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Ramesh N. Patel - One of the best experts on this subject based on the ideXlab platform.
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Conversion of 7-deoxy-10-Deacetylbaccatin-III into 6-alpha-hydroxy-7-deoxy-10-Deacetylbaccatin-III by Nocardioides luteus.
Biotechnology and applied biochemistry, 2020Co-Authors: Ronald L Hanson, Joydeep Kant, Ramesh N. PatelAbstract:6-alpha-Hydroxy-7-deoxy-10-Deacetylbaccatin-III is an intermediate that is potentially useful for synthesis of analogues of paclitaxel. Screening of microbial strains identified an enzyme activity in Nocardioides luteus SC 13912 (A.T.C.C. 55426) which converted 7-deoxy-10-Deacetylbaccatin-III into 6-hydroxy-7-deoxy-10-Deacetylbaccatin-III with a maximum yield of 44%.
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Enzymatic C-4 deacetylation of 10-Deacetylbaccatin III.
Biotechnology and applied biochemistry, 2020Co-Authors: Ronald L Hanson, William L Parker, Ramesh N. PatelAbstract:Second-generation paclitaxel analogues that require replacement of the C-4 acetate by other substituents are in development. An enzyme able to specifically remove the C-4 acetate from paclitaxel could simplify preparation of the analogues. Several strains were isolated from soil samples that contain enzyme activities able to 4-deacetylate 10-DAB (10-Deacetylbaccatin III). Selection was made using plates containing 10-DAB as the sole carbon source and screening colonies for deacetylation of 10-DAB. Two strains initially isolated were identified as Rhodococcus sp. and deposited with the A.T.C.C. (Manassas, VA, U.S.A.) as strains 202191 and 202192. Whole cells were able to convert 10-DAB into 4,10-DDAB (4-deacetyl-10-Deacetylbaccatin III) in 90% yield. The enzyme activity in these strains was not effective with paclitaxel and 10-deacetylpaclitaxel, although 4,10-DDAB was produced from baccatin III. The activity in these strains was associated with an insoluble fraction of cell extracts. Several additional isolates were obtained that were identified as variants of Stenotrophomonas maltophilia, and a soluble C-4 deacetylase was purified approx. 218-fold from one of them. The activity of this enzyme was limited to 10-DAB, and the enzyme was not effective with paclitaxel or baccatin III.
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Conversion of 7-deoxy- 10-Deacetylbaccatin-III into 6-α-hydroxy-7-deoxy-10-Deacetylbaccatin-III by Nocardioides luteus
Biotechnology and Applied Biochemistry, 2004Co-Authors: Ronald L Hanson, Joydeep Kant, Ramesh N. PatelAbstract:6-α-Hydroxy-7-deoxy-10-Deacetylbaccatin-III is an intermediate that is potentially useful for synthesis of analogues of paclitaxel. Screening of microbial strains identified an enzyme activity in Nocardioides luteus SC 13912 (A.T.C.C. 55426) which converted 7-deoxy-10-Deacetylbaccatin-III into 6-hydroxy-7-deoxy-10-de-acetylbaccatin-III with a maximum yield of 44%.
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Enzymatic acetylation of 10-Deacetylbaccatin III to baccatin III by C-10 deacetylase from Nocardioides luteus SC 13913
Enzyme and Microbial Technology, 2000Co-Authors: Ramesh N. Patel, Amit Banerjee, Venkata B. NanduriAbstract:Baccatin III is a polycyclic diterpene which can be used for the semi-synthesis of paclitaxel and analogs. An enzymatic process was developed for the conversion of 10-Deacetylbaccatin III (10-DAB) to baccatin III without requiring protection of the 7-hydroxyl group. A C-10 deacetylase from Nocardioides luteus SC 13912 was immobilized on diethylaminoethyl cellulose (DEAE-Cellulose) and the immobilized enzyme was used in the biotransformation process. The reaction was catalyzed using vinyl acetate as acyl donor at ambient temperature and at pH 7. A reaction yield of 51% was obtained.
