- Synthesis, utility, and x-ray crystal structure of novel complexes of baccatin III with imidazole and 2-propanol
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(matrix presented) Baccatin III forms crystalline complexes 4 and 5 with imidazole and 2-propanol, respectively. These compounds are useful in the purification of baccatin III from mixtures of taxanes derived from plant-cell fermentation.
- Gibson, Frank S.,Wei, Jianmei,Vemishetti, Purushotham,Gao, Qi,Dillon, John L.
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Read Online
- In vitro enzymatic synthesis of baccatin III with novel and cheap acetyl donors by the recombinant taxoid 10β-O-acetyl transferase
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Despite the importance of baccatin III as a precursor to paclitaxel, a widely used chemotherapeutic agent, efficient enzymatic synthesis methods are lacking. Therefore, in this study, the recombinant taxoid 10β-O-acetyl transferase was prepared to produce baccatin III in vitro. The recombinant enzyme could use vinyl acetate, butyl acetate, sec-butyl acetate, isobutyl acetate, amyl acetate, and isoamyl acetate as novel and cheap alternative acetyl group donors to replace the expensive acetyl CoA for the enzymatic synthesis of baccatin III. A molecular docking study further confirmed that these acetyl donors could reasonably bind to the enzyme molecule. Using the aqueous two-phase bio-catalytic reaction system, hexane and ethyl acetate could increase the yield of product baccatin III by 2.8% and 1.1% respectively. This approach using novel and cheap acetyl donors is promising for the enzymatic synthesis of baccatin III for the future industrial production of paclitaxel.
- You, Lin-Feng,Huang, Jia-Jun,Lin, Shu-Ling,Wei, Tao,Zheng, Qian-Wang,Jiang, Bing-Hua,Lin, Jun-Fang,Guo, Li-Qiong
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Read Online
- Selective protection of the C(7) and C(10) hydroxyl groups in 10- deacetyl baccatin III
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New protocols for the selective protection of the C(7) and C(10) hydroxyl groups of 10-deacetyl baccatin III are described, leading to more efficient semisyntheses of taxol and taxol analogs. The C(10) hydroxyl group of 10-DAB can be highly selectively acylated or silylated, and subsequent selective protection of the C(7) hydroxyl group then becomes straightforward.
- Holton, Robert A.,Zhang, Zhuming,Clarke, Paul A.,Nadizadeh, Hossain,Procter, D. John
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Read Online
- Total Synthesis of Paclitaxel
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The total synthesis of paclitaxel (Taxol) is described. Double Rubottom oxidation of the bis(silyl enol ether) derived from a tricarbocyclic diketone effectively installed a bridgehead olefin and C-5/C-13 hydroxy groups in a one-step operation. The novel Ag-promoted oxetane formation smoothly constructed the tetracyclic framework of paclitaxel.
- Chida, Noritaka,Fukaya, Keisuke,Iiyama, Shota,Mochizuki, Shota,Noguchi, Takashi,Oishi, Takeshi,Saio, Ryosuke,Sato, Takaaki,Watanabe, Ami,Yamaguchi, Yu,Yamamoto, Hiroaki
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supporting information
(2021/12/27)
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- Fluorinated taxane compound, preparation method therefor and application of fluorinated taxane compound
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The invention discloses a fluorinated taxane compound, a preparation method therefor and an application of the fluorinated taxane compound. The compound has a structural general formula represented bya formula I. Proven by pharmacological experiments, compared with paclitaxel, a series of fluorinated taxane derivatives synthesized by the method have cytotoxicity superior to that of the paclitaxelto a multidrug-resistant human mammary cancer cell line MCF-7/Adr and an ovarian cancer cell line NCI/Adr and represent cytotoxicity superior to that of the paclitaxel to a colon cancer cell line HCT-116 with overexpressed neoplasm stem cells.
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Paragraph 0048; 0085; 0093-0095
(2019/08/30)
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- A semi-synthetic taxane derivative and its preparation method and application
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The invention discloses a semi-synthetic taxane derivative. An anti-tumor effect test shows that the semi-synthetic taxane derivative has relatively good anti-tumor activity on a human lung adenocarcinoma cell line A549, a human breast cancer cell line MCF-7, a human glioblastoma cell line U251, a human pancreatic cancer cell line PANC-1, a human colon cancer cell line HCT116 and a human non-small lung cancer cell line H460. The semi-synthetic taxane derivative can be used for preparing anti-tumor drugs.
