- 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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Read Online
- 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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Read Online
- A clickable caging group as a new platform for modular caged compounds with improved photochemical properties
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A 6-bromo-7-hydroxycoumarin-4-ylmethyl (Bhc) caged compound having a click-modifiable chemical handle was designed and synthesized. This molecule was applied to the synthesis of modular caged paclitaxels (PTXs) in which additional functional units could be easily installed. This system was used to prepare water-soluble caged PTXs with improved photolysis efficiencies.
- Suzuki, Akinobu Z.,Sekine, Ryota,Takeda, Shiori,Aikawa, Ryosuke,Shiraishi, Yukiko,Hamaguchi, Tomomi,Okuno, Hiroyuki,Tamamura, Hirokazu,Furuta, Toshiaki
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Read Online
- Intermediate compound for preparing paclitaxel, synthetic method of intermediate compound and synthetic method of paclitaxel
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The invention relates to an intermediate compound for preparing paclitaxel, a synthetic method of the intermediate compound and a synthetic method of paclitaxel. The intermediate compound for preparing paclitaxel is selected from at least one of compounds shown in the specification, wherein Ts represents p-toluenesulfonyl, TES represents triethylsilyl, TMS represents trimethylsilyl, and Ms represents methylsulfonyl. The paclitaxel can be prepared with high yield by taking the intermediate compounds as raw materials, the structure of the paclitaxel can be easily modified, a series of lead compounds can be screened out to research the biological activity of the paclitaxel, and the paclitaxel is believed to have a breakthrough in the field of research and development of tumor drugs. The synthesis method of the paclitaxel and the intermediate thereof has the advantages of chirality controllability, high yield, high product purity, simplicity, high efficiency, wide raw material source, cheap and easily available reagents, simple reaction, simple operation, greenness, environmental protection and suitableness for industrial large-scale production.
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- 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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- Asymmetric Total Synthesis of Taxol
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Taxol is one of the most famous natural diterpenoids and an important anticancer medicine. Taxol represents a formidable synthetic challenge and has prompted significant interest from the synthetic community. However, in all the previous syntheses of Taxol, there have been no reports of closing the desired eight-membered ring through C1-C2 bond formation. Furthermore, the existence of Taxol-resistant tumors and side effects of Taxol make the development of new approaches to synthesize Taxol and its derivatives highly desirable. Here, we report the asymmetric total synthesis of Taxol using a concise approach through 19 isolated intermediates. The synthetically challenging eight-membered ring was constructed efficiently by a diastereoselective intramolecular SmI2-mediated pinacol coupling reaction to form the C1-C2 bond. The unique biomimetic oxygen ene reaction and the newly developed facile tandem C2-benzoate formation and C13 side chain installation improved the efficiency of the synthesis. The mild oxygen ene reaction under light conditions would be an alternative reaction involved in Taxol biosynthesis. This new convergent approach will allow the diverse creation of Taxol derivatives to enable further biological research.
- Hu, Ya-Jian,Gu, Chen-Chen,Wang, Xin-Feng,Min, Long,Li, Chuang-Chuang
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p. 17862 - 17870
(2021/11/04)
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- Two-Phase Synthesis of Taxol
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Taxol (a brand name for paclitaxel) is widely regarded as among the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural (plant material) or biosynthetically derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol.
- Kanda, Yuzuru,Nakamura, Hugh,Umemiya, Shigenobu,Puthukanoori, Ravi Kumar,Murthy Appala, Venkata Ramana,Gaddamanugu, Gopi Krishna,Paraselli, Bheema Rao,Baran, Phil S.
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p. 10526 - 10533
(2020/07/27)
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- Method for synthesizing paclitaxel from cephalomannine (by machine translation)
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The method comprises the following steps: (≥ 9997%) bases as a raw material, N - Butene keys on the side chains of the bases 13 through low-temperature acid hydrolysis; and protecting; and NH (NH-7 ') in the side chains 2, 13 -'. 2 The method has the advantages of mild 7 and 2 controllable reaction conditions, low cost, high yield, high product purity, low impurity content, and suitability for industrial production and market popularization and application 99%. the method comprises the following steps: synthesizing and converting paclitaxel crude product through crystallization, carrying out one-time column chromatography and primary recrystallization purification to obtain paclitaxel. (by machine translation)
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- Process of synthesizing paclitaxel from 10-deacetyltaxol
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The invention relates to a process of synthesizing paclitaxel from 10-deacetyltaxol (10-DAT). The process includes: taking 10-DAT as the starting raw material, conducting acetic anhydride acetylation,and under an alkaline condition, hydrolyzing the 2'-acetyl with dimethylamine to obtain paclitaxel. The route has the characteristics of short steps, shortened production cycle, no need for side chain, and reduction of the raw material cost.
