Editing Paclitaxel (section)

=== Semisynthesis ===
Concurrently, synthetic chemists in the U.S. and France had been interested in paclitaxel, beginning in the late 1970s.{{citation needed|date=June 2014}} As noted, by 1992 extensive efforts were underway to accomplish the [[total synthesis]] of paclitaxel, efforts motivated by the desire to generate new chemical understanding rather than to achieve practical commercial production. In contrast, the French group of [[Pierre Potier]] at the [[Centre national de la recherche scientifique]] (CNRS) addressed the matter of overall process yield, showing that it was feasible to isolate relatively large quantities of the compound [[10-deacetylbaccatin]] from the European yew, ''[[Taxus baccata]]'', which grew on the CNRS campus and whose needles were available in large quantity.{{citation needed|date=June 2014}}  By virtue of its structure, 10-deacetylbaccatin was seen as a viable starting material for a short [[semisynthesis]] to produce paclitaxel. By 1988, Poitier and collaborators had published a semisynthetic route from needles of the European yew to paclitaxel.{{sfn|Goodman|Walsh|2001|pp=100–1}}

The view of the NCI, however, was that even this route was not practical.{{citation needed|date=June 2014}} The group of [[Robert A. Holton]] had also pursued a practical semisynthetic production route; by late 1989, Holton's group had developed a semisynthetic route to paclitaxel with twice the yield of the Potier process.<ref>{{cite book | vauthors = Holton RA, Biediger RJ, Boatman PD | chapter = Semisynthesis of taxol and taxotere | veditors = Suffness M | title = Taxol: Science and Applications | date = 1999 | pages = 97–121 | location =  Boca Raton | publisher = CRC press | isbn = 978-0-13-873736-8 }}</ref>  The main innovation was "Ojima−Holton coupling", a ring-opening method independently discovered by Holton and Ojima.<ref name=Ojima2018>{{cite journal | vauthors = Ojima I, Wang X, Jing Y, Wang C | title = Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery | journal = Journal of Natural Products | volume = 81 | issue = 3 | pages = 703–721 | date = March 2018 | pmid = 29468872 | doi = 10.1021/acs.jnatprod.7b01012 | pmc = 5869464 | doi-access = free | bibcode = 2018JNAtP..81..703O }}</ref> [[Florida State University]], where Holton worked, signed a deal with [[Bristol-Myers Squibb]] (BMS) to license their semisynthesis and future patents.{{citation needed|date=June 2014}} In 1992, Holton patented an improved process with an 80% yield, and BMS took the process in-house and started to manufacture paclitaxel in Ireland from 10-deacetylbaccatin isolated from the needles of the European yew.{{citation needed|date=June 2014}} In early 1993, BMS announced that it would cease reliance on Pacific yew bark by the end of 1995, effectively terminating ecological controversy over its use.{{citation needed|date=June 2014}} This announcement also made good their commitment to develop an alternative supply route, made to the NCI in their [[cooperative research and development agreement]] (CRADA) application of 1989.{{cn|date=September 2024}}