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Paragraph 0052-0055
(2019/03/10)
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- Antagonizing NOD2 Signaling with Conjugates of Paclitaxel and Muramyl Dipeptide Derivatives Sensitizes Paclitaxel Therapy and Significantly Prevents Tumor Metastasis
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A noncleavable paclitaxel (PTX) and N-acetylmuramyl-l-alanyl-d-isoglutamine (MDP) derivative conjugate, 22 (DY-16-43), and its analogues were prepared and characterized as antagonists of NOD2 signaling. This conjugate enhanced the antitumor and antimetastatic efficacy of PTX in Lewis lung carcinoma (LLC) tumor-bearing mice. This work first describes a molecular strategy that enables the sensitization of a chemotherapeutic response via antagonizing NOD2 inflammatory signaling and suggests NOD2 antagonist as potential adjunct in treating non-small-cell lung cancer (NSCLC).
- Dong, Yi,Wang, Suhua,Wang, Chunting,Li, Zihua,Ma, Yao,Liu, Gang
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supporting information
p. 1219 - 1224
(2017/02/19)
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- Docetaxel side chain 2'-derived novel taxanes antitumor compound as well as synthesis method and application thereof
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The invention discloses a docetaxel side chain 2'-derived novel taxanes antitumor compound shown as the general structure formula (I) as well as a synthesis method and application thereof. In the formula, X is N or O, R is H or acetyl, and R' is H, nitryl, cyano, methoxyl or a halogen group. The synthesis method takes 10-deacetylbaccatin is used as a raw material; after 7-OH and 10-OH are protected, condensation with phenylisoserine (side chain) protecting 3'-NHBoc and 2'-OH in the presence of condensation agents DCC (Dicyclohexylcarbodiimide) and DMAP (Dimethylaminopyridine) is performed; esterification with substituted phenyl isoxazole carboxylic acid or substituted phenyl oxadiazole methyl carboxylic acid in the presence of the DCC and the DMAP is performed; finally, a protecting group is removed to obtain the compound. The compound disclosed by the invention has relatively high activity on tumor cells.
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Paragraph 0019
(2017/08/29)
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- Novel taxane anti-tumor compound as well as synthesis method and application thereof
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The invention discloses a novel taxane anti-tumor compound shown in a structural formula (I). 10-DAB (10-deacetylbaccatin) is adopted as a raw material, and is condensed with phenylisoserine (side chain) with protected 3'-NH2 and 2'-OH in the presence of condensing agents DCC and DMAP after 7-OH and 10-OH are protected, the side chain and a protecting group on a baccatin ring are simultaneously removed in the presence of zinc powder, and coupling is performed with substituted phenylisoxazole in an alkaline medium to obtain a target product. The compound has relatively high anti-tumor activity. (The structural formula (I) is shown in the description.).
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Paragraph 0018
(2017/08/29)
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- A process for the preparation of paclitaxel
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The invention discloses a preparation method of paclitaxel. A side chain which performs condensation reaction on 13-hydroxyl of 7-TES-barca III is di(3R, 4S)-1-benzoyl-3-hydroxyl-4-phenylazepane-2-butanone. According to the preparation method, a new side chain is used for performing condensation reaction; a new preparation method is expanded, the quantity of reaction byproducts is small, and the yield is high.
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Paragraph 0071-0073
(2018/02/04)
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- Organocatalytic site-selective acylation of 10-deacetylbaccatin III
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Organocatalytic site-selective diversification of 10-deacetylbaccatin III, a key natural product for the semisynthesis of taxol, has been achieved. Various acyl groups were selectively introduced into the C(10)-OH of 10-deacetylbaccatin III. The C(10)-OH selective acylation was also applied to acylative site-selective dimerization of 10-deacetylbaccatin III to provide the structurally defined dimer.
