Taxoid

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 3228 Experts worldwide ranked by ideXlab platform

Iwao Ojima - One of the best experts on this subject based on the ideXlab platform.

  • Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery
    Journal of natural products, 2018
    Co-Authors: Iwao Ojima, Xin Wang, Yunrong Jing, Changwei Wang
    Abstract:

    Paclitaxel and docetaxel are among the most widely used chemotherapeutic drugs against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop next-generation Taxoid anticancer agents with better pharmacological properties and improved activity especially against drug-resistant and metastatic cancers. The SAR studies by the authors have led to the development of numerous highly potent novel second- and third-generation Taxoids with systematic modifications at the C-2, C-10, and C-3′ positions. The third-generation Taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the next-generation Taxoids also exhibited excellent potency against cancer stem cells. This account summarizes concisely investigations into Taxoids over 25 years based on a strong quest for the discovery and development of efficacious next-generation Taxoids. Discussed herein are SAR studies on dif...

  • synthesis of a next generation Taxoid by rapid methylation amenable for 11c labeling
    Journal of Organic Chemistry, 2018
    Co-Authors: Joshua D. Seitz, Tao Wang, Jacob G Vineberg, Tadashi Honda, Iwao Ojima
    Abstract:

    Next-generation Taxoids, such as SB-T-1214, are highly potent cytotoxic agents that exhibit remarkable efficacy against drug-resistant tumors in vivo, including those that overexpress the P-glycoprotein (Pgp) efflux pump. As SB-T-1214 is not a substrate for Pgp-mediated efflux, it may exhibit a markedly different biodistribution and tumor-accumulation profile than paclitaxel or docetaxel, which are both Pgp substrates. To investigate the biodistribution and tumor-accumulation levels of SB-T-1214 using positron emission tomography (PET), a new synthetic route has been developed to allow the incorporation of 11C, a commonly employed positron-emitting radionucleide, via methyl iodide at the last step of chemical synthesis. This synthetic route features a highly stereoselective chiral ester enolate–imine cyclocondensation, regioselective hydrostannation of the resulting β-lactam, and the Stille coupling of the novel vinylstannyl Taxoid intermediate with methyl iodide. Conditions have been established to allow...

  • Synthesis of a Next-Generation Taxoid by Rapid Methylation Amenable for 11C‑Labeling
    2018
    Co-Authors: Joshua D. Seitz, Jacob G Vineberg, Tao Wang, Tadashi Honda, Iwao Ojima
    Abstract:

    Next-generation Taxoids, such as SB-T-1214, are highly potent cytotoxic agents that exhibit remarkable efficacy against drug-resistant tumors in vivo, including those that overexpress the P-glycoprotein (Pgp) efflux pump. As SB-T-1214 is not a substrate for Pgp-mediated efflux, it may exhibit a markedly different biodistribution and tumor-accumulation profile than paclitaxel or docetaxel, which are both Pgp substrates. To investigate the biodistribution and tumor-accumulation levels of SB-T-1214 using positron emission tomography (PET), a new synthetic route has been developed to allow the incorporation of 11C, a commonly employed positron-emitting radionucleide, via methyl iodide at the last step of chemical synthesis. This synthetic route features a highly stereoselective chiral ester enolate–imine cyclocondensation, regioselective hydrostannation of the resulting β-lactam, and the Stille coupling of the novel vinylstannyl Taxoid intermediate with methyl iodide. Conditions have been established to allow the rapid methylation and HPLC purification of the target compound in a time frame amenable to 11C-labeling for applications to PET studies

  • poly 2 oxazoline based micelles with high capacity for 3rd generation Taxoids preparation in vitro and in vivo evaluation
    Journal of Controlled Release, 2015
    Co-Authors: Anita Schulz, Iwao Ojima, Joshua D. Seitz, Xiaomeng Wan, Herdis Bludau, Daria Y Alakhova, David B Darr, Charles M Perou, Rainer Jordan, Alexander V Kabanov
    Abstract:

    Abstract The clinically and commercially successful taxanes, paclitaxel and docetaxel suffer from two major drawbacks, namely their very low aqueous solubility and the risk of developing resistance. Here, we present a method that overcomes both drawbacks in a very simple manner. We formulated 3rd generation Taxoids, able to avoid common drug resistance mechanisms with doubly amphiphilic poly(2-oxazoline)s (POx), a safe and highly efficient polymer for the formulation of extremely hydrophobic drugs. We found excellent solubilization of different 3rd generation Taxoids irrespective of the drug's chemical structures with essentially quantitative drug loading and final drug to polymer ratios around unity. The small, highly loaded micelles with a hydrodynamic diameter of less than 100 nm are excellently suited for parenteral administration. Moreover, a selected formulation with the Taxoid SB-T-1214 is about one to two orders of magnitude more active in vitro than paclitaxel in the multidrug resistant breast cancer cell line LCC6-MDR. In contrast, in wild-type LCC6, no difference was observed. Using a q4d × 4 dosing regimen, we also found that POx/SB-T-1214 significantly inhibits the growth of LCC6-MDR orthotropic tumors, outperforming commercial paclitaxel drug Taxol and Cremophor EL formulated SB-T-1214.

  • Targeted and armed oncolytic adenovirus via chemoselective modification
    Bioorganic & medicinal chemistry letters, 2011
    Co-Authors: Partha S. Banerjee, Iwao Ojima, Edison S. Zuniga, Isaac S. Carrico
    Abstract:

    Oncolytic adenoviruses (Ads) are an emerging alternative therapy for cancer; however, clinical trial have not yet demonstrated sufficient efficacy. When oncolytic Ads are used in combination with Taxoids a synergistic increase in both cytotoxicity and viral replication is observed. In order to generate a next generation oncolytic adenovirus, virion were physically conjugated to a highly potent Taxoid, SB-T-1214, and a folate targeting motif. Conjugation was enabled via the metabolic incorporation of non-canonical monosaccharides (O-GlcNAz) and amino acids (homopropargylglycine), which served as sites for chemoselective modification.

Rodney Croteau - One of the best experts on this subject based on the ideXlab platform.

  • Synthesis and in vitro evaluation of taxol oxetane ring D precursors
    Tetrahedron Letters, 2010
    Co-Authors: Rüdiger Kaspera, Raymond E.b. Ketchum, Jonathan L. Cape, Juan A. Faraldos, Rodney Croteau
    Abstract:

    A series of potential Taxoid substrates was prepared in radiolabeled form to probe in vitro for the oxirane formation step and subsequent ring expansion step to the oxetane (ring D) presumably involved in the biosynthesis of the anticancer agent Taxol. None of the Taxoid test substrates underwent transformation in cell-free systems from Taxus suggesting that these surrogates bore substitution patterns inappropriate for recognition or catalysis by the target enzymes, or that Taxoid oxiranes and oxetanes arise by independent biosynthetic pathways.

  • taxol biosynthesis identification and characterization of two acetyl coa Taxoid o acetyl transferases that divert pathway flux away from taxol production
    Archives of Biochemistry and Biophysics, 2009
    Co-Authors: Daniela Hampel, Christopher J D Mau, Rodney Croteau
    Abstract:

    Two cDNAs encoding Taxoid-O-acetyl transferases (TAX 9 and TAX 14) were obtained from a previously isolated family of Taxus acyl/aroyl transferase cDNA clones. The recombinant enzymes catalyze the acetylation of taxadien-5α,13α-diacetoxy-9α,10β-diol to generate taxadien-5α,10β,13α-tri-acetoxy-9α-ol and taxadien-5α,9α,13α-triacetoxy-10β-ol, respectively, both of which then serve as substrates for a final acetylation step to yield taxusin, a prominent side-route metabolite of Taxus. Neither enzyme acetylate the 5α- or the 13α-hydroxyls of Taxoid polyols, indicating that prior acylations is required for efficient peracetylation to taxusin. Both enzymes were kinetically characterized, and the regioselectivity of acetylation was shown to vary with pH. Sequence comparison with other Taxoid acyl transferases confirmed that primary structure of this enzyme type reveals little about function in Taxoid metabolism. Unlike previously identified acetyl transferases involved in Taxol production, these two enzymes appear to act exclusively on partially acetylated Taxoid polyols to divert the Taxol pathway to side-route metabolites.

  • Administering cultured Taxus cells with early precursors reveals bifurcations in the Taxoid biosynthetic pathway
    Phytochemistry, 2006
    Co-Authors: Raymond E.b. Ketchum, Deyou Qiu, Robert M. Williams, Tohru Horiguchi, Rodney Croteau
    Abstract:

    Administering Taxus suspension cells with labeled 5alpha-hydroxytaxadiene and 5alpha,10beta-dihydroxytaxadiene, and the corresponding 5alpha-acetate esters, demonstrated that acetylation at C5 of the monool precursor promotes the formation of 14beta-hydroxy Taxoids, such as taxuyunnanine C, at the expense of 13alpha-hydroxy Taxoids, including Taxol and its congeners, but that the major bifurcation in Taxoid biosynthesis, toward 13alpha- or 14beta-hydroxy Taxoids, occurs after 10beta-hydroxylation of the taxane core.

  • genetic engineering of taxol biosynthetic genes in saccharomyces cerevisiae
    Biotechnology and Bioengineering, 2006
    Co-Authors: Jinghong M Dejong, Stefan Jennewein, Robert M Long, Arthur P Bollon, David G Williams, Rodney Croteau
    Abstract:

    : Baccatin III, an intermediate of Taxol biosynthesis and a useful precursor for semisynthesis of the anti-cancer drug, is produced in yew (Taxus) species by a sequence of 15 enzymatic steps from primary metabolism. Ten genes encoding enzymes of this extended pathway have been described, thereby permitting a preliminary attempt to reconstruct early steps of taxane diterpenoid (Taxoid) metabolism in Saccharomyces cerevisiae as a microbial production host. Eight of these Taxoid biosynthetic genes were functionally expressed in yeast from episomal vectors containing one or more gene cassettes incorporating various epitope tags to permit protein surveillance and differentiation of those pathway enzymes of similar size. All eight recombinant proteins were readily detected by immunoblotting using specific monoclonal antibodies and each expressed protein was determined to be functional by in vitro enzyme assay, although activity levels differed considerably between enzyme types. Using three plasmids carrying different promoters and selection markers, genes encoding five sequential pathway steps leading from primary isoprenoid metabolism to the intermediate taxadien-5alpha- acetoxy-10beta-ol were installed in a single yeast host. Metabolite analysis showed that yeast isoprenoid precursors could be utilized in the reconstituted pathway because products accumulated from the first two engineered pathway steps (leading to the committed intermediate taxadiene); however, a pathway restriction was encountered at the first cytochrome P450 hydroxylation step. The means of overcoming this limitation are described in the context of further development of this novel approach for production of Taxol precursors and related Taxoids in yeast.

  • Regioselectivity of Taxoid-O-acetyltransferases: heterologous expression and characterization of a new taxadien-5α-ol-O-acetyltransferase☆☆☆
    Archives of biochemistry and biophysics, 2004
    Co-Authors: Mydoanh Chau, Robert M Long, Kevin D. Walker, Rodney Croteau
    Abstract:

    In addition to the anticancer drug Taxol, yew (Taxus) species produce a large variety of other taxane diterpenoids which differ mainly in the type of acyl and aroyl groups appended to the many hydroxyl functions on the taxane core; acetate esters are particularly common. Taxol bears an acetate at C10 and another at C4 thought to originate by intramolecular migration of a C5 acetate function in the process of oxetane ring formation, but many other naturally occurring Taxoids bear acetate groups at C1, C2, C7, C9, and C13, in addition to C5 and C10. cDNAs encoding a Taxoid 5α-O-acetyltransferase (taxadien-5α-ol as substrate) and a Taxoid 10β-O-acetyltransferase (10-deacetylbaccatin III as substrate) have been acquired from a recently isolated family of Taxus acyl/aroyltransferase clones. To explore the origins of other acetylated Taxoids, the group of recombinant Taxus acyltransferases was investigated with a range of polyhydroxylated Taxoids as substrates. From this survey, a new acetyltransferase clone (denoted TAX19) was identified that was capable of acetylating taxadien-5α-ol with activity comparable to that of the previously identified 5α-O-acetyltransferase (clone TAX1). However, when these two recombinant enzymes were presented with taxadien-triol and tetraol substrates, they exhibited different regiospecificities. The TAX1 enzyme preferentially acetylates the “northern” hemisphere hydroxyls at C9 and C10, whereas the TAX19 enzyme preferentially acetylates the “east–west” pole positions at C5 and C13. The TAX1 enzyme possesses the lowest KM value with taxadien-5α-ol (an early pathway metabolite) as substrate, with much higher KM values for the polyhydroxylated Taxoid substrates, whereas the TAX19 enzyme possesses lower KM values (than the TAX1 transferase) for all Taxoid substrates tested. These results suggest that both TAX1 and TAX19 acyltransferases may function at the early C5 acetylation step of Taxoid metabolism, and that the TAX19 acyltransferase, because of its broader specificity for polyhydroxylated Taxoids, may also function later in metabolism and be responsible for the production of many other acetylated Taxoids.

Pierre Potier - One of the best experts on this subject based on the ideXlab platform.

  • Neutral and basic Taxoid contents in the needles of Taxus species.
    Planta Medica, 2000
    Co-Authors: Christiane Poupat, Daniel Guénard, Alain Ahond, Dairine Dempsey, Séverine Breuillet, Marie-thérèse Adeline, Françoise Guéritte, Xiu-ping Wang, Ingrid Hook, Pierre Potier
    Abstract:

    The concentrations of paclitaxel, 10-deacetylbaccatin III (10-DAB III), basic Taxoids (= total alkaloids, TA), taxine B and isotaxine B (= taxines B, TBS) in the dried needles of 127 trees belonging to 30 Taxus cultivars and species were determined by HPLC. Neutral and basic Taxoid contents varied in individual trees within species as well as among varieties and species. The objective of this large analysis was to select the highest-yielding trees for each metabolite.

  • Seasonal variation of neutral and basic Taxoid contents in shoots of European Yew (Taxus baccata)
    Phytochemistry, 1999
    Co-Authors: Ingrid Hook, Daniel Guénard, Christiane Poupat, Alain Ahond, Dairine Dempsey, Séverine Breuillet, Marie-thérèse Adeline, Françoise Guéritte, Xiu-ping Wang, Pierre Potier
    Abstract:

    Abstract Seasonal variations of Taxoid constituents were determined in shoots of European Yew collected from two locations. The first samples originated from a male Taxus baccata tree growing in Gif, France. The second samples were obtained from genetically identical female Irish Yew trees ( T. baccata var. fastigiata ), of the same age and growing at one site in Dublin, Ireland. Shoots were collected monthly for one year and separated into needles and stems. Neutral Taxoids (paclitaxel and 10-deacetylbaccatin III (10-DAB III)) and basic Taxoids (including taxines B) were extracted and quantified. Needles yielded significantly higher levels of Taxoids than stems. 10-DAB III contents in needles of French samples showed considerable monthly fluctuations, while in needles of the Irish samples maximum yields of 10-DAB III were found in June. Highest levels of paclitaxel were present between February and April. Basic Taxoids occurred in highest concentrations (total alkaloids 9.49 g/kg) in the August collection of French samples, but in needles of the Irish Yew in November and December (total alkaloids 16.9 g/kg; taxines B 10.9 g/kg). No conclusion could be drawn as to the optimum time of year for harvesting, since this varies from tree to tree, depending on T. baccata variety, location and Taxoid type.

  • studies towards the total synthesis of Taxoids a straightforward procedure for the Taxoid bc substructure
    Tetrahedron Letters, 1993
    Co-Authors: Siméon Arseniyadis, D V Yashunsky, Munoz M Dorado, Brondi R Alves, E Toromanoff, L Toupet, Pierre Potier
    Abstract:

    Abstract The aldol condensation of the ketone 6 and the aldehyde 7 followed by an annelation-fragmentation afforded the bicyclo[6.4.0]dodecane derivative 3 with the appropriate functionalities for further elaboration.

Sunil K. Chattopadhyay - One of the best experts on this subject based on the ideXlab platform.

  • Taxoid from the needles of the Himalayan yew Taxus wallichiana with cytotoxic and immunomodulatory activities.
    Bioorganic & medicinal chemistry letters, 2006
    Co-Authors: Sunil K. Chattopadhyay, Anirban Pal, Prakas R. Maulik, Tanpreet Kaur, Ankur Garg, Suman Preet Singh Khanuja
    Abstract:

    The needles of Taxus wallichiana gave a Taxoid 1-hydroxy- 2-deacetoxy-5-decinnamoyl-taxinine j, whose structure has been established by spectroscopic data and confirmed by X-ray crystallography. The Taxoid possesses significant cytotoxic and immunomodulatory activity.

  • Studies on the Himalayan yew Taxus wallichiana: Part IX — The chemical constituents of the seeds of Taxus wallichiana
    Indian Journal of Chemistry Section B-organic Chemistry Including Medicinal Chemistry, 2002
    Co-Authors: Sunil K. Chattopadhyay, V K Mehta, Koneni V. Sashidhara, V Tripathi, Bhawani S. Joshi
    Abstract:

    The systematic investigation on the seeds of Taxus wallichiana has resulted in the isolation of three non-Taxoid constituents, ursolic acid 1, the cyanogenic glycoside amygdalin 2 and β-sitosterol glucoside 3. It is a very important finding that the seeds of the Himalayan yew did not contain any Taxoids in contrast to the presence of Taxoids in the seeds of other species of Taxus and amygdalin is the major constituent of the seeds. The detailed NMR data of amygdalin are also provided.

  • MS/MS profiling of Taxoids from the needles of Taxus wallichiana.
    Phytochemical analysis : PCA, 2002
    Co-Authors: K. P. Madhusudanan, Sunil K. Chattopadhyay, Koneni V. Sashidhara, V.k. Tripathi, Sushil Kumar
    Abstract:

    Ammonium cationisation has been used for Taxoid profiling of partially purified methanolic extracts of needles of Taxus wallichiana growing in different regions of the Himalayas (Kashmir, Himachal Pradesh, UP Hills, Darjeeling, Sikkim and Arunachal Pradesh) by electrospray ionisation tandem mass spectrometry (MS/MS). The MS/MS spectra of the [M + NH4]+ or [M + H]+ ions gave structurally diagnostic fragment ions which revealed information about the taxane skeleton as well as the number and nature of the substituents. The rearranged 11(15  1)-abeo-taxanes showed a characteristic elimination of the hydroxyisopropyl group with an acetoxy/benzoyloxy group from C-9. The identification of the Taxoids was achieved by comparison of the MS/MS spectra with those of authentic Taxoids or was based on biogenetic grounds. The results were corroborated by liquid chromatography–MS analysis. Out of the 50 Taxoids identified, 21 belonged to the rearranged class. The presence of paclitaxel in the samples from four regions was confirmed: the study also revealed the occurrence of several basic Taxoids in these samples. ­MS/MS profiling by electrospray ionisation was shown to be a fast and reliable technique for the analysis of Taxoid samples. Copyright © 2001 John Wiley & Sons, Ltd.

  • LC-ESI-MS analysis of Taxoids from the bark of Taxus wallichiana†
    Biomedical chromatography : BMC, 2002
    Co-Authors: K. P. Madhusudanan, Sunil K. Chattopadhyay, Koneni V. Sashidhara, V.k. Tripathi, A. K. Kukreja, S. P. Jain
    Abstract:

    LC-ESI-MS analysis was carried out for Taxoid profiling of partially purified methanol extracts of the stem bark of Taxus wallichiana growing in different regions of the Himalayas (Kashmir, Himachal Pradesh, UP hills, Sikkim and Arunachal Pradesh). Cone voltage fragmentation of the protonated, ammonium or sodium cationized molecular species resulted in diagnostic fragment ions. Thus, information about the number and nature of substituents and the taxane skeleton (whether it is normal or rearranged) was readily available from the LC-ESI-MS spectra. The rearranged 11(15→1)-abeo-taxanes showed a characteristic elimination of the hydroxyisopropyl along with an acetoxy group. The identification of the Taxoids was achieved by comparison of the ESI mass spectra with those of the authentic Taxoids available to us or by interpreting the ESI mass spectra. The results were also corroborated by MS/MS analysis of the partially purified extract injected directly into the ESI source. Paclitaxel, its analogues and their xylosides are present in samples from all the regions. An interesting observation is the detection of a large number of basic Taxoids having nitrogen-containing side chains. Copyright © 2002 John Wiley & Sons, Ltd.

  • Isolation of Taxoids from Cell suspension cultures of Taxus wallichiana
    Planta medica, 2000
    Co-Authors: Shipra Agrawal, Sunil K. Chattopadhyay, V K Mehta, Suchitra Banerjee, M. Kulshrestha, K. P. Madhusudanan, Sushil Kumar
    Abstract:

    Cell suspension cultures of stem-derived callus of Taxus wallichiana in MS-F culture media were found to produce three C-14 oxygenated Taxoids and one regular Taxoid. The Taxoids were identified as yunnanxane (1), 2α,5α,10β,14β-tetraacetoxy-4(20),11-taxadiene (2), 2α,5α,10β-triacetoxy-14β-(2-methyl)-butyryloxy-4(20),11-taxadiene (3) and 1β-hydroxybaccatin I (4).

Jun'ichi Kobayashi - One of the best experts on this subject based on the ideXlab platform.

  • Modulation of multidrug resistance by taxuspine C and other Taxoids from Japanese yew.
    Bioorganic & medicinal chemistry letters, 1998
    Co-Authors: Jun'ichi Kobayashi, Xiao-xia Wang, Hideyuki Shigemori, Hirokazu Hosoyama, Yojiro Sudo, Takashi Tsuruo
    Abstract:

    Taxuspine C (1), a new Taxoid from the Japanese yew Taxus cuspidata, increasing the cellular accumulation of vincristine (VCR) in multidrug-resistant tumor cells as potent as verapamil enhanced the chemotherapeutic effect of VCR in P388/VCR-bearing mice. When taxuspine C (1) was given i.p. daily at 200 mg/kg with 0.2 mg/kg VCR for 5 days, a treated/control (T/C) value of 138% was obtained. The other new Taxoids, taxezopidines G (8) and H (9), from the yew also increased the VCR accumulation as potent as verapamil. These results suggest that some Taxoids may be useful for overcoming multidrug resistance in tumor cells.

  • Taxezopidines B-H, new Taxoids from Japanese yew Taxus cuspidata
    Journal of Natural Products, 1998
    Co-Authors: Xiao-xia Wang, Hideyuki Shigemori, Jun'ichi Kobayashi
    Abstract:

    Seven new Taxoids, taxezopidines B-H (1-7), have been isolated from seeds and stems of Japanese yew Taxus cuspidata Sieb. et Zucc. and the structures elucidated on the basis of spectroscopic data. Taxezopidine B (1) is the first Taxoid with a double bond at C-3 and C-4.

  • Taxezopidine A, a Novel Taxoid from Seeds of Japanese Yew Taxus cuspidata
    Tetrahedron Letters, 1997
    Co-Authors: Xiao-xia Wang, Hideyuki Shigemori, Jun'ichi Kobayashi
    Abstract:

    Abstract A novel Taxoid, taxezopidine A ( 1 ), has been isolated from seeds of Japanese yew Taxus cuspidata Sieb. et Zucc. and the structure elucidated on the basis of spectroscopic data. Taxezopidine A ( 1 ) is the first Taxoid with a hemiketal ring at C-11 ∼ C-13, C-15, and C-17. © 1997 Elsevier Science Ltd.

Related terms

Taxoid - 15 days free trial to Access Experts & Abstracts