As of 2013, BMS was using the semisynthetic method utilizing needles from the European yew to produce paclitaxel.<ref>{{cite web|url=http://wgcriticalcare.com/injectable-pharmaceuticals/wp-content/uploads/2014/01/WGCC-Paclitaxel-PI-June-2013.pdf|title=Paclitaxel Injection, USP|website=Injectable Pharmaceuticals|language=en-US|access-date=22 April 2016|url-status=dead|archive-url=https://web.archive.org/web/20160918114404/http://wgcriticalcare.com/injectable-pharmaceuticals/wp-content/uploads/2014/01/WGCC-Paclitaxel-PI-June-2013.pdf|archive-date=18 September 2016}}</ref> Another company which worked with BMS until 2012,<ref>{{cite web|url=http://www.phytonbiotech.com/history/|title=History|access-date=22 April 2016|url-status=live|archive-url=https://web.archive.org/web/20160524143938/http://www.phytonbiotech.com/history/|archive-date=24 May 2016}}</ref> Phyton Biotech, Inc., uses plant cell fermentation (PCF) technology.<ref>{{cite web|url=http://www.phytonbiotech.com/paclitaxel/|title=Phyton BioTech Paclitaxel|access-date=22 April 2016|url-status=live|archive-url=https://web.archive.org/web/20160807223136/http://www.phytonbiotech.com/paclitaxel/|archive-date=7 August 2016}}</ref> By cultivating a specific ''Taxus'' [[cell line]] in fermentation tanks, they no longer need ongoing sourcing of material from actual yew tree plantations.<ref>{{cite book|chapter=Suspension Culture of Plant Cells under Heterotrophic Conditions | vauthors = Imseng N, Schillberg S, Schürch C, Schmid D, Schütte K, Gorr G, Eibl D, Eibl R | date = 2014 | veditors = Meyer HP, Schmidhalter D |title=Industrial Scale Suspension Culture of Living Cells|publisher=Wiley-Blackwell |isbn=978-3-527-33547-3 |pages=224–257 }}</ref> Paclitaxel is then captured directly from the suspension broth by a resin allowing concentration to highly enriched powder containing about 40% paclitaxel. The compound is then purified by one [[chromatographic]] step followed by [[crystallization]].<ref>Gilbert Gorr and Roland Franke. Commercial Pharmaceutical Production of Complex APIs via Plant Cell Fermentation (PCF) Technology. Presentation at CPhI 2015, 13 Oct..</ref> Compared to the semisynthesis method, PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy.<ref name="2004_EPA_award">{{cite web|url=https://www.epa.gov/greenchemistry/presidential-green-chemistry-challenge-2004-greener-synthetic-pathways-award|title=2004 Greener Synthetic Pathways Award: Bristol-Myers Squibb Company: Development of a Green Synthesis for Taxol Manufacture via Plant Cell Fermentation and Extraction|url-status=live|archive-url=https://web.archive.org/web/20061002105234/http://www.epa.gov/greenchemistry/pubs/pgcc/winners/gspa04.html|archive-date=2 October 2006}}</ref>

In 1993, paclitaxel was discovered as a natural product in ''Taxomyces andreanae'', a newly described [[endophytic]] [[fungus]] living in the yew tree.<ref>{{cite journal | vauthors = Stierle A, Strobel G, Stierle D | title = Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew | journal = Science | volume = 260 | issue = 5105 | pages = 214–216 | date = April 1993 | pmid = 8097061 | doi = 10.1126/science.8097061 | bibcode = 1993Sci...260..214S }}</ref> It has since been reported in a number of other endophytic fungi, including ''Nodulisporium sylviforme'',{{citation needed|date=November 2019}} ''Alternaria taxi'', ''Cladosporium cladosporioides'' MD2, ''[[Metarhizium anisopliae]]'', ''Aspergillus candidus'' MD3, ''Mucor rouxianus'', ''Chaetomella raphigera'', ''Phyllosticta tabernaemontanae'', ''[[Phomopsis]]'', ''Pestalotiopsis pauciseta'', ''[[Phyllosticta citricarpa]]'', ''[[Podocarpus]]'' sp., ''[[Fusarium solani]]'', ''Pestalotiopsis terminaliae'', ''Pestalotiopsis breviseta'', ''Botryodiplodia theobromae'', ''Gliocladium'' sp., ''Alternaria alternata'' var. ''monosporus'', ''[[Cladosporium cladosporioides]]'', ''Nigrospora'' sp. and ''[[Pestalotiopsis versicolor]]''. However, there has been contradictory evidence for its production by endophytes, with other studies finding independent production is unlikely.<ref>{{cite journal | vauthors = Staniek A, Woerdenbag HJ, Kayser O | title = Taxomyces andreanae: a presumed paclitaxel producer demystified? | journal = Planta Medica | volume = 75 | issue = 15 | pages = 1561–1566 | date = December 2009 | pmid = 19809969 | doi = 10.1055/s-0029-1186181 | bibcode = 2009PlMed..75.1561S | s2cid = 260283080 }}</ref><ref>{{cite journal|doi=10.1007/s13225-013-0228-7|title=Getting to the bottom of taxol biosynthesis by fungi|year=2013|vauthors = Heinig U, Scholz S, Jennewein S|journal=Fungal Diversity|volume=60|pages=161–170|s2cid=18642421|url=https://link.springer.com/content/pdf/10.1007%2Fs13225-013-0228-7.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://link.springer.com/content/pdf/10.1007%2Fs13225-013-0228-7.pdf |archive-date=9 October 2022 |url-status=live|doi-access=free }}</ref>