- Yanagi, Masanori,Ninomiya, Ryo,Ueda, Yoshihiro,Furuta, Takumi,Yamada, Takeshi,Sunazuka, Toshiaki,Kawabata, Takeo
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p. 907 - 912
(2016/07/14)
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- Synthesis and anticancer activity of novel quinoline-docetaxel analogues
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A series of novel quinoline-docetaxel analogues (6a-6g, 13a-13g) were designed and synthesized by introducing bioactive quinoline scaffold to C2′-OH of docetaxel. The anticancer activities of these novel analogues were investigated against different human cancer cell lines including Hela, A549, A2780, MCF-7 and two resistant strains A2780-MDR and MCF-7-MDR. The data showed these analogues possessed similar to better cytotoxicity than docetaxel. Compound 6c was found to be the most potent one, and its IC50 value against MCF-7-MDR was 8.8 nM (IC50 of docetaxel was 180 nM). The work indicated that the introduction of quinolyl group in docetaxel could enhance cytotoxicity and reduce drug-resistance.
- Chen, Ming,Chen, Hui,Ma, Jiangwei,Liu, Xueying,Zhang, Shengyong
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p. 2867 - 2870
(2014/06/10)
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- A structure-based design of new C2- and C13-substituted taxanes: Tubulin binding affinities and extended quantitative structure-activity relationships using comparative binding energy (COMBINE) analysis
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Ten novel taxanes bearing modifications at the C2 and C13 positions of the baccatin core have been synthesized and their binding affinities for mammalian tubulin have been experimentally measured. The design strategy was guided by (i) calculation of interaction energy maps with carbon, nitrogen and oxygen probes within the taxane-binding site of β-tubulin, and (ii) the prospective use of a structure-based QSAR (COMBINE) model derived from an earlier series comprising 47 congeneric taxanes. The tubulin-binding affinity displayed by one of the new compounds (CTX63) proved to be higher than that of docetaxel, and an updated COMBINE model provided a good correlation between the experimental binding free energies and a set of weighted residue-based ligand-receptor interaction energies for 54 out of the 57 compounds studied. The remaining three outliers from the original training series have in common a large unfavourable entropic contribution to the binding free energy that we attribute to taxane preorganization in aqueous solution in a conformation different from that compatible with tubulin binding. Support for this proposal was obtained from solution NMR experiments and molecular dynamics simulations in explicit water. Our results shed additional light on the determinants of tubulin-binding affinity for this important class of antitumour agents and pave the way for further rational structural modifications. The Royal Society of Chemistry 2013.
- Coderch, Claire,Tang, Yong,Klett, Javier,Zhang, Shu-En,Ma, Yun-Tao,Shaorong, Wang,Matesanz, Ruth,Pera, Benet,Canales, Angeles,Jimenez-Barbero, Jesus,Morreale, Antonio,Diaz, J. Fernando,Fang, Wei-Shuo,Gago, Federico
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supporting information
p. 3046 - 3056
(2013/07/26)
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- PROCESS FOR PREPARING TAXOIDS FROM BACCATIN DERIVATIVES USING LEWIS ACID CATALYST
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The present invention relates to a process of preparing a taxoid (X) by reacting a protected baccatin derivative (B) with a β-lactam (C) in the presence of one or more Lewis acids and a base agent. The present invention also relates to a process of preparing the protected baccatin derivative (B) from a baccatin derivative (A) comprising a protection reaction catalyzed by one or more Lewis acids with an optional base agent.
