A Green Method to Synthesize Taxol Developed by Bristol-Myers Squibb Company


by Olimpia Suciu
University of New Hampshire, Manchester
Organic Chemistry, Fall 2010
email: opb2@cisunix.unh.edu



Introduction


Bristol-Myers Squibb Company developed a green method for the synthesis of Taxol via Plant Cell Fermentation for which it was awarded the Presidential Green Chemistry Challenge Award in the U.S. in 2004.(5)

The active substance in Taxol (registered trademark of Bristol-Myers Squibb) is known as Paclitaxel. This is found in the bark of Pacific yew tree ( Taxus Brevifolia) and in the needles of English yew (Taxus Baccata) and other species of Taxus. Its unique mechanism of action makes this drug a a special tool in treating ovarian, lung, and breast cancer. (1,2)

Taxus_Brevifolia.jpg
Taxus Brevifolia needles and fruits

paclitaxel_structure.jpg
Paclitaxel chemical structure

Paclitaxel_2.jpg
Paclitaxel 3D structure











History


The 31-year Journey of Paclitaxel from Bark to the Most Important Cancer-Fighting Drug Lately Discovered


In the '60, scientists from National Cancer Institute ( NCI ) were convinced that the cure for cancer could be found somewhere in nature. Consequently, they launched a campaign to collect and test extracts from plants, animals, and even insects.(1)
1962
Barclay, a botanist working for US Department of agriculture, collected hundreds of samples of trees, shrubs, and weeds. Among them, he collected a piece of Pacific yew tree bark.(1)
1964
The chemist Wall found that the extract of Pacific yew tree had anti-tumor activity.(1)
1967
Wall and Wani identified the active ingredient in the bark. They wrote in a paper presented to the American Chemistry Society that the bark extract "exhibited an unusually broad spectrum of anti-tumor activity". The process of extracting the active substance Paclitaxel, from the bark had a low yield and for every 30 pounds of bark, Wall could barely produce half of gram of the active substance.(1)
1971
Wall finalized his work determining the structure of Paclitaxel.(1)
1977
Paclitaxel was approved by NCI to go into the phase of animal testing and formulation.The project was almost abandoned because Paclitaxel was found practically insoluble in water and in any other safe solution that could have been delivered intravenously. After one year of research, the NCI formulation team discovered that this stubborn substance was soluble in a special elixir made of castor oil.(1)
1979
Susan B Horwitz - a molecular pharmacologist published the results of her study about paclitaxel mechanism of action. Her conclusion was that Paclitaxel 's mechanism of action was different compared to other anti-tumor drugs. While the other anti-tumor drugs prevent microtubular polymerization, Paclitaxel acts differently, hyper-stabilizing these structures, in this way disrupting the mechanism of cell division.(1,2)
1980
NCI gives paclitaxel the geen light to move to the next stage: toxicological studies . In order to sustain this stage a huge amount of Pacific yew bark tree was needed. The environmental organizations protested against the killing of the trees because it was part of a sensitive ecosystem and it takes 200 years for a tree to mature.(1)
1983
Paclitaxel entered in phase one of clinical trials in humans.(7)
1985
The results of phase two clinical trials were very encouraging: 30% of patients with ovarian cancer were seeing tumors shrinking. The demand for drug increased. NCI estimated that if Paclitaxel was made available for all ovarian cancer patients in the U.S. that year, the NCI would have to come up with roughly 240 pounds of the drug. This would require approximately 360,000 trees.(1) The problem of supply became a serious issue.
1989
Holton - an organic chemist at Florida State University announced that he had found an economically viable semi-synthetic way to produce Paclitaxel from a closely related analog named baccatin III (10 DAB) found in the needles and twigs of the ubiquitous shrub Taxus baccata (English yew)(1,2)
The cost of sustaining Paclitaxel project was becoming too high and NCI signed a Cooperative Research and Development Agreement (CRADA) with BMS Company(1,7)
1990
Bristol-Myers Squibb and Florida State University signed a licensing agreement allowing BMS to use Holton's method of semi synthesis. The problem of supply was solved.(1,7)
The results from clinical trials shown a 48% tumor shrinkage in patients with metastatic breast cancer after they already experienced one prior chemotherapy regime.(8)
1993
BMS launched Taxol to the public as a treatment for ovarian cancer.(7)
1994
Holton and Nicolau teams announced almost simultaneously that they produced Paclitaxel by total synthesis (the method has a low product yields and is very expensive)(2,4)


Plant Cell Fermentation



References


1. Research in Review, A Tale of Taxol by Frank Stephenson, date retrieved Dec.2010, http://www.rinr.fsu.edu/fall2002/taxol.html
2. Taxol by Neil Edwards, date retrieved Dec. 2010, School of Chemistry University of Bristol http://www.bris.ac.uk/Depts/Chemistry/MOTM/taxol/taxol2.htm
3. Phyton Biotech http://www.phytonbiotech.com/
4. Plant Metabolic Engineering for Pharmaceutical Production by Susan C Roberts, date retrieved November 2010 http://www.metabolicengineering.gov/me2005/Roberts.pdf
5. Green Chemistry Resources Exchange, date retrieved Nov.2010 http://www.greenchemex.org/?module=resources.edit&id=9&fs=1
6. Paclitaxel production through plant cell culture: An exciting approach to harnessing biodiversity http://old.iupac.org/symposia/proceedings/phuket97/venkat.html
7.Chemical & Engineering News,Cover Story,Maximizing Returns,by Susan M Morrissey,Sept.15 2003,vol 81 number 37, http://pubs.acs.org/cen/coverstory/8137/8137taxol.html
8.Fighting Ovarian Cancer From the Forest.Date retrieved Dec.12.2010, http://www.botgard.ucla.edu/html/botanytextbooks/economicbotany/Taxus/