- CoA recycling by a benzoate coenzyme A ligase in cascade reactions with aroyltransferases to biocatalyze paclitaxel analogs
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A Pseudomonas CoA ligase (BadA) biocatalyzed aroyl CoA thioesters used by a downstream N-benzoyltransferase (NDTNBT) in a cascade reaction made aroyl analogs of the anticancer drug paclitaxel. BadA kept the high-cost aroyl CoA substrates at saturation for the downstream NDTNBT by recycling CoA when it was added as the limiting reactant. A deacylated taxane substrate N-debenzoyl-2′-deoxypaclitaxel was converted to its benzoylated product at a higher yield, compared to the converted yield in assays in which the BadA ligase chemistry was omitted, and benzoyl CoA was added as a cosubstrate. The resulting benzoylated product 2′-deoxypaclitaxel was made at 196% over the theoretical yield of product that could be made from the CoA added at 50 μM, and the cosubstrates benzoic acid (100 μM), and N-debenzoyl-2′-deoxypaclitaxel (500 μM) added in excess. In addition, a 2-O-benzoyltransferase (mTBT) was incubated with BadA, aroyl acids, CoA, a 2-O-debenzoylated taxane substrate, and cofactors under the CoA-recycling conditions established for the NDTNBT/BadA cascade. The mTBT/BadA combination also made various 2-O-aroylated products that could potentially function as next-generation baccatin III compounds. These ligase/benzoyltransferase cascade reactions show the feasibility of recycling aroyl CoA thioesters in vitro to make bioactive acyl analogs of paclitaxel precursors.
- Nawarathne, Irosha N.,Sullivan, Sean A.,Walker, Kevin D.
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- SOLID STATE FORMS OF CABAZITAXEL AND PROCESSES FOR PREPARATION THEREOF
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The invention relates to solid state forms of Cabazitaxel, and processes for preparation, via novel synthetic intermediates, thereof, and formulations comprising one or more of the solid state forms of Cabazitaxel. The present invention further provides pharmaceutical compositions comprising one or more of the solid state forms of Cabazitaxel, and a method of treating hormone-refractory prostate cancer.
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Page/Page column 31-32
(2012/11/06)
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- Point mutations (Q19P and N23K) increase the operational solubility of a 2α-o-benzoyltransferase that conveys various acyl groups from CoA to a taxane acceptor
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Two site-directed mutations within the wild-type 2-o-benzoyltransferase (tbf) cDNA, from Taxus cuspidata plants, yielded an encoded protein containing replacement amino acids at Q19P and N23K that map to a solvent-exposed loop region. The likely significant changes in the biophysical, properties invoked by these mutations caused the overexpressed, modified TBT (mTBT) to partition into the soluble enzyme fraction about 5-fold greater than the wild-type enzyme. Sufficient protein could now be acquired to examine the scope of the substrate specificity of mTBT by incubation with 7,13-O,O-diacetyl-2-Odebenzoylbaccatin III that was mixed individually with various substituted benzoyls, alkanoyls, and (E)-butenoyl CoA donors. The mTBT catalyzed the conversion of each 7,13-O,O-diacetyl-2-O-debenzoylbaccatin III to several 7,13-O,O-diacetyl-2O- acyl-2-O-debenzoylbaeeatin III analogues. The relative catalytic efficiency of mTBT with the 7,13-O,O-diacetyl-2-Odebenzoyl surrogate substrate and heterole carbonyl CoA substrates was slightly greater than with the natural aroyl substrate benzoyl CoA, while substituted benzoyl CoA thioesters were less productive. Short-chain hydrocarbon carbonyl and cyclohexanoyl CoA thioesters were also productive, where C4 substrates were transferred by mTBT with ~10- to 17-fold greater catalytic efficiency compared to the transfer of benzoyl. The described broad specificity of mTBT suggests that a plethora of 2-O-acyl variants of the antimitotic paclitaxel can be assembled through biocatalytic sequences.
- Nawarathne, Irosha N.,Walker, Kevin D.
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experimental part
p. 151 - 159
(2010/07/06)
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- CONVERSION 9-DIHYDRO-13-ACETYLBACCATIN III TO 10-DEACETYLBACCATIN III
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The present invention relates to a process is provided for the conversion of 9-dihydro-13-acetylbaccatin to 10-deacetylbaccatin III. The process includes four specific interrelated steps. The first step involves protecting the 7-hydroxyl group of 9-dihydro-13-acetylbaccatin and converting that 7-hydroxyl-protected 9-dihydro-13-acetylbaccatin to 7, 13-diacetyl-9-dihydrobaccatin III. The second step involves reacting that 7, 13-diacetyl-9-dihydrobaccatin III with 4-methylmorpholine N-oxide in a suitable solvent and oxidizing that reaction product to yield 7, 13-diacetylbaccatin. The third step involves deacetylating that 7, 13-diacetyl-9-dihydrobaccatin III to yield 7-acetylbaccatin III. The fourth and final step involves converting that 7-acetylbaccatin III to 10-deacetylbaccatin III.
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Page/Page column 8-9
(2008/06/13)
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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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- 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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- CHEMICAL STUDIES OF 10-DEACETYL BACCATIN III. HEMISYNTHESIS OF TAXOL DERIVATIVES.
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The chemical reactivities of 10-deacetyl baccatin III and of baccatin III, two natural products extracted from Taxus baccata L., were studied with aim of synthesizing taxol analogues having a modified side-chain at C-13, thereby restoring good binding to tubulin.
- Gueritte-Voegelein, F.,Senilh, V.,David, B.,Guenard, B.,Potier, P.
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p. 4451 - 4460
(2007/10/02)
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