Methods for obtaining taxanes

Details Methods for obtaining taxanes Methods for obtaining taxanes

2001-07-06

2003-10-28

Prats, Francisco (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,...

C435S118000, C435S132000, C435S147000, C435S155000, C435S171000, C435S252100, C435S254100, C435S911000, C549S510000, C549S511000

Reexamination Certificate

active

06638742

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed generally to methods for obtaining paclitaxel and other important taxanes from novel plant sources of taxanes. The present invention is also directed to methods for obtaining paclitaxel and other taxanes by culturing fungal endophytes of these novel sources.
BACKGROUND OF THE INVENTION
Paclitaxel is the active ingredient in the anticancer drug TAXOL® (“taxol”) marketed by Bristol Myers Squibb. Taxol has been approved for treatment of ovarian and breast cancers, Kaposi's sarcoma, and non-small-cell lung cancer. It is also in clinical trial for treatment of several other cancers in combination with other chemotherapeutic agents. Several other uses for paclitaxel have been identified, including possible treatments for psoriasis, polycystic kidney disease, multiple sclerosis, and Alzheimer's disease. With the increasing number of uses, the need for new sources of paclitaxel is becoming ever more apparent.
Paclitaxel is a complex diterpenoid compound originally extracted from the bark of the Pacific yew tree,
Taxus brevifolia
. A number of related compounds, collectively known as “taxanes,”are also found in the yew extract. Paclitaxel is currently obtained from various species of yew or is made by partial synthesis from other taxanes also obtained from yew. Taxanes other than paclitaxel are therefore of interest for medicinal use. The chemical structures of six taxanes are shown in FIG.
1
.
Yields of taxanes from yew are generally quite small (on the order of milligrams per kilogram of dried plant material). At the present time, there may be enough paclitaxel for FDA-approved uses in chemotherapy. As the numerous clinical trials involving this compound draw to a close, however, it is clear that demand for paclitaxel will increase. Accordingly, it is important to identify alternative sources for this compound.
Laboratory (chemical) synthesis of paclitaxel has been reported from groups led by Holton, Nicoloau, Wender, and Danis hefsky and in patent references directed to chemical synthesis of paclitaxel and other taxanes, or to taxane precursors of paclitaxel:
U.S. Pat. No. 4,468,458 to Sato et al. entitled Two-Functional-Group Terpenoids, Preparation, and Anti-Ulcer Agents.
U.S. Pat. No. 4,814,470 to Colin et al. entitled Taxol Derivatives, Their Preparation, and Pharmaceutical Compositions.
U.S. Pat. No. 4,857,653 to Colin et al. entitled Process for the Preparation of Taxol and 10-Deacetyltaxol.
U.S. Pat. No. 4,924,011 to Denis et al. entitled Process for Preparing Taxol.
U.S. Pat. No. 4,960,790 to Stella et al. entitled Derivatives of Taxol, Pharmaceutical Compositions, and Preparation.
U.S. Pat. No. 5,202,448 to Carver et al. entitled Processes of Converting Taxanes Into Baccatin III.
U.S. Pat. No. 5,232,684 to Blumberg et al. entitled Labeled Resiniferatoxin, Compositions Thereof, and Methods for Using.
U.S. Pat. No. 5,243,045 to Holton et al. entitled Certain Alkoxy Substituted Taxanes and Pharmaceutical Compositions.
Another reference, U.S. Pat. No. 6,043,072 to Croteau et al. entitled Nucleic Acids Encoding Taxus Geranylgeranyl Diphosphate Synthase, claims a nucleic acid sequence and genetic technology for creating nucleic acid sequences that code for taxanes. Many of these syntheses, however, are too complex and costly for commercial use. Accordingly, these syntheses are not a practical method for supplying enough of the drug for all patients. Other references claim cancer treatment methods using taxanes:
U.S. Pat. No. 4,206,221 to Miller et al. entitled Cephalomannine and Its Use in Treating Leukemic Tumors.
U.S. Pat. No. 4,942,184 to Haugwitz et al. entitled Water-Soluble, Antineoplastic Derivatives of Taxol.
U.S. Pat. No. 5,958,741 to Stierle et al. entitled Taxol Production by a Microbe.
Twelve references claim methods for recovering taxanes from plant tissue or from microorganisms obtained from plant tissue:
U.S. Pat. No. 5,019,504 to Christen et al. entitled Production of Taxol or Taxol-like Compounds in Cell Culture.
U.S. Pat. No. 5,322,779 to Strobel et al. entitled Taxol Production by Taxomyces Andreanae.
U.S. Pat. No. 5,445,809 to Strobel et al. entitled Production of Taxol From the Yew Tree.
U.S. Pat. No. 5,451,392 to Strobel et al. entitled Production of Taxol.
U.S. Pat. No. 5,670,663 to Durzan et al. entitled Recovery of Taxanes From Conifers.
U.S. Pat. No. 5,861,302 to Stierle et al. entitled Taxol Production by a Microbe.
U.S. Pat. No. 5,908,759 to Stierle et al. entitled Taxol Production by a Microbe.
U.S. Pat. No. 5,916,783 to Stierle et al. entitled Taxol Production by a Microbe.
U.S. Pat. No. 5,981,777 to Durzan et al. entitled Recovery of Taxanes From Plant Material.
U.S. Pat. No. 6,013,493 to Stierle et al. entitled Taxol Production by a Microbe.
U.S. Pat. No. 6,030,818 to Pagé et al. entitled Bacterial Mass-Production of Taxanes.
U.S. Pat. No. 6,066,748 to Han et al. entitled Process of Extracting TAXOL® From Taxus Cuspidata.
Researchers such as Strobel, Stierle, Han, and Pagé have shown that several of the bacteria and fungi native to yew trees are capable of making paclitaxel and suggest that fungal cultures may be a viable alternative source for paclitaxel. A number of other bioreactive compounds have also been obtained from plant endophytes isolated from yew and related species.
The following references describe generally the work done by Drs. Strobel and Stierle and their colleagues, which was limited to plants (yew trees) within the genus Taxus:
Stierle, A., G. Strobel, D. Stierle (1993) Taxol and taxane production by
Taxomyces andreanae
, an endophytic fungus of Pacific Yew.
Science
260:214-216.
Strobel, G., X. Yang, J. Sears, R. Kramer, R. S. Sidhu, W. M. Hess (1996) Taxol from
Pestalotiopsis microspora
, an endophytic fungus of
Taxus wallachiana. Microbiology
142:435-440.
Stierle, A., D. Stierle, G. Strobel, G. Bignami, P. Grothaus (1995) Bioactive metabolites of the endophytic fungi of pacific yew,
Taxus brevifolia
: paclitaxel, taxanes, and other bioactive compounds. In:
Taxane Anticancer Agents: Basic Science and Current Status
. G. I. Georg, T. T. Chen, I. Ojima, D. M. Vyas, eds. ACS Symposium Series 583, Wash. D.C., pp. 81-97.
U.S. Pat. No. 5,451,392 to Strobel et al. entitled Production of Taxol.
U.S. Pat. No. 5,445,809 to Strobel et al. entitled Production of Taxol From the Yew Tree.
U.S. Pat. No. 5,322,779 to Strobel et al. entitled Taxol Production by
Taxomyces Adreanae.
U.S. Pat. No. 6,013,493 to Stierle et al. entitled Taxol Production by a Microbe.
U.S. Pat. No. 5,958,741 to Stierle et al. entitled Taxol Production by a Microbe.
U.S. Pat. No. 5,916,783 to Stierle et al. entitled Taxol Production by a Microbe.
U.S. Pat. No. 5,908,759 to Stierle et al. entitled Taxol Production by a Microbe.
U.S. Pat. No. 5,861,302 to Stierle et al. entitled Taxol Production by a Microbe.
Other researchers, such as Don J. Durzan and Frank Ventimiglia, discovered taxane-producing plants outside of the genus Taxus but still within the botanical order containing the genus Taxus. U.S. Pat. No. 5,670,663 to Durzan et al. (the “Durzan reference”) is directed to recovery of taxanes from conifers. The Durzan reference is significant for broadening the state of the art with regard to plant species from which taxanes may be obtained. Before the work of Durzan et al., it was thought that taxanes could be obtained only from plants of the genus Taxus. The Durzan reference suggested that taxane-producing plants are limited to gymnosperms of the order of conifers, including the genus Taxus. Neither the work of Strobel and Stierle et al. nor the work of Durzan et al. suggests that taxanes could ever be discovered in angiosperms or in other gymnosperms.
Background information on the inventor's work may be found in the following publication coauthored by the inventor:
Hoffman, A., W. Khan, J. Worapong, G. Strobel, D. Griffen, B. Arbogast, D. Barofsky, R. B. Boone, L. Ning, P. Zheng, L. Daley (1998) Bioprospecting for Taxol in angiosperm plant extracts: Using high performance liquid ch

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