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Paragraph 0011
(2019/05/08)
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- Dual-sensitive targeted nanoparticle preparation for loading chemotherapeutic drugs and preparation method
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The invention provides a dual-sensitive targeted nanoparticle preparation for loading chemotherapeutic drugs and a preparation method. The nanoparticle preparation comprises an amphiphilic polymer. The amphiphilic polymer comprises gelatin and at least one chemotherapeutic drug molecule. Each chemotherapeutic drug molecule is chemically bonded to the gelatin via a first chemical group, and the backbone of each first chemical group comprises a disulfide bond. The disulfide bonds with redox sensitivity can be broken to release drugs when the concentration of glutathione around tumor tissues is high. The gelatin, as a substrate of an MMP-2 enzyme, can be degraded into small particles around the tumor tissues by the overexpressed MMP-2 enzyme, so that the permeability in the tumor tissues is improved, and the dual-sensitive drugs are released.
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Paragraph 0082; 0085
(2019/10/01)
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- Methods for preparing semi-synthetic paclitaxel and intermediate thereof
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The invention relates to methods for preparing semi-synthetic paclitaxel and an intermediate thereof. The method for preparing the semi-synthetic paclitaxel comprises the following steps: dissolving 10-DABIII (10-deacetylbaccatinIII) into pyridine, protecting hydroxyl on position-7 carbon on the 10-DABIII with triethyl silicyl to obtain an intermediate I, acetylating hydroxyl on position-10 carbon of the intermediate I to obtain an intermediate II, reacting the intermediate II, a side-chain radical compound and 4-dimethylaminopyridine in an organic solvent to prepare an intermediate III, and reacting the intermediate III with trifluoroacetic acid under an acidic condition to obtain a crude paclitaxel product. The preparation methods are simple and easy for industrialization; the active hydroxyl of the raw material 10-DABIII is effectively protected, so that fewer byproducts are finally generated, and a prepared paclitaxel product has high molar yield of 70 to 81 percent and high paclitaxel purity of 99.5 to 99.9 percent; the residual rate of the raw material in the steps of synthesizing the intermediate II and synthesizing the paclitaxel is low, side reactions are reduced, and the raw material is high in reaction selectivity and utilization rate; the product can be directly used as a raw material for the medical field of treatment of ovarian cancer, breast cancer and the like.
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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 0080-0081
(2018/02/04)
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- Far-Red Light-Activatable Prodrug of Paclitaxel for the Combined Effects of Photodynamic Therapy and Site-Specific Paclitaxel Chemotherapy
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Paclitaxel (PTX) is one of the most useful chemotherapeutic agents approved for several cancers, including ovarian, breast, pancreatic, and nonsmall cell lung cancer. However, it causes systemic side effects when administered parenterally. Photodynamic therapy (PDT) is a new strategy for treating local cancers using light and photosensitizer. Unfortunately, PDT is often followed by recurrence due to incomplete ablation of tumors. To overcome these problems, we prepared the far-red light-activatable prodrug of PTX by conjugating photosensitizer via singlet oxygen-cleavable aminoacrylate linker. Tubulin polymerization enhancement and cytotoxicity of prodrugs were dramatically reduced. However, once illuminated with far-red light, the prodrug effectively killed SKOV-3 ovarian cancer cells through the combined effects of PDT and locally released PTX. Ours is the first PTX prodrug that can be activated by singlet oxygen using tissue penetrable and clinically useful far-red light, which kills the cancer cells through the combined effects of PDT and site-specific PTX chemotherapy.
- Thapa, Pritam,Li, Mengjie,Bio, Moses,Rajaputra, Pallavi,Nkepang, Gregory,Sun, Yajing,Woo, Sukyung,You, Youngjae
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p. 3204 - 3214
(2016/05/19)
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- Water-soluble prodrugs of paclitaxel containing self-immolative disulfide linkers
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A new series of disulfide-containing prodrugs of paclitaxel were designed, synthesized and evaluated against 6 cancer cell lines. Some of these prodrugs exhibited nearly equal or slightly better anticancer activity when compared to that of paclitaxel. These prodrugs contain water-soluble groups such as amino, carboxyl, hydroxyl, amino acids, etc., and exhibited 6-140 fold increase in aqueous solubility when compared to paclitaxel. One of these prodrugs exhibited improved water solubility, better in vitro anticancer activity and significantly superior oral bioavailability in mice when compared to those of paclitaxel. Thus, we have identified a very promising lead compound for further optimization and evaluation as a potentially bioavailable water-soluble prodrug of paclitaxel.