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Page/Page column 13
(2012/06/18)
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- The taxol pathway 10-O-acetyltransferase shows regioselective promiscuity with the oxetane hydroxyl of 4-deacetyltaxanes
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The 10-deacetylbaccatin III:10β-O-acetyltransferase isolated from Taxus cuspidata regiospecifically transfers short-chain alkanoyl groups from their corresponding CoA thioesters to the C10 hydroxyl of 10-deacetylbaccatin III. This 10-O-acetyltransferase along with five other Taxus acyltransferases on the paclitaxel (Taxol) biosynthetic pathway and one additional Taxus-derived acyltransferases of unknown function were screened for 4-O-acetyltransferase activity against 4-deacetylbaccatin III, 7-acetyl-, 13-acetyl-, and 7,13-diacetyl-4-deacetylbaccatin III. These 4-deacyl derivatives were semisynthesized from the natural product baccatin III via silyl protecting group manipulation, regioselective reductive ester cleavage with sodium bis(2-methoxyethoxy)aluminum hydride, and regioselective acetylation with acetic anhydride. Assays with the 4-deacetylated diterpene substrates and acetyl CoA revealed the taxane 10β-O-acetyltransferase was able to catalyze the 4-O-acetylation of 4-deacetylbaccatin III to baccatin III and 13-acetyl-4-deacetylbacatin III to 13-acetylbaccatin III, although each was converted at lesser efficiency than with the natural substrate. In contrast, this enzyme was unable to acetylate 7-acetyl-4-deacetylbaccatin III and 7,13-diacetyl-4-deacetylbaccatin III substrates at C4, suggesting that the C7 hydroxyl of baccatin III must remain deacylated for enzyme function. The biocatalytic transfer of an acyl group to the tertiary hydroxyl on the oxetane moiety at C4 of the taxane ring demonstrates that the regiochemistry of the 10β-acetyltransferase is mutable.
- Ondari, Mark E.,Walker, Kevin D.
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scheme or table
p. 17187 - 17194
(2009/04/13)
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- Paclitaxel-initiated, controlled polymerization of lactide for the formulation of polymeric nanoparticulate delivery vehicles
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(Chemical Equation Presented) Paclitaxel-polylactide nanoconjugates were prepared by the site-specific polymerization of lactide mediated by a paclitaxel-metal complex followed by nanoprecipitation (see scheme). The resulting nanoconjugates have nearly 100% paclitaxel incorporation efficiencies and predefined drug loadings, and are less than 100 nm in diameter. The drug burst release effect is completely eliminated with this drug delivery vehicle.
- Tong, Rong,Cheng, Jianjun
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supporting information; experimental part
p. 4830 - 4834
(2009/02/08)
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- New methods and strategies for asymmetric synthesis of organophosphorus compounds
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New methods for the asymmetric synthesis of organophosphorus compounds were developed and applied for the preparation of a number of biologically important enantiomerically pure products. Copyright Taylor & Francis Group, LLC.
- Kolodiazhnyi,Guliayko,Gryshkun,Kolodiazhna,Nesterov,Kachkovskyi
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scheme or table
p. 393 - 398
(2009/04/04)
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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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- 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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- Design, synthesis and structure-activity relationships of novel taxane-based multidrug resistance reversal agents
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A series of novel taxane-based multidrug resistance (MDR) reversal agents (TRAs) has been designed and synthesized. Structure - activity relationship (SAR) study clearly indicates that modification of the C-7 position with hydrophobic arenecarbonylcinnamoyl groups brings about high potency against drug efflux mediated by P-glycoprotein (P-gp). Six TRAs exhibit ability to modulate a wide range of ATP-binding cassette (ABC) transporters, such as P-gp, multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP), which may serve as novel broad-spectrum modulators of ABC transporters.
- Ojima, Iwao,Borella, Christopher P.,Wu, Xinyuan,Bounaud, Pierre-Yves,Oderda, Cecilia Fumero,Sturm, Matthew,Miller, Michael L.,Chakravarty, Subrata,Chen, Jin,Huang, Qing,Pera, Paula,Brooks, Tracy A.,Baer, Maria R.,Bernacki, Ralph J.
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p. 2218 - 2228
(2007/10/03)
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- Methods for preparing new taxoids and pharmaceutical compositions containing them
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Methods of preparing methylthiomethyloxy taxoids of formula (XXXIV) from baccatin and β-lactam are presented. These new taxoids display noteworthy anti-tumor and anti-leukemic properties.
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- Stable isotope labeling of paclitaxel
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A chemical compound comprising an isotopically labeled analog of a standard taxane molecule, wherein said isotopically labeled analog is synthetically formed to have incorporated therein at a selected position a stable isotope of an element existing at said selected positon in said standard taxane molecule, said isotope having amass different form a mass of a mass of a most abundantly occurring isotope of said element in nature, such that said isotopically labeled analog has a molecular weight different form a molecular weight of said standard taxane molecule.
