paclitaxel paclitaxel paclitaxel (ptx), sold under the brand name taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, kaposi's sarcoma, cervical cancer, and pancreatic cancer. it is administered by intravenous injection. there is also an albumin-bound formulation. paclitaxelclinical datatrade namestaxol, othersahfs/drugs.commonographmedlineplusa607070license data eu ema: by inn us dailymed: paclitaxel pregnancycategory au: d routes ofadministrationintravenous (iv)atc codel01 l01cd03 (who) (paclitaxel poliglumex)legal statuslegal status au: s4 (prescription only) ca: ℞-only uk: pom (prescription only) us: ℞-only eu: rx-only pharmacokinetic databioavailability6.5% (by mouth)protein binding89 to 98%metabolismliver (cyp2c8 and cyp3a4)elimination half-life5.8 hoursexcretionfecal and urinaryidentifiers iupac name (2α,4α,5β,7β,10β,13α)-4,10-bis(acetyloxy)-13--1,7-dihydroxy-9-oxo-5,20-epoxytax-11-en-2-yl benzoate cas number33069-62-4 ypubchem cid36314iuphar/bps2770drugbankdb01229 ychemspider10368587 yuniip88xt4is4dkeggd00491 ychebichebi:45863 ychemblchembl428647 npdb ligandta1 (pdbe, rcsb pdb)comptox dashboard (epa)dtxsid9023413 echa infocard100.127.725 chemical and physical dataformulac47h51no14molar mass853.918 g·mol−13d model (jsmol)interactive image smiles cc1=c2(((34((oc4)c(3(c(=o)2oc(=o)c)c)o)oc(=o)c)oc(=o)c5ccccc5)(c1oc(=o)(o)(nc(=o)c6ccccc6)c7ccccc7)o)(c)c inchi inchi=1s/c47h51no14/c1-25-31(60-43(56)36(52)35(28-16-10-7-11-17-28)48-41(54)29-18-12-8-13-19-29)23-47(57)40(61-42(55)30-20-14-9-15-21-30)38-45(6,32(51)22-33-46(38,24-58-33)62-27(3)50)39(53)37(59-26(2)49)34(25)44(47,4)5/h7-21,31-33,35-38,40,51-52,57h,22-24h2,1-6h3,(h,48,54)/t31-,32-,33+,35-,36+,37+,38-,40-,45+,46-,47+/m0/s1 ykey:rciniconznjxqf-mzxodvadsa-n y ny (what is this?) (verify) common side effects include hair loss, bone marrow suppression, numbness, allergic reactions, muscle pains, and diarrhea. other side effects include heart problems, increased risk of infection, and lung inflammation. there are concerns that use during pregnancy may cause birth defects. paclitaxel is in the taxane family of medications. it works by interference with the normal function of microtubules during cell division. paclitaxel was isolated in 1971 from the pacific yew and approved for medical use in 1993. it is on the world health organization's list of essential medicines. it has been made from precursors, and more recently through cell culture. medical use paclitaxel is approved in the uk for ovarian, breast, lung, bladder, prostate, melanoma, esophageal, and other types of solid tumor cancers as well as kaposi's sarcoma. it is recommended in national institute for health and care excellence (nice) guidance of june 2001 for non-small-cell lung cancer in patients unsuitable for curative treatment, and in first-line and second-line treatment of ovarian cancer. in september 2001, nice recommended paclitaxel for the treatment of advanced breast cancer after the failure of anthracyclic chemotherapy, but that its first-line use should be limited to clinical trials. in september 2006, nice recommended paclitaxel should not be used in the adjuvant treatment of early node-positive breast cancer. as of 2018, it is approved in the united states for the treatment of breast, pancreatic, ovarian, kaposi's sarcoma and non-small-cell lung cancers. similar compounds further information: protein-bound paclitaxel and docetaxel albumin-bound paclitaxel (trade name abraxane, also called nab-paclitaxel) is an alternative formulation where paclitaxel is bound to albumin nanoparticles. much of the clinical toxicity of paclitaxel is associated with the solvent cremophor el in which it is dissolved for delivery. abraxis bioscience developed abraxane, in which paclitaxel is bonded to albumin as an alternative delivery agent to the often toxic solvent delivery method. this was approved by the fda in january 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. it has since been approved for locally advanced or metastatic non-small cell lung cancer and metastatic adenocarcinoma of the pancreas as well. synthetic approaches to paclitaxel production led to the development of docetaxel. docetaxel has a similar set of clinical uses to paclitaxel, and it is marketed under the brand name taxotere. taxanes, including paclitaxel, 10-deacetylbaccatin iii, baccatin iii, paclitaxel c, and 7-epipaclitaxel, have been found in the leaves and shells of hazel. the finding of these compounds in shells, which are considered discarded material and are mass-produced by many food industries, is of interest for the future availability of paclitaxel. restenosis paclitaxel is used as an antiproliferative agent for the prevention of restenosis (recurrent narrowing) of coronary and peripheral stents; locally delivered to the wall of the artery, a paclitaxel coating limits the growth of neointima (scar tissue) within stents. paclitaxel drug-eluting stents for coronary artery placement