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TOUR DE PACLITAXEL: Biocatalysis for Semisynthesis
Annual Review of Microbiology, 1998Co-Authors: Ramesh N. PatelAbstract:In collaboration with the National Cancer Institute, Bristol-Myers Squibb has developed paclitaxel for treatment of various cancers; it has been approved by the Food and Drug Administration for the treatment of ovarian and metastatic breast cancer. Originally paclitaxel was isolated and purified from the bark of Pacific yew trees. This source of paclitaxel was considered to be economically and ecologically unsuitable as it required the destruction of the yew trees. This review article describes alternate methods for the production of paclitaxel, specifically, a semisynthetic approach and the application of biocatalysis in enabling the semisynthesis of paclitaxel. Three novel enzymes were discovered in our laboratory that converted the variety of taxanes to a single molecule, namely 10-Deacetylbaccatin III (paclitaxel without C-13 side chain and C-10 acetate), a precursor for paclitaxel semisynthesis. These enzymes are C-13 taxolase (catalyzes the cleavage of C-13 side chain of various taxanes), C-10 deacetylase (catalyzes the cleavage of C-10 acetate of various taxanes), and C-7 xylosidase (catalyzes the cleavage of C-7 xylose from various xylosyltaxanes). Using a biocatalytic approach, paclitaxel and a variety of taxane in extracts of a variety of Taxus cultivars were converted to a 10-Deacetylbaccatin III. The concentration of 10-Deacetylbaccatin III was increased by 5.5- to 24-fold in the extracts treated with the enzymes, depending upon the type of Taxus cultivars used. Biocatalytic processes have also been described for the preparation of C-13 paclitaxel side chain synthons. The chemical coupling of 10-Deacetylbaccatin III or baccatin III to C-13 paclitaxel side chain has been summarized to prepare paclitaxel by semisynthesis.
Ezio Bombardelli - One of the best experts on this subject based on the ideXlab platform.
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Microbial transformation of 10-Deacetylbaccatin III (10-DAB) by Curvularia lunata and Trametes hirsuta
Journal of Molecular Catalysis B-enzymatic, 2006Co-Authors: Alberto Arnone, Ezio Bombardelli, Adriana Bava, Stefano Alemani, Gianluca Nasini, Gabriele FontanaAbstract:Abstract The microbial transformation of 10-Deacetylbaccatin III (10-DAB) ( 1a ) and 13-DeBAC ( 4b ) was investigated. Trametes hirsuta induced 13-oxidation of 10-DAB to give ( 4a ) in high yield, whereas incubation with Curvularia lunata resulted in the isolation of the 7- epi -10-DAB ( 2 ) and the 7- epi -10-oxo-10-DAB ( 3 ). 13-DeBAC ( 4b ) was biotransformed into compounds ( 4a ) and ( 4c ) by Alternaria alternata .
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Synthesis and biological evaluation of methoxylated analogs of the newer generation taxoids IDN5109 and IDN5390.
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Luciano Barboni, Giovanni Appendino, Gabriele Fontana, Roberto Ballini, Guido Giarlo, Ezio BombardelliAbstract:Starting from 10-Deacetylbaccatin III (7), the 2-debenzoyl-2-m-methoxybenzoyl analogs of the newer generation taxoids IDN5109 (3) and IDN5390 (4) were synthesized. The biological evaluation of these compounds (5 and 6, respectively) showed a general increase of cytotoxicity, as observed in first-generation anticancer taxanes.
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Diastereoselective 14β-Hydroxylation of Baccatin III Derivatives
Journal of Organic Chemistry, 2003Co-Authors: Eleonora Baldelli, Ezio Bombardelli, Gabriele Fontana, Arturo Battaglia, Giacomo Carenzi, Andrea Gambini, Maria Luisa Gelmi, A. Guerrini, Donato PocarAbstract:14β-Hydroxybaccatin III, a compound with limited availability by natural sources, is the starting material for the synthesis of the second-generation anticancer taxoid ortataxel. The 7-tert-butoxycarbonyl (1a) and 7-triethylsilyl (1b) derivatives of 14β-hydroxybaccatin III 1,14-carbonate were synthesized from 10-Deacetylbaccatin III (3). The crucial steps were (a) the C14β hydroxylation of the corresponding 13-oxobaccatin III derivatives by oxaziridine-mediated electrophilic oxidation and (b) the reduction of the C13 carbonyl group with sodium or alkylammonium borohydrides. This protocol provides a practical way for the semisynthesis of ortataxel from 10-Deacetylbaccatin III, a compound readily available from various yews.
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Synthesis of paclitaxel (docetaxel) / 2-deacetoxytaxinine J dimers
Tetrahedron, 1999Co-Authors: Giovanni Appendino, Jasmin Jakupovic, Emanuela Belloro, Sven Jakupovic, Bruno Danieli, Ezio BombardelliAbstract:Abstract Starting from taxanes available in multigram amounts from widespread ornamental yews (10-Deacetylbaccatin III (4) and 2′-deacetoxyaustrospicatine (5)), two dimeric taxoids (3a, 3b) with potential dual target specificity (β-tubulin and P-gp) were synthesised. Both compounds lacked significant cytotoxicity, though 3b retained a strong activity in the tubulin depolimerisation assay.
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Anti‐proliferative activity of a new class of taxanes (14β‐hydroxy‐10‐deacetylbaccatin III derivatives) on multidrug‐resistance‐positive human cancer cells. Int. J. Cancer,72, 844–850 (1997)
International Journal of Cancer, 1998Co-Authors: Mariagrazia Distefano, Ezio Bombardelli, Iwao Ojima, Giovanni Scambia, Cristiano Ferlini, Gaggini C, R. De Vincenzo, Antonella Riva, Andrea Fattorossi, P. Benedetti PaniciAbstract:Distefano, M., Scambia, G., Ferlini, C., Gaggini, C., De Vincenzo, R., Riva, A., Bombardelli, E., Ojima, I., Fattorossi, A., Benedetti Panici, P. and Mancuso, S., Anti-proliferative activity of a new class of taxanes (14β-hydroxy-10-Deacetylbaccatin III derivatives) on multidrug-resistance-positive human cancer cells. Int. J. Cancer,72, 844–N850 (1997). The incorrect version of Figure 2 was published in the above-noted article. The correct version of the figure is printed here along with the legend. The Authors regret the error.
Joëlle Dubois - One of the best experts on this subject based on the ideXlab platform.
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Semisynthesis and biological evaluation of a novel D-seco docetaxel analogue.
Organic Letters, 2006Co-Authors: Sylviane Thoret, Daniel Guénard, Francoise Gueritte, Joëlle DuboisAbstract:A 4-methyl-5-oxo docetaxel analogue has been prepared starting from 10-Deacetylbaccatin III. This new D-seco docetaxel analogue is slightly less potent than docetaxel at microtubule stabilization in vitro and has about 1/1000th the cytotoxicity of docetaxel. The lack of improved activity for this compound compared to other D-modified taxoids confirms that a C-5 oxygen atom is not required for biological activity.
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Semisynthesis and biological evaluation of a novel D-seco docetaxel analogue
Organic Letters, 2006Co-Authors: Sylviane Thoret, Daniel Guénard, Francoise Gueritte, Joëlle DuboisAbstract:[reaction: see text] A 4-methyl-5-oxo docetaxel analogue has been prepared starting from 10-Deacetylbaccatin III. This new D-seco docetaxel analogue is slightly less potent than docetaxel at microtubule stabilization in vitro and has about 1/1000th the cytotoxicity of docetaxel. The lack of improved activity for this compound compared to other D-modified taxoids confirms that a C-5 oxygen atom is not required for biological activity.
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Deletion of the oxetane ring in docetaxel analogues: synthesis and biological evaluation.
Organic Letters, 2003Co-Authors: Vaishali Deka, Joëlle Dubois, Sylviane Thoret, Francoise Gueritte, Daniel GuénardAbstract:Two new docetaxel analogues have been prepared starting from 10-Deacetylbaccatin III. Both derivatives lack the oxetane D-ring but possess the 4α-acetoxy group, which is important for biological activity. The influence of a more or less constrained C-ring was evaluated by adding, or not adding, a double bond in this ring. Both compounds were found to be equally less active than docetaxel in biological assays.
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Semisynthesis of D-Ring Modified Taxoids: Novel Thia Derivatives of Docetaxel
Journal of Organic Chemistry, 2001Co-Authors: Ludovic Merckle, Daniel Guénard, Sylviane Thoret, Joëlle Dubois, Francoise Gueritte, Christiane Poupat, Estelle Place, A. Ahond, Pierre PotierAbstract:Two novel 5(20)-thia analogues of docetaxel have been synthesized from 10-Deacetylbaccatin III or taxine B and isotaxine B. The key step of these syntheses is the concomitant thietane ring formation and acetylation of the tertiary alcohol at C-4. Both compounds are less cytotoxic than docetaxel but have divergent activity on microtubule disassembly.
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Taxoids: 11,12-dihydro-4-deacetyldocetaxel
Tetrahedron Letters, 1996Co-Authors: Raphaële Marder, Daniel Guénard, Joëlle Dubois, Laurent Bricard, Francoise Gueritte-voegeleinAbstract:Abstract 11,12-dihydro-4-deacetyldocetaxel was prepared from 10-Deacetylbaccatin III via its reduced derivative at C11, C12. The title compound is not active on microtubules disassembly.
Iwao Ojima - One of the best experts on this subject based on the ideXlab platform.
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Anti‐proliferative activity of a new class of taxanes (14β‐hydroxy‐10‐deacetylbaccatin III derivatives) on multidrug‐resistance‐positive human cancer cells. Int. J. Cancer,72, 844–850 (1997)
International Journal of Cancer, 1998Co-Authors: Mariagrazia Distefano, Ezio Bombardelli, Iwao Ojima, Giovanni Scambia, Cristiano Ferlini, Gaggini C, R. De Vincenzo, Antonella Riva, Andrea Fattorossi, P. Benedetti PaniciAbstract:Distefano, M., Scambia, G., Ferlini, C., Gaggini, C., De Vincenzo, R., Riva, A., Bombardelli, E., Ojima, I., Fattorossi, A., Benedetti Panici, P. and Mancuso, S., Anti-proliferative activity of a new class of taxanes (14β-hydroxy-10-Deacetylbaccatin III derivatives) on multidrug-resistance-positive human cancer cells. Int. J. Cancer,72, 844–N850 (1997). The incorrect version of Figure 2 was published in the above-noted article. The correct version of the figure is printed here along with the legend. The Authors regret the error.
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New taxanes as highly efficient reversal agents for multi-drug resistance in cancer cells
Bioorganic & Medicinal Chemistry Letters, 1998Co-Authors: Iwao Ojima, Craig S. Takeuchi, Paula Pera, Pierre-yves Bounaud, Ralph J. BernackiAbstract:Abstract 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.
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Anti‐proliferative activity of a new class of taxanes (14β‐hydroxy‐10‐deacetylbaccatin III derivatives) on multidrug‐resistance‐positive human cancer cells
International Journal of Cancer, 1997Co-Authors: Mariagrazia Distefano, Ezio Bombardelli, Iwao Ojima, Giovanni Scambia, Cristiano Ferlini, Gaggini C, R. De Vincenzo, Antonella Riva, Andrea Fattorossi, P. Benedetti PaniciAbstract:Paclitaxel, docetaxel and a series of new analogs synthesized from 14β-hydroxy-10-Deacetylbaccatin III (14-OH-DAB), a natural diterpene closely related to the core synthon of the 2 above prototypes, were tested in vitro for their growth-inhibitory activity on different human cancer cell lines, including some expressing the classic multidrug-resistant (MDR) phenotype (MCF-7 ADRr and CEM VBLr). The 14-OH-DAB derivatives showed enhanced anti-proliferative activity as compared to the parent compounds on the MDR-positive cancer cell lines. Particularly, IDN 5109 showed a 25- to 30-fold higher activity than paclitaxel. The fold change in activity between paclitaxel and analogs (IC50 paclitaxel/IC50 analogs) on the MDR-positive cell lines was calculated and a significant correlation observed. As far as the MDR-negative MDA-MB 231 cells are concerned, docetaxel and IDN 5109 exhibited a more potent activity than paclitaxel. On the basis of the data obtained on cell growth inhibition, we selected the most active compounds to study their effect on the cell cycle. Cell cycle analysis showed that all of the compounds tested were able to induce cell cycle block at G2/M in a concentration-dependent manner. The amount of cell block, measured as a G1/G2 ratio, was correlated significantly (p < 0.001) with apoptosis, as evaluated in the sub-G1 region (% of DNA fragmentation), thereby suggesting that the G2/M-blocked cells underwent apoptosis. To confirm the occurrence of apoptosis in this system, DNA gel agarose electrophoresis was performed and showed the typical ladder pattern. Int. J. Cancer 72:844–850, 1997. © 1997 Wiley-Liss, Inc.
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Syntheses and Structure−Activity Relationships of Taxoids Derived from 14β-Hydroxy-10-Deacetylbaccatin III
Journal of Medicinal Chemistry, 1997Co-Authors: Iwao Ojima, John C. Slater, Scott D. Kuduk, Craig S. Takeuchi, Rayomand H. Gimi, Young Hoon Park, Paula Pera, Jean Veith, Ralph J. BernackiAbstract:A series of new taxoids derived from 14β-hydroxy-10-Deacetylbaccatin III was synthesized by means of the β-lactam synthon method. Most of the new taxoids thus synthesized possess excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines, and several of these taxoids show subnanomolar IC50 values which are severalfold to 1 order of magnitude better than those of paclitaxel and docetaxel. Modifications at the 3‘- and 3‘-N-positions exert marked effects on the activity. For the substituents at C-3‘, the cytotoxicity decreases in the order 2-furyl ∼ 2-methyl-1-propenyl ≥ 2-methylpropyl > (E)-1-propenyl ≥ n-propyl > phenyl ≫ 2,2-dimethylpropyl. For the 3‘-N substituents, the activity decreases in the order t-BuOCO > Ph > n-hexanoyl. A significant increase in the cytotoxicity against the doxorubicin-resistant human breast cancer cell line MCF7-R that expresses the multidrug resistance (MDR) phenotype is observed by the proper modificatio...
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Syntheses of new fluorine-containing taxoids by means of β-Lactam Synthon Method
Tetrahedron, 1996Co-Authors: Iwao Ojima, John C. Slater, Scott D. Kuduk, Rayomand H. GimiAbstract:Abstract A series of new fluorine-containing analogs of paclitaxel and docetaxel are synthesized using the coupling of (3 R ,4 S )-1-acyl- β -lactams with high enantiomeric purity with properly protected baccatin III, 10-Deacetylbaccatin III, and 14β-hydroxy-10-Deacetylbaccatin III as the key step (β- Lactam Synthon Method ). (3 R ,4 S )-1-Acyl- β -lactams are prepared through efficient chiral ester enolate - imine cyclocondensation.
Ronald L Hanson - One of the best experts on this subject based on the ideXlab platform.
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Conversion of 7-deoxy-10-Deacetylbaccatin-III into 6-alpha-hydroxy-7-deoxy-10-Deacetylbaccatin-III by Nocardioides luteus.
Biotechnology and applied biochemistry, 2020Co-Authors: Ronald L Hanson, Joydeep Kant, Ramesh N. PatelAbstract:6-alpha-Hydroxy-7-deoxy-10-Deacetylbaccatin-III is an intermediate that is potentially useful for synthesis of analogues of paclitaxel. Screening of microbial strains identified an enzyme activity in Nocardioides luteus SC 13912 (A.T.C.C. 55426) which converted 7-deoxy-10-Deacetylbaccatin-III into 6-hydroxy-7-deoxy-10-Deacetylbaccatin-III with a maximum yield of 44%.
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Enzymatic C-4 deacetylation of 10-Deacetylbaccatin III.
