Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
2000-08-17
2002-02-19
Lilling, Herbert J. (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S117000, C435S195000
Reexamination Certificate
active
06348337
ABSTRACT:
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to a process using microorganisms or enzymes derived therefrom for deacetylation of taxanes at C-4 to give 4-deacetyltaxanes, useful intermediates for the synthesis of new anti-cancer agents.
BACKGROUND OF THE INVENTION
Taxanes are diterpene compounds which find utility in the pharmaceutical field. For example, taxanes containing aryl heterocyclic or cycloalkyl groups on the C-13 sidechain find utility as anti-cancer agents. Taxanes include pacltitaxel, cephalomannine, taxol c, 10-deacetylpaclitaxel, 10-deacetylcephalomannine, 7-&bgr;-xylosylpaclitaxel, baccatin-III, 10-deacetylbaccatin III, 7-&bgr;-xylosyl-10-deacetyl cephalomannine, 7-&bgr;-xylosyl-10-deacetylbaccatin III, 7-&bgr;-xylosylbaccatin III, and 10-deacetyl-taxol c.
Paclitaxel (Taxol), a diterpene taxane compound, is a natural product extracted from the bark of the Pacific yew tree, Taxus Brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis during the cell cycle. Taxol has recently been approved for the treatment of refractory advanced ovarian cancer, breast cancer, non-small cell lung cancer, and most recently, AIDS-related Kaposi's Sarcoma. The results of paclitaxel clinical studies are replete in scientific periodicals and have been reviewed by numerous authors, such as Rowinsky and Donehower in “The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics”,
Phamac. Ther
., 52, pp. 35-84 (1991); Spencer and Faulds, Paclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer,
Drugs
, 48 (5), pp. 794-847 (1994); K. C. Nicolau et al., Chemistry and Biology of Taxol,
Angew. Chem., Int. Ed. Eng
., 33, pp. 15-44 (1994); F. A. Holmes, A. P. Kudelka, J. J. Kavanaugh, M. H. Huber, J. A. Ajani, and V. Valero, “Taxane Anticancer Agents—Basic Science and Current Status”, edited by Gunda I. Georg, Thomas C. Chen, lwao Ojima, and Dolotrai M. Vyas, pp. 31-57 American Chemical Society, Wash., D.C. (1995); Susan G. Arbuck and Barbara Blaylock, “Taxol( Science and Applications”, edited by Matthew Suffness, pp. 379-416, CRC Press, Boca Raton, Fla. (1995) and the references cited therein.
The structure of Taxol® is shown below along with the conventional numbering system for molecules belonging to the Taxane class; such numbering system is also employed in this application.
With reference to the numbering of the taxane, reference to a particular carbon on the taxane structure shall be indicated throughout this application by a “C-number”, which signifies the carbon on the taxane according to the above numbering system. For example, “C-13” refers to the carbon at position 13 on the taxane ring as shown above, having a sidechain coupled thereto.
The central backbone structural unit of paclitaxel is baccatin III, a diterpenoid having the chemical structure:
It is also very similar in structure to 10-deacetylbaccatin III (“10-DAB III”), which has the chemical structure:
but which lacks an acetate ester at the 10-position alcohol.
Chemical modification of the paclitaxel structure at C-4 and other positions has been explored by many groups to determine structure/activity relationships and to try to obtain compounds with superior efficacy to taxol to develop as second generation drugs. See U.S. Pat. No. 5,773,461; Gunda I. George, Syed M. Ali, Thomas C. Boge, Apurba Datta, and Lise Falborg, “Selective C-2 and C-4 Deacylation of Taxol: The First Synthesis of a C-4 Substituted Taxol Analogue”,
Tetrahedron Let
., 35:48, pp. 8931-8934 (1994); Shu-Hui Chen, John F. Kadow, Vittorio Farina, Craig R. Fairchild and Kathy A. Johnston, “First Synthesis of Novel Paclitaxel (Taxol) Analogs Modified at the C-4 Position”,
J. Org. Chem
. 59, pp. 6156-6158 (1994); S. Py, and F. Khuong-Huu, “A Novel Rearrangement of The Taxane Skeleton”,
Bull. Soc. Chim. Fr
., 130, pp. 189-191 (1993).
Replacement of the C-4-acetyl group of paclitaxel with other substituents has lead to compounds with improved potency in activity assays (S. Chen et al., Biorganic and Medicinal Chemistry Letters, 5:2741-2748 (1995)). An enzyme capable of specifically removing the C-4-acetyl group from taxanes will be useful in the synthesis of C-4-modified paclitaxel analogs to provide starting material to allow incorporation of other groups at this position, for example C-4 butyrate esters, C-4 cyclobutyl esters, C-4 propyl esters, C-4 cyclopropyl esters and C-4 methyl and ethyl carbonates.
REFERENCES:
patent: 5516676 (1996-05-01), Hanson et al.
patent: 5547866 (1996-08-01), Durzan et al.
patent: 5739359 (1998-04-01), Kingston et al.
patent: 5773461 (1998-06-01), Wittman et al.
Chen, Tetrahedron Letters, vol. 37, No. 23, pp. 3935-3938, 1996.
Yuan et al, “Synthesis of 6&agr;-Hydroxypaclitaxel, the Major Human Metabolite of Paclitaxel”, Tetrahedron Letters, 29 (1998) 4967-4970.
Georg et al, “Selecective C-2 and C-4 Deacylation and Acylation of Taxol: The First Synthesis of a C-4 Substituted Taxol Analogue”, Tetrahedron Letters, vol. 35, No. 48, pp. 8931-8934, 1994.
Chen et al, “First Syntheses of Novel Paclitaxel (Taxol) Analogs Modified at the C4-Position”, J. Org. Chem. 1994, 59, 6156-6158.
Chen et al, “Synthesis and Biological Evaluation of C-13 Amide-Linked Paclitaxel (Taxol) Analogs”, J. Org. Chem. 1996, 61, 2065-2070.
Chen et al, “Novel C-4 Paclitaxel (Taxol®) Analogs: Potent Antitumor Agents”, Bioorganic & Medicinal Chemistry Letters, vol. 5, No. 22, pp. 2741-2746, 1995.
Samaranayake et al, “Modified Taxols, 8 Deacylation and Reacylation of Baccatin III”, Journal of Natural Products, vol. 56, No. 6, pp. 884-898, Jun. 1993.
Uoto et al, “A New Method to Modify the C-4 Position of 10-Deacetylbaccatin III”, Chem. Pharm. Bull. 45(12) pp. 2093-2095 (1997).
Kim et al, “Migration Between C-2 and C-4 Hydroxyl Groups in Paclitaxel Core”, Korean J. of Med. Chem., vol. 7, No. 1, 1997.
Py et al, “A novel rearrangement of the taxane skeleton”, Bull.Soc. Chim. Fr. (1993) 130, 189-191.
Hanson Ronald L.
Patel Ramesh N.
Lilling Herbert J.
Lopez Gabriel
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