- Gund, Machhindra,Khanna, Amit,Dubash, Nauzer,Damre, Anagha,Singh, Kishore S.,Satyam, Apparao
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supporting information
p. 122 - 127
(2015/02/19)
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- Novel photoactivatable paclitaxel derivatives and uses thereof, in particular in cellbiology and cancer treatment
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The present invention provides novel photoactivatable paclitaxel derivatives wherein at least the C7 position, preferably both the C2' and C7 positions, of the paclitaxel molecule is/are substituted with a photocleavable moiety such as a chromophore. Typically, the chromophore is selected from the group comprising 2-nitrobenzyl ethers, carbamates or carbonates and their 4,5-dialkoxy substituted variants; 2-nitrophenylethyl ethers, carbamates or carbonates and their 4,5-dialkoxy substituted variants, or their p-substituted derivatives; α-carboxy-2-nitrobenzyl ethers, carbamates or carbonates and their 4,5-dialkoxy substituted variants; 2(2-nitrophenyl)ethyl ethers, carbamates or carbonates and their 4,5-dialkoxy substituted variants; coumarin-4-ylmethyl ethers, or carbonates and their 7-alkoxy, 6,7-dialkoxy, 6-bromo-7-alkoxy or 7-dialkylamino substituted variants; p-hydroxyphenacyl ethers or carbamates and their meta-substituted derivatives or structurally related compounds. More specifically, the chromophore is 4,5-dimethoxy-2-nitrobenyloxycarbonyl (Nvoc) or a structurally related compound. Further aspects of the invention relate to the use of these paclitaxel derivatives in biological, medical and pharmaceutical applications, in particular in cellbiology and cancer treatment. A closely related aspect is an antitumor medicament comprising the above paclitaxel derivatives.
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Paragraph 0016-0017; 0044-0047
(2013/03/26)
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- Development of a diketopiperazine-forming dipeptidyl Gly-Pro spacer for preparation of an antibody-drug conjugate
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We developed a novel diketopiperazine-forming dipeptidyl spacer aimed at application in antibody-drug conjugates. Enzymatic cleavage of a peptide linked to the Gly-Pro spacer resulted in formation of diketopiperazine, which was stable and non-toxic, and release of the parent drug. The Royal Society of Chemistry 2013.
- Manabe, Shino,Machida, Hikaru,Aihara, Yoshiyuki,Yasunaga, Masahiro,Ito, Yukishige,Matsumura, Yasuhiro
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supporting information
p. 792 - 796
(2013/08/26)
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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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- SILICATE PRODRUGS AND NANOPARTICLES
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The invention provides silicate prodrugs comprising a therapeutic agent linked to one or more groups of formula (I): -Si(OR)3 (I); wherein each R independently has any of the values defined herein, as well as nanoparticles comprising such compounds.
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Page/Page column 34
(2013/02/28)
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- METHOD OF PREPARING TAXANE DERIVATIVES AND INTERMEDIATES USED THEREIN
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The present invention relates to a novel method of preparing a taxane derivative having an anti-tumor and anti-leukemia activity, and intermediates used therein.
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Page/Page column 8
(2010/12/29)
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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 10; 12
(2010/02/17)
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- A CATALYTIC ASYMMETRIC METHOD FOR THE PREPARATION OF THE PACLITAXEL (TAXOL) C-13 SIDE-CHAIN DERIVATIVES AND ITS USE IN THE PREPARATION OF TAXANE DERIVATIVES
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A new catalytic asymmetric two-step or one-pot method for the preparation of the C-13 side-chain of paclitaxel (Taxol) and derivatives of the general formula (I) in the form of an acid, salt or ester, in which R represents an aryl group or alkyl group, R1 represents an aryl group or alkyl group, Y represents O, H or alkyl, and X1 represent -CH2-Ph, alkyl, aryl, SiR3 (where the silyl group is a common protective group) or other suitable protective group.
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Page/Page column 21-22
(2010/06/17)
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- Combinatorial drug conjugation enables nanoparticle dual-drug delivery
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A new approach to loading multiple drugs onto the same drug-delivery nanocarrier in a precisely controllable manner, by covalently preconjugating multiple therapeutic agents through hydrolyzable linkers to form drug conjugates, is reported. In contrast to loading individual types of drugs separately, this drug-conjugates strategy enables the loading of multiple drugs onto the same carrier with a predefined stoichiometric ratio. The cleavable linkers allow the therapeutic activity of the individual drugs to be resumed after the drug conjugates are delivered into the target cells and unloaded from the delivery vehicle. As a proof of concept, the synthesis and characterization of paclitaxel-gemcitabine conjugates are demonstrated. The time-dependent hydrolysis kinetics and cytotoxicity of the combinatorial drug conjugates against human pancreatic cancer cells are examined. It is shown that the synthesized drug conjugates can be readily encapsulated into a lipid-coated polymeric drug-delivery nanoparticle, which significantly improves the cytotoxicity of the drug conjugates as compared to the free drug conjugates.
- Aryal, Santosh,Hu, Che-Ming Jack,Zhang, Liangfang
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experimental part
p. 1442 - 1448
(2010/11/04)
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- PROCESS FOR CONVERTING 9-DIHYDRO-13-ACETYLBACCATIN III INTO DOCETAXEL OR PACLITAXEL
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Processes for the preparation of docetaxel and paclitaxel or analogs from 9-dihydro-13-acetylbaccatin III via key intermediates (4), (5), (6), (6'), (8) and (8') or via intermediate (12) as well as processes for the preparation of said intermediates are d
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Page/Page column 48-49
(2009/04/25)
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- Highly enantioselective organocatalytic addition of aldehydes to N-(Phenylmethylene)benzamides: Asymmetric synthesis of the paclitaxel side chain and its analogues
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A simple highly enantioselective organocatalytic addition of aldehydes to N-(phenylmethylene)benzamides is presented. The application of (R)-proline as the catalyst and subsequent oxidation of the protected α-hydroxy-β- benzoylami-noaldehydes (92-99% ee) gives access to esterification-ready phenylisoserine derivatives such as the protected paclitaxel (taxol) side chain. Esterification of these derivatives with baccatin III gives access to the cancer chemotherapeutic substance paclitaxel and its analogues that do not exist in nature.
- Dziedzic, Pawel,Schyman, Patrie,Kullberg, Martin,Cordova, Armando
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supporting information; experimental part
p. 4044 - 4048
(2009/12/01)
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- PROCESS FOR THE PURIFICATION 10-DEACETYBACCATINE III FROM 10-DEACETYL-2-DEBENZOYL-2-PENTENOYLBACCATINE III
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A process for the preparation of 10-deacetyl-7,10-bis-trichloroacetylbaccatine III with HPLC purity higher than 99% and free from 2-debenzoyl-2-pentenoylbaccatine III by purification of 10-deacetyl-7,10-bis-trichloroacetylbaccatineIII followed by alkaline hydrolysis of the protecting groups in position 7 and 10.
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Page/Page column 2
(2009/12/23)
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- An N-aroyltransferase of the bahd superfamily has broad aroyl CoA specificity in vitro with analogues of N-dearoylpaclitaxel
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The native N-debenzoyl-2'-deoxypaclitaxel:N-benzoyltransferase (NDTBT), from Taxus plants, transfers a benzoyl group from the corresponding CoA thioester to the amino group of the β -phenylalanine side chain of N-debenzoyl-2'-deoxypaclitaxel, which is purportedly on the paclitaxel (Taxol) biosynthetic pathway. To elucidate the substrate specificity of NDTBT overexpressed in Escherichia coli, the purified enzyme was incubated with semisynthetically derived N-debenzoyltaxoid substrates and aroyl CoA donors (benzoyl; ortho-, meta-, and para-substituted benzoyls; various heterole carbonyls; alkanoyls; and butenoyl), which were obtained from commercial sources or synthesized via a mixed anhydride method. Several unnatural N-aroyl-N-debenzoyl-2'-deoxypaclitaxel analogues were biocatalytically assembled with catalytic efficiencies (V max/Km) ranging between 0.15 and 1.74 nmol.min -1.mM -1. In addition, several N-acyl-N-debenzoylpaclitaxel variants werebiosynthesized when N-debenzoylpaclitaxel and N-de(tert-butoxycar-bonyl )docetaxel (i.e., 10-deacetyl-N-debenzoylpaclitaxel) were used as substrates. The relative velocity (v rel) for NDTBT with the lattertwo N-debenzoyl taxane substrates ranged between '1percent and 200pe rcent for the array of aroyl CoAs compared to benzoyl CoA. Interestingly, NDTBT transferred hexanoyl, acetyl, and butyryl more rapidly than butenoyl or benzoyl from the CoA donor to taxanes with isoserinoyl side chains, whereas N-debenzoyl-2'-deoxypaclitaxel was more rapidly converted toits N-benzoyl derivative than to its N-alkanoyl or N-butenoyl congeners . Biocatalytic N-acyl transfer of novel acyl groups to the amino functional group of N-debenzoylpaclitaxel and its 2'-deoxy precursor reveal thesurprisingly indiscriminate specificity of this transferase. This featu re of NDTBT potentially provides a tool for alternative biocatalytic N-aroylation/ alkanoylation to construct next generation taxanes or other novel bioactive diterpene compounds.