are sold under the trade name taxus by boston scientific in the united states. paclitaxel drug-eluting stents for femoropopliteal artery placement are also available. side effects common side effects include nausea and vomiting, loss of appetite, change in taste, thinned or brittle hair, pain in the joints of the arms or legs lasting two to three days, changes in the color of the nails, and tingling in the hands or toes. more serious side effects such as unusual bruising or bleeding, pain, redness or swelling at the injection site, hand-foot syndrome, change in normal bowel habits for more than two days, fever, chills, cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe exhaustion, skin rash, facial flushing, female infertility by ovarian damage, and chest pain can also occur. neuropathy may also occur. dexamethasone is given prior to paclitaxel infusion to mitigate some of the side effects. a number of these side effects are associated with the excipient used, cremophor el, a polyoxyethylated castor oil. allergies to cyclosporine, teniposide, and other drugs delivered in polyoxyethylated castor oil may increase the risk of adverse reactions to paclitaxel. mechanism of action complex of α, β tubulin subunits and paclitaxel. paclitaxel is shown as yellow stick. paclitaxel is one of several cytoskeletal drugs that target tubulin. paclitaxel-treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division. unlike other tubulin-targeting drugs, such as colchicine, that inhibit microtubule assembly, paclitaxel stabilizes the microtubule polymer and protects it from disassembly. chromosomes are thus unable to achieve a metaphase spindle configuration. this blocks the progression of mitosis and prolonged activation of the mitotic checkpoint triggers apoptosis or reversion to the g0-phase of the cell cycle without cell division. the ability of paclitaxel to inhibit spindle function is generally attributed to its suppression of microtubule dynamics, but other studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. at the higher therapeutic concentrations, paclitaxel appears to suppress microtubule detachment from centrosomes, a process normally activated during mitosis. paclitaxel binds to the beta-tubulin subunits of microtubules. chemistry the nomenclature for paclitaxel is structured on a tetracyclic 17-atom skeleton. there are a total of 11 stereocenters. the active stereoisomer is (−)-paclitaxel (shown here). position numberingabsolute stereochemistry(1s,2s,3r,4s,7r,9s,10s,12r,15s)-4,12-diacetoxy-15--1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracycloheptadec-13-en-2-yl rel-benzoate production undisturbed pacific yew bark contains paclitaxel and related chemicals. bark processing the bark is peeled and processed to provide paclitaxel. from 1967 to 1993, almost all paclitaxel produced was derived from bark of the pacific yew, taxus brevifolia, the harvesting of which kills the tree in the process. the processes used were descendants of the original isolation method of monroe wall and mansukh wani; by 1987, the u.s. national cancer institute (nci) had contracted hauser chemical research of boulder, colorado, to handle bark on the scale needed for phase ii and iii trials. while both the size of the wild population of the pacific yew and the magnitude of the eventual demand for paclitaxel were uncertain, it was clear that an alternative, sustainable source of the natural product would be needed. initial attempts to broaden its sourcing used needles from the tree, or material from other related taxus species, including cultivated ones, but these attempts were challenged by the relatively low and often highly variable yields obtained. early in the 1990s, coincident with increased sensitivity to the ecology of the forests of the pacific northwest, paclitaxel was successfully extracted on a clinically useful scale from these sources. semisynthesis concurrently, synthetic chemists in the u.s. and france had been interested in paclitaxel, beginning in the late 1970s. 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. 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. the view of the nci, however, was that even this route was not practical. 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. florida state university, where holton worked, signed a deal with bristol-myers squibb (bms) to license their semisynthesis and future patents. 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. 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. 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. as of 2013, bms was using the semisynthetic method utilizing needles from the european yew to produce paclitaxel. another company which worked with bms until 2012, phyton biotech, inc., uses plant cell fermentation (pcf) technology. by cultivating a specific taxus cell line in fermentation tanks, they no longer need ongoing sourcing of material from actual yew tree plantations. