mamber, Stephen W.,Farina, Vittorio
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p. 2927 - 2928
(2007/10/02)
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- THE CHEMISTRY OF TAXANES: REACTIONS OF TAXOL AND BACCATIN DERIVATIVES WITH LEWIS ACIDS IN APROTIC AND PROTIC MEDIA
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Several Lewis acids were shown to cleanyl open the oxetane ring of taxol and baccatin derivatives.The reaction is shown to proceed via anchimeric assistance by the C-4 acetate group.Several minor products, including a novel derivative possessing a bridged C-ring, were also isolated.A mechanistric rationale is provides for all compounds formed.When taxol derivatives were treated with Lewis acids in methanol, ester cleavage reactions were observed.We provide conditions that are selective for C-10 acetate cleavage and for C-13 side-chain methanolysis.
- Chen, Shu-Hui,Huang, Stella,Wei, Jianmei,Farina, Vittorio
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p. 2805 - 2828
(2007/10/02)
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- Process for the preparation of taxol and 10-deacetyltaxol
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Taxol, 10-deacetyltaxol and other taxane derivatives are prepared from naturally occurring taxane-7-xylosides by the oxidative-cleavage of the 7-xyloside moieties.
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- Relationships between the structure of taxol analogues and their antimitotic activity
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A variety of synthetic analogues of taxol, a naturally occurring antitumor diterpene, were examined for their potency to inhibit microtubule disassembly. For some of the compounds, the in vitro cytotoxic properties showed a good correlation with the tubulin assay. This structure-activity relationship study shows that inhibition of microtubule disassembly is quite sensitive to the configuration at C-2' and C-3'. A correlation between the conformation of the side chain at C-13 and the activity is suggested. Of all the compounds examined, one of the most potent in inhibiting microtubule disassembly and in inhibiting murine P388 leukemic cells, N-debenzoyl-N-tert-(butoxycarbonyl)-10-deacetyltaxol, named taxotere, was selected for evaluation as a potential anticancer agent.
- Gueritte-Voegelein,Guenard,Lavelle,Le Goff,Mangatal,Potier
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p. 992 - 998
(2007/10/02)
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