- Nevarez, Danielle M.,Mengistu, Yemane A.,Nawarathne, Irosha N.,Walker, Kevin D.
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experimental part
p. 5994 - 6002
(2009/09/24)
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- PROCESSES FOR PREPARATION OF TAXANES AND INTERMEDIATES THEREOF
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A paclitaxel intermediate of formula 1: wherein R1 is acetyl, R2 is tert-butyloxycarbonyl (BOC), R3 and R4 are phenyl and R5 is 1-ethoxyethyl, is provided. Also provided are processes for preparing taxane intermediates of formula 1 comprising reacting a compound of formula 2 with a compound of formula 3 wherein, R1, R2 and R5 are independently a hydroxyl protecting group; R3 is phenyl, substituted phenyl, a straight or branched alkyl containing 1 to 12 carbon atoms, alkenyl containing 2 to 12 carbon atoms, cycloalkyl containing 4 to 15 carbon atoms, cycloalkenyl or an R6—O— group in which R6 is: phenyl, substituted phenyl group, a C1-C8 straight or branched alkyl, a C2-C8 straight or branched alkenyl group, a C3-C8 straight or branched alkynyl, a C3-C7 cycloalkyl, C4-C7 cycloalkenyl, a C7-C11 bicycloalkyl substituent, or a saturated or unsaturated nitrogen; and R4 is phenyl or a substituted phenyl group.
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Page/Page column 11;12
(2009/12/05)
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- Development of novel water-soluble photocleavable protective group and its application for design of photoresponsive paclitaxel prodrugs
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A novel coumarin-based highly water-soluble photocleavable protective group was designed and synthesized, and then this photosensitive protecting group was used to design paclitaxel prodrugs. These novel paclitaxel conjugates demonstrated excellent water solubility, over 100 mg mL-1. Thus, the use of a detergent in the formulation can be omitted completely, even at high doses. Phototaxel 11 released the parent drug, paclitaxel, quickly and efficiently by minimal tissue-damaging 365 nm UV light irradiation at low power, while laser activation at 355 nm led to extensive decomposition of the prodrug. The carbamate-type prodrug, phototaxel 11, was stable in the dark prior to activation, whereas carbonate-type phototaxel 9 demonstrated poor stability under aqueous conditions. For such prodrugs, tumor-tissue targeting after administration could be achieved by selective light delivery, similar to that used in photodynamic therapy. In addition, newly designed coumarin derivative 8 can be applied in organic chemistry as a photosensitive protective group and for the design of caged compounds.
- Noguchi, Mayo,Skwarczynski, Mariusz,Prakash, Halan,Hirota, Shun,Kimura, Tooru,Hayashi, Yoshio,Kiso, Yoshiaki
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p. 5389 - 5397
(2008/12/20)
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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 OF PREPARING TAXANE DERIVATIVES AND INTERMEDIATES USED THEREIN
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The present invention relates to a novel method of preparing a taxane derivative having an anti-tumor and anti-leukemia activity, and intermediates used therein.
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Page/Page column 19-20
(2008/12/06)
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- Method for Preparing Paclitaxel
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The invention concerns a method for preparing paclitaxel characterized in that it consists in starting with 10-deacety)-baccatine in accordance with a “one-pot” reaction including the following three steps: a) protecting the hydroxy radical in position 7 of 10-deacetylbaccatine with a silylated radical, then b) acetylating the hydroxy radical in position 10, c) optionally crystallizing the resulting baccatine III derivative, followed by condensation of (4S,5R)-3-N-benzoyl-2RS-methoxy-4-phenyl-1,3-oxazolidine-5-carboxylic acid, by esterifying in position 13 the acetylated 10-baccatine III derivative previously obtained, then opening the oxazolidine of the cyclic side chain and simultaneously releasing the hydroxy radical in position 7.
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Page/Page column 3
(2008/12/08)
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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 6; 7
(2008/12/09)
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- STATIONARY PHASE AND COLUMN USING CUCURBITURIL BONDED SILICA GEL, AND SEPARATION METHOD OF TAXOL USING THE COLUMN
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Provided are a stationary phase and a column using a cucurbituril-bound silica g el, and a method of separating taxane using the column. The taxane separation meth od includes: preparing a column for taxane separation, the column being packed with a stationary phase including a cucurbituril-bound silica gel in which a cucurbituril represen ted by Formula 1 or 2 is covalently bound to a modified silica gel represented by Formul a 3; dissolving a taxane powder in a solvent to prepare a taxane-containing solution; ap plying the taxane-containing solution to the column; supplying a mobile-phase solvent t o the column to obtain a taxane extract from the column; and purifying taxane from the t axane extract. Therefore, highly purified taxane can be separated from a low-purity cr ude taxane extract.
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(2008/06/13)
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- SEMI-SYNTHETIC ROUTE FOR THE PREPARATION OF PACLITAXEL, DOCETAXEL, AND 10-DEACETYLBACCATIN III FROM 9-DIHYDRO-13-ACETYLBACCATIN III
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A novel semisynthetic route has been provided in the preparation of docetaxel and paclitaxel. This new process involves the conversion of 9-dihydro-13-acetylbaccatinIII to docetaxel and paclitaxel by the step of converting 9-dihydro-13-acetylbaccatin III into 7-O-triethylsilyl-9,10-diketobaccatin III, and adding docetaxel and paclitaxel side chain precursors, respectively, to form a new class of taxane intermediates, such as 7-O-triethylsilyl-9,10-diketodocetaxel and 7-O-triethylsilyl-9,10-diketopaclitaxeltaxel. These new intermediates then by a series reduction, acetylation of the 10-hydroxyl position for paclitaxel and finally deprotection to yield docetaxel and paclitaxel, the most important anti-cancer drugs.
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Page/Page column 8
(2008/06/13)
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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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- Modulating paclitaxel bioavailability for targeting prostate cancer
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Four novel water-soluble peptide-paclitaxel conjugates were designed and synthesized as prostate-specific antigen (PSA)-activated prodrugs for prostate cancer therapy. These prodrugs were composed of a peptide, HSSKLQ or SSKYQ, each of which is selectively cleavable by PSA; a self-immolative linker, either para-aminobenzyl alcohol (PABS) or ethylene diamine (EDA); and the parent drug, paclitaxel. Introduction of a PABA or EDA linker between the peptide and paclitaxel in prodrugs 2-5 resulted in products with an increased rate of hydrolysis by PSA. The stability of prodrugs 2 and 3, with the PABA linker, was poor in the serum-containing medium because of the weak carbonate bond between the PABA and paclitaxel; however, this disadvantage was overcome by introducing a carbamate bond using an EDA linker in prodrugs 4 and 5. Thus, the incorporation of an EDA linker increased both the stability and PSA-mediated activation of these prodrugs. The cytotoxicity of each prodrug, as compared to paclitaxel, was determined against a variety of cell lines, including the PSA-secreting CWR22Rv1 prostate cancer cell line. The EDA-derived prodrug of paclitaxel 5 was stable and capable of being efficiently converted to an active drug that killed cells specifically in the presence of PSA, suggesting that this prodrug and similarly designed PSA-cleavable prodrugs may have potential as prostate cancer-specific therapeutic agents.
- Kumar, Srinivas K.,Williams, Simon A.,Isaacs, John T.,Denmeade, Samuel R.,Khan, Saeed R.
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p. 4973 - 4984
(2008/03/13)
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- NEW METHODS FOR THE PREPARATION OF TAXANES USING CHIRAL AUXILIARIES
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The present invention relates to a stereoselective synthesis of novel β-lactam dimers as useful precursors for the preparation of paclitaxel, docetaxel, and analogues thereof. More particularly, the new β-lactams are prepared from readily available and enantiomerically pure chiral auxiliaries. The β-lactams are then reacted with a suitably protected taxane to produce diastereomerically enriched side chain-bearing taxanes. Finally, the chiral auxiliary is cleaved and protecting groups are removed to provide the desired taxane.