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- Methods for preparing new taxoids and pharmaceutical compositions containing them
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Methods of preparing methylthiomethyloxy taxoids of formula (XXXIV) from baccatin and β-lactam are presented. These new taxoids display noteworthy anti-tumor and anti-leukemic properties.
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- Process for selective derivatization of taxanes
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A process is described for converting the C(7) hydroxy group of a 10-acyloxy-7-hydroxytaxane to an acetal or ketal, the process comprising treating the 10-acyloxy-7-hydroxytaxane with a ketalizing agent in the presence of an acid catalyst to form a C(7) ketalized taxane of the formula or wherein either X31 or X32 represents the 10-acyloxy-7-hydroxytaxane moiety and the other of X31 and X32 as well as X33 and X34 are independently hydrocarbyl, substituted hydrocarbyl or heteroaryl moieties. Taxanes having a ketalized C(7) hydroxy group are also described.
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- Process for selective derivatization of taxanes
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A process for the acylation of a C(10) hydroxy group of a taxane comprises treating the taxane with an acylating agent selected from dicarbonates, thiodicarbonates, and isocyanates in a reaction mixture containing less than one equivalent of a base for each equivalent of taxane to form a C(10) acylated taxane.
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- Process for selective derivatization of taxanes
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A process for the silylation of a C(10) hydroxy group of a taxane comprises treating the taxane with a silylamide or a bissilylamide to form a C(10) silylated taxane.
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- Conversion of 9-dihydro-13-acetylbaccatin III to baccatin III and 10-deacetyl baccatin III
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Novel methods and synthetic intermediates to prepare baccatin III and 10-deacetylbaccatin from readily available 9-dihydro-13-acetylbaccatin III are described. Selective protection and deprotection of the C-7 hydroxyl functionality provides an entry into facile synthesis of novel taxol intermediates, as well as, providing new methods for the preparation of paclitaxel and docetaxel in large scale. Selective oxidation of the C-9 hydroxyl without the need for protection of the C-7 hydroxyl is described.
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- Process for selective derivatization of taxanes
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Processes for the preparation of taxol and other taxanes through selective derivatization of the C(7) and C(10) hydroxyl groups of 10-DAB, particularly a novel process using a new strategy in which the C(10) hydroxyl group is protected or derivatized prior to the C(7) hydroxyl group; and the provision of C(7) and C(10) derivatized 10-DAB compounds.
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- Crystalline complexes of baccatin III with imidazole, 2-methylimidazole or isopropanol
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Disclosed are crystalline complexes of baccatin III with imidazole, 2-methylimidazole or isopropanol, which are useful for isolating baccatin III from plant tissue cell culture and plant extracts containing baccatin Ill.
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- Process for converting 9-dihydro-13-acetylbaccatin III into taxol and derivatives thereof
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Process for preparing taxol, baccatin III and 10-deacetylbaccatin III by oxidation of 9-dihydro-13-acetylbaccatin III.
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- Taxus canadensis abundant taxane: Conversion to paclitaxel and rearrangements
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An efficient conversion of Taxus canadensis abundant taxane, 9-dihydro-13-acetylbaccatin III to baccatin III is described. Since the synthesis of paclitaxel from baccatin III has been reported, this work can be used for additional supply of this powerful anticancer drug. In addition, new taxanes derived from skeletal rearrangements originating from oxidation-reduction reactions of the Canadian yew major taxane, are reported. Copyright (C) 2000 Elsevier Science Ltd.
- Nikolakakis, Anastasia,Caron, Gaetan,Cherestes, Alice,Sauriol, Francoise,Mamer, Orval,Zamir, Lolita O.