Biotechnology and applied biochemistry, 2020Co-Authors: Ronald L Hanson, William L Parker, Ramesh N. PatelAbstract:Second-generation paclitaxel analogues that require replacement of the C-4 acetate by other substituents are in development. An enzyme able to specifically remove the C-4 acetate from paclitaxel could simplify preparation of the analogues. Several strains were isolated from soil samples that contain enzyme activities able to 4-deacetylate 10-DAB (10-Deacetylbaccatin III). Selection was made using plates containing 10-DAB as the sole carbon source and screening colonies for deacetylation of 10-DAB. Two strains initially isolated were identified as Rhodococcus sp. and deposited with the A.T.C.C. (Manassas, VA, U.S.A.) as strains 202191 and 202192. Whole cells were able to convert 10-DAB into 4,10-DDAB (4-deacetyl-10-Deacetylbaccatin III) in 90% yield. The enzyme activity in these strains was not effective with paclitaxel and 10-deacetylpaclitaxel, although 4,10-DDAB was produced from baccatin III. The activity in these strains was associated with an insoluble fraction of cell extracts. Several additional isolates were obtained that were identified as variants of Stenotrophomonas maltophilia, and a soluble C-4 deacetylase was purified approx. 218-fold from one of them. The activity of this enzyme was limited to 10-DAB, and the enzyme was not effective with paclitaxel or baccatin III.
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Conversion of 7-deoxy- 10-Deacetylbaccatin-III into 6-α-hydroxy-7-deoxy-10-Deacetylbaccatin-III by Nocardioides luteus
Biotechnology and Applied Biochemistry, 2004Co-Authors: Ronald L Hanson, Joydeep Kant, Ramesh N. PatelAbstract:6-α-Hydroxy-7-deoxy-10-Deacetylbaccatin-III is an intermediate that is potentially useful for synthesis of analogues of paclitaxel. Screening of microbial strains identified an enzyme activity in Nocardioides luteus SC 13912 (A.T.C.C. 55426) which converted 7-deoxy-10-Deacetylbaccatin-III into 6-hydroxy-7-deoxy-10-de-acetylbaccatin-III with a maximum yield of 44%.
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Enzymic hydrolysis of 7‐xylosyltaxanes by xylosidase from Moraxella sp.
Biotechnology and Applied Biochemistry, 1997Co-Authors: Ronald L Hanson, Ramesh N. Patel, Jeffrey M. Howell, David B. Brzozowski, Susan A. Sullivan, Laszlo J. SzarkaAbstract:The production of large quantities of paclitaxel for use as an anticancer treatment has been a difficult problem because of the low concentration of the compound in yew trees (Taxus sp.) and its occurrence as part of a mixture of other taxanes. 7-Xylosyltaxanes are major components of the mixture found in the bark of the Pacific yew (Taxus brevifolia). A bacterial strain isolated from soil and identified as a Moraxella sp. was able to remove the xylosyl group from 7-xylosylpaclitaxel, 7-xylosyl-10-deacetylpaclitaxel, 7-xylosylbaccatin III and 7-xylosyl-10-Deacetylbaccatin III, thereby making the xylosyltaxanes available as sources of 10-Deacetylbaccatin III for semisynthesis of paclitaxel. The activity was located in both the soluble and particulate fractions of the cell.
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Fermentation and isolation of C10‐deacetylase for the production of 10‐deacetylbaccatin III from baccatin III
Biotechnology and Bioengineering, 1995Co-Authors: Venkata B. Nanduri, Ramesh N. Patel, Ronald L Hanson, Thomas L. Laporte, Raphael Y. Ko, Laszlo J. SzarkaAbstract:10-Deacetylbaccatin III (10 DAB), an important precursor for paclitaxel semisynthesis, is enhanced in yew extracts using C10-deacetylase and C13-deacylase enzymes. 4 C10-deacetylase is an intracellular enzyme produced by the fermentation of a soil microorganism, Nocardioides luteus (SC 13912). During the fermentation of Nocardioides luteus, the growth of cells reaches a maximum growth at 28 h. C10-deacetylase enzyme activity starts at 26 h and peaks at 38 h of the fermentation. The cells are recovered by centrifugation. The C10-deacetylase enzyme was purified from the Nocardioides luteus cells. The enzyme was purified 190-fold to near homogeneity. The purified enzyme appeared as a single band on 12.5% SDS-PAGE analysis with a molecular weight of 40,000 daltons.