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Page/Page column 42-43
(2008/06/13)
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- PROCESS FOR THE SEPARATION OF PACLITAXEL AND CEPHALOMANNIN
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Paclitaxel is separated from a mixture containing cephalomannin by column chromatography on silica gel using a solvent mixture containing methyl isobutyl ketone and a less polar solvent as the mobile phase. The less polar solvent can be a (C5-C8) aliphatic hydrocarbon, a (C6-C8) aromatic hydrocarbon, a (C1-C4) dialkyl ether or their mixtures.
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Page/Page column 11-12
(2008/06/13)
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- PROCESS FOR THE ISOLATION OF PACLITAXEL
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Paclitaxel is isolated by a process including normal phase chromatography using a polyamide stationary phase and a mixture containing a dialkyl ketone and a less polar solvent as a mobile phase. Suitable dialkyl ketones include acetone or methyl isobutyl ketone. Suitable less polar co-solvents include a (C5-C8) aliphatic hydrocarbon, a (C6-C8) aromatic hydrocarbon, a (C1-C4) dialkyl ether or their mixtures.
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Page/Page column 12-14
(2008/06/13)
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- Protecting groups for glucuronic acid: Application to the synthesis of new paclitaxel (taxol) derivatives
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To prepare two new glucuronide conjugates, allyl ester and allyl carbonates were used as protecting groups of the glucuronic moiety. In this way, an aniline glycosyl carbamate spacer linked to the 2′-OH of paclitaxel was obtained. By using palladium chemistry, an efficient one-step removal of all the allyl groups at the end of the synthesis afforded the desired compounds in good yields.
- El Alaoui, Abdessamad,Schmidt, Frederic,Monneret, Claude,Florent, Jean-Claude
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p. 9628 - 9636
(2007/10/03)
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- Method and compositions for preparing a compound using a benzoylating agent essentially free of ring chlorination
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This invention relates to methods and compositions for preparing compounds using a benzoylating agent essentially free of ring chlorination. In one alternative embodiment, the present invention relates to methods and compositions for preparing taxanes essentially free of ring chlorinated impurities. In another alternative embodiment, the present invention comprises methods of converting taxane amine with a benzoylating agent essentially free of ring chlorination.
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Page/Page column 4
(2010/10/19)
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- A PROCESS FOR THE PURIFICATION OF 10-DEACETYLBACCATINE III FROM 10-DE ACET YL-2- DEBENZOYL-2-PENTENOYLBACCATINE III
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A process for the preparation of 10-deacetyl-7,10-bis- trichloroacetylbaccatine III with HPLC purity higher than 99% and free from 2-debenzoyl-2-pentenoylbaccatine III by purification of 10-deacetyl-7,10-bis- trichloroacetylbaccatineIII followed by alkaline hydrolysis of the protecting groups in position 7 and 10.
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Page/Page column 6-7
(2008/06/13)
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- Method for purification of paclitaxel from paclitaxel-containing materials
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This invention relates to methods for purification of paclitaxel from a paclitaxel-containing material. The method comprises the following steps: (a) extracting a paclitaxel-containing material with an organic solvent to obtain an extract, and concentrating the extract; (b) adding the concentrate with an organic solvent which is not mixed with water to separate an organic solvent phase and then concentrating; (c) subjecting the concentrate to normal phase chromatography to obtain an eluate; (d) dissolving the eluate in an acetone or dichloromethane followed by adding pentane or hexane to form a precipitate; and (e) subjecting the precipitate to high performance liquid chromatography. According to the method of the present invention, paclitaxel of over 99.5% purity can be easily obtained from a Taxus genus plant with a high yield.
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Page/Page column 4
(2008/06/13)
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- DUAL PHASE DRUG RELEASE SYSTEM
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The present invention relates to conjugate comprising a carrier substituted with one or more occurrences of a moiety having the structure (I): wherein each occurrence of M is independently a modifier having a molecular weight ≤ 10 kDa; denotes direct of indirect attachment of M to linker LM; and each occurrence of LM is independently an optionally substituted succinamide-containing linker, whereby the modifier M is directly or indirectly attached to the succinamide linker through an amide bond, and the carrier is linked directly or indirectly to each occurrence of the succinamide linker through an ester bond. In another aspect, the invention provides compositions comprising the conjugates, methods for their preparation, and methods of use thereof in the treatment of various disorder, including, but not limited to cancer.