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p. 1269 - 1280
(2007/10/03)
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- Purification and characterization of acetyl coenzyme A: 10- hydroxytaxane O-acetyltransferase from cell suspension cultures of Taxus chinensis
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An O-acetyltransferase that catalyzes the regiospecific acetylation of a range of taxanes possessing an unsubstituted 10-hydroxyl group was detected and purified to apparent electrophoretic homogeneity from a cytosolic fraction of Taxus chinensis cell cultures. The purification involved negative calcium phosphate adsorption, sephadex desalting, DEAE, AcA44 chromatography, HighQ, CHT II, HiTrap Blue, Phenylsepharose and Mimetic Green purification steps. The purified acetyltransferase was found to be a monomeric protein of 71 ± 1.5 kDa that is highly regio- and stereospecific towards the 10β- hydroxyl group of the taxane molecule and is also active towards 10- desacetylbaccatine III. The acetyltransferase reaction had a pH optimum of 9.0 with halfmaximal activities at pH 6.8 and 10.8, respectively. The temperature optimum was at 35°C and the isoelectric point at 5.6. The apparent K(m) values for 10-desacetyltaxuyunnanine C and acetyl CoA were 23 and 61 μM, respectively. The turnover rate for the enzyme using both substrates was 0.2 mol mol-1 of enzyme. The kinetic optimum was determined to be K(cat)/K(m) = 8.7 s-1 L M-1.
- Menhard, Birgitta,Zenk, Meinhart H.
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p. 763 - 774
(2007/10/03)
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- Taxoids, preparation thereof, and pharmaceutical compositions containing same
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Novel taxoids of general formula (I), wherein R is a substituted alkyl radical or an alkenyl, alkynyl, cycloalkyl, optionally substituted cycloalkenyl or phenyl radical, or an aromatic 5- or 6-membered heterocyclic radical; and Z is a hydrogen atom or a radical of general formula (II), wherein R1 is an optionally substituted benzoyl, thenoyl or furoyl radical or a radical R2 --O--CO, where R2 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted phenyl, or heterocycl radical, and R3 is an aromatic heterocyclic, alkyl, alkenyl, alkynyl cycloalkyl, phenyl or naphthyl radical. The novel products of general formula (I), wherein Z is a radical of general formula (II), have remarkable antitumoral activity. STR1
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- Tricyclic and tetracyclic taxanes
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The synthesis of taxol and other tricyclic and tetracyclic taxanes.
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- Method for the preparation of baccatin III and derivatives thereof from 10-deacetylbaccatin III
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10-Deacetylbaccatin III is selectively acylated to baccatin III and derivatives thereof in high yield with anhydrides (e.g. acetic anhydride), catalysed by Lewis acids. Extremely effective catalysts in this reaction are compounds of the formula MLx wherein M is a rare earth metal and L is a anion, preferably a strong electron withdrawing counterion such as triflate.
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- Asymmetric total synthesis of Taxol
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The asymmetric total synthesis of Taxol was achieved by way of B to BC to ABC to ABCD ring construction. Optically active 8-membered ring enones 1 and 2 corresponding to the B ring of Taxol have been synthesized in high yields from the linear precursors 28 and 32, respectively, by intramolecular aldol cyclization using SmI2. The optically active linear polyoxy compounds 28 and 32 were obtained by way of diastereoselective aldol reaction between aldehyde 4 and ketene silyl acetal 8 catalyzed by MgBr2 · OEt2. The chiral pentanal 4 was synthesized either by asymmetric aldol reaction of achiral aldehyde 7 and ketene silyl acetal 8 by means of a chiral Lewis acid or by diastereoselective aldol reaction between the chiral aldehyde 16, derived from L-serine, and the lithium enolate derived from methyl isobutyrate. Optically active bicyclo[6.4.0]dodecanone 38β, corresponding to the BC ring system of Taxol, was prepared from 8-membered ring enone 2 in high yield by stereoselective Michael addition and successive intramolecular aldol cyclization. Furthermore, baccatin III, the ABCD ring system of Taxol, was efficiently synthesized from the BC ring system 38β by successive construction of the A and D rings by intramolecular pinacol coupling cyclization, introduction of the C-13 hydroxyl group and an oxetane-forming reaction. Finally, the total synthesis of Taxol was accomplished by dehydration condensation between a protected N-benzoylphenylisoserine 70 or 75 and 7-TES baccatin III, prepared from baccatin III. Taxol side chains 70, 73, 75, and 77, optically active protected N-benzoylphenylisoserines, were synthesized by enantioselective aldol reaction from two achiral starting materials, benzaldehyde and an enol silyl ether 65 derived from S-ethyl benzyloxyethanethioate.