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Page/Page column 83
(2008/06/13)
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- METHOD FOR INVERTING THE C2’ HYDROXYL GROUP OF TAXANE ESTERS
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The present invention provides a method for inverting the 2’-hydroxy position of selected taxanes. The method includes protecting the 2’ hydroxyl group of a first selected taxane with a hydroxyl protecting group, such as a tosyl group, a mesyl group or a nosyl group. The protected taxane compound is then converted to an oxazole compound having an oxazole ring. The oxaxole ring is then opened by an appropriate process, such as by hydrolyzing the oxaxole compound thereby to form an intermediate compound, which is then converted to a second taxane. The intermediate compound may be an anime salt that is treated with a base to form the second taxane. The method contemplated by be used to convert 2’epi paclitaxel into paclitaxel. Alternatively, the method may be used to convert paclitaxel into 2’epi paclitaxel. The present invention also relates to novel compounds and intermediates formed by the process.
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Page/Page column 11-12
(2008/06/13)
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- PROCESS FOR PREPARATION OF PACLITAXEL TRIHYDRATE AND DOCETAXEL TRIHYDRATE
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A process for the preparation of paclitaxel trihydrate and doctaxel trihydrate comprising (a) treating taxane selected from paclitaxel and docetaxel with a mixture of alkane and chlorinated alkane to obtain a crude product of 65-75% assay, (b) dissolving
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- Process for the preparation of paclitaxel
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A process for the preparation of paclitaxel starting from 10-deacetylbaccatine III.
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- Nanoparticulate bioactive agents
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Bioactive agents may be reproducibly converted into particles having diameters in the range of about 5 to about 2000 nanometers (nm). Conversion is accomplished by dissolving the bioactive agent in a solvent for the bioactive agent, and rapidly altering the polarity of the solution to make it a non-solvent for the bioactive agent, for example by diluting the bioactive agent solution with an excess of a liquid that is a non-solvent for the bioactive agent but is miscible with the solvent. Precipitated bioactive agent nanoparticles are collected by centrifugation, filtration or lyophilization. The nanoparticles have a relatively narrow size distribution, and the average diameter can be controlled by choice of solvent and non-solvent. The nanoparticles are typically amorphous. A surfactant may be added to ensure dispersion of the particles when administered. In the preferred embodiment, the bioactive agent is a drug with low aqueous solubility.
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- Carbohydrate derivatives of paclitaxel and docetaxel, method for producing same and uses thereof
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The invention relates to new carbohydrate derivatives of paclitaxel and docetaxel with increased solubility in water as compared to the parent compounds, paclitaxel and docetaxel These derivatives are produced from naturally occurring precursor molecules which upon hydrolysis yield these natural precursors and the original paclitaxel and docetaxel molecules. The present invention also related to the composition and the use of such derivatives for cancer therapy. These derivatives may also be used in antifungal or antiviral therapy.
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- THE METHOD FOR PRODUCTION OF SEMI-FINISHED PRODUCTS USEFUL IN SYNTHESIS OF PACLITAXEL
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The method for production of the semi-finished products useful in synthesis of Paclitaxel with the generalized formula (2), characterized in that phenyl isoserine derivatives, or mixtures of their epimerides with various configurations on the carbon 2' or their salts, are treated with triazine type condensing agent, possible in the presence of tertiary amine, in medium of anhydrous organic solvent, and the triazine esters produced are treated with Baccatin III, in medium of anhydrous organic solvent, possible in the presence of a catalyst.
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- METHODS AND COMPOSITIONS FOR CONVERTING TAXANE AMIDES TO PACLITAXEL OR OTHER TAXANES
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The invention relates to methods and compositions for converting taxane amides to paclitaxel or other taxanes. In one alternative embodiment, the present invention comprises; (i) selectively protecting at least one OH group of a taxane amide; (ii) contacting the taxane amide with a transition metal compound to reduce the amide; (iii) contacting the reduced amide with an agent capable of substantially removing the transition metal; (iv) contacting the reduced amide with a hydrolyzing amount of acid to form a taxane amine salt in solution; (v) adding a sufficient amount of solvent to solidify the amine salt; and (vi) converting the taxane amine salt into paclitaxel or other taxanes.
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