- Mukaiyama, Teruaki,Shiina, Isamu,Iwadare, Hayato,Saitoh, Masahiro,Nishimura, Toshihiro,Ohkawa, Naoto,Sakoh, Hiroki,Nishimura, Koji,Tani, Yu-Ichirou,Hasegawa, Masatoshi,Yamada, Koji,Saitoh, Katsuyuki
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p. 121 - 161
(2007/10/03)
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- Methyleniminium salts as acylating agent - One step synthesis of baccatin III from 10-deacetylbaccatin III with high selectivity
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New methyleniminium salts were investigated as acylating agent of 10- deacetylbaccatin III. Thus, synthesis of baccatin III was performed in one step with 79% isolated yield and 98% selectivity using the iminium salt and from mesyl chloride and N-ethylacetamide.
- Cravallee, Christelle,Didier, Eric,Pecquet, Pascal
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p. 4263 - 4266
(2007/10/03)
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- New taxanes as highly efficient reversal agents for multidrug resistance in cancer cells
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New non-cytotoxic taxanes synthesized from 10-deacetylbaccatin III and special hydrophobic acylating agents show remarkable MDR reversal activity (≤99.8%) against drug-resistant human breast cancer cells when co-administered with paclitaxel or doxorubicin. This activity is ascribed to the highly efficient blocking of P-glycoprotein efflux by these new taxanes.
- Ojima, Iwao,Bounaud, Pierre-Yves,Takeuchi, Craig,Pera, Paula,Bernacki, Ralph J.
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p. 189 - 194
(2007/10/03)
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- Lanthanide trifluoromethanesulfonate catalysed selective acylation of 10-deacetylbaccatin III
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The selective C-10 acylation of 10-deacetylbaccatin III to baccatin III and derivatives is very efficiently catalysed by lanthanide trifluoromethanesulfonates. Baccatin III, now readily available through this procedure, is an important precursor for an economically viable semisynthesis of paclitaxel and its derivatives.
- Damen, Eric W. P.,Braamer, Lesly,Scheeren, Hans W.
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p. 6081 - 6082
(2007/10/03)
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- Process for the preparation of 7-hydroxytaxanes
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This invention relates to a process for the preparation of 7-hydroxy taxanes of general formula (I) from 7-trialkylsilyl taxanes of general formula (II), wherein R1 is hydrogen, alkoxy, acyloxy, or alkoxyacetoxy, and Z is a hydrogen atom or a radical of general formula (III), wherein R2 is an optionally substituted benzyl radical or an R'2 --O--CO-- radical wherein R'2 is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted phenyl or heterocyclyl radical, R3 is an aromatic alkyl, alkenyl, alkynyl, cycloalyl, phenyl, naphthyl or heterocyclyl radical and either R4 is a hydrogen atom and R5 is a hydroxyl function protecting group, or R4 and R5 together form a saturated 5- or 6-membered heterocylic ring. In general formula (II), each R, which are the same or different, is an alkyl radical optionally substituted by a phenyl radical. STR1
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- Taxoid reversal agents for drug-resistance in cancer chemotherapy and pharmaceutical compositions thereof
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The present invention is directed to novel taxoids possessing strong reversing activities for drug-resistance associated with anti-cancer agents, the preparation of these reversal agents and pharmaceutical compositions thereof. The new taxoids of the present invention have the formula (I). STR1
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- A new method for the synthesis of baccatin III
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Baccatin III was efficiently synthesized from the BC ring system of Taxol, 2α,10β-dibenzyloxy-11β-(t-butyldimethylsiloxy)-7β-hydroxy- 1α-(4-methoxybenzyloxy)-8β,15,15-trimethyl-4-methylene-trans- bicyclo[6.4.0]dodecan-9-one (1), by successive constructions of A and D rings via respective intramolecular pinacol coupling and oxetane forming reaction.
- Shiina, Isamu,Iwadare, Hayato,Sakoh, Hiroki,Hasegawa, Masatoshi,Tani, Yu-Ichirou,Mukaiyama, Teruaki
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- Paclitaxel stability in solution
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Research in this laboratory has focused on the cytokinetic effect of taxanes on nonmammalian systems. Taxanes are a class of natural products that includes the well-known anticancer compound, paclitaxel (Taxol). Our methodology for the study of fungal growth in liquid medium amended with paclitaxel included membrane solid phase extraction (SPE) of the fungal broth. This was followed by elution of paclitaxel from the SPE membrane using methanol. The methanolic solution was evaporated under relatively mild conditions, namely 41-43°C and approximately 85 kPag. Analysis of the concentrated solution indicated that it contained a considerable quantity of 7-epi-taxol and smaller quantities of 7-epi-10-deacetyltaxol, 10-deacetyltaxol, and baccatin III, in addition to paclitaxel, even in those cases where the medium had not been inoculated with fungus. Obviously, fungal metabolism could not account for these observations. Although epimerization in solution at carbon 7 in the C ring of the taxane core has been observed and reported previously, no detailed study of the solution kinetics of paclitaxel degradation, including epimerization, is available. We report here our investigation of the stability of paclitaxel in several solvent systems at various temperatures and pressures. The investigations indicate that the apparent activation energy barrier (Ea) for paclitaxel degradation is highly dependent on experimental conditions. These stability studies emphasize the need to demonstrate explicitly that all taxane degradation, including epimerization, observed during in vitro studies is not an artifact of the analytical methodology employed.
- MacEachern-Keith,Butterfield, L. J. Wagner,Mattina, M. J. Incorvia
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- Synthetic process for the preparation of tricyclic and tetracyclic taxanes
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Process for the synthesis of taxol and other tricyclic and tetracyclic taxanes.
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- Tricyclic and tetracyclic taxanes
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The synthesis of taxol and other tricyclic and tetracyclic taxanes.
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- Total synthesis of baccatin III and taxol
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An intramolecular Heck reaction (90 → 91) serves as the key step in the total synthesis of the titled compounds. The synthetic route is based on utilizing the Wieland-Miescher ketone (5) as a matrix to provide the C and D rings of the targets and to provide functionality implements for joining this sector to an A ring precursor (6). Catalytically induced enantiotopic control and early emplacement of the oxetane are other features of the route.
- Danishefsky, Samuel J.,Masters, John J.,Young, Wendy B.,Link,Snyder, Lawrence B.,Magee, Thomas V.,Jung, David K.,Isaacs, Richard C. A.,Bornmann, William G.,Alaimo, Cheryl A.,Coburn, Craig A.,Di Grandi, Martin J.
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p. 2843 - 2859
(2007/10/03)
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- Transformations of taxol
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A method for esterifying C13 deoxy taxoid intermediates employs three steps, i.e., oxygenation of the C13 deoxy taxoid intermediate to produce a C13 enone taxoid intermediate; reduction of the C13 enone to produce an alcohol; followed by esterification of the C13 alcohol. Key intermediates include C13 deoxy taxoids; C13 enone substituted taxoids; and C1-C2 cyclo carbonate esters of taxoids.
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- New and effective synthesis of 7-triethylsilylbaccatin III from 7β,13α-bistriethylsiloxy-1β,2α,10β-trihydroxy-9-oxo- 4(20),11-taxadiene
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7β,13α-Bistriethylsiloxy-1β,2α,10β-trihydroxy -9- oxo-4(20), 11-taxadiene (2), derived from 10-deacetylbaccatin III via degradation of oxetane ring, was conveniently converted into 7-triethylsilylbaccatin III (1) by way of a new and effective method for constructing oxetane ring. Thus, the synthesis of a precursor of taxol from novel taxoid 2 was accomplished.
- Shiina, Isamu,Saitoh, Masahiro,Nishimura, Koji,Saitoh, Katsuyuki,Mukaiyama, Teruaki
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p. 223 - 224
(2007/10/03)
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- Eine Totalsynthese von Taxol
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Keywords: Baccatin III; Heck-Reaktionen; Taxol; Totalsynthesen
- Masters, John J.,Link, J. T.,Snyder, Lawrence B.,Young, Wendy B.,Danishefsky, Samuel J.
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p. 1886 - 1888
(2007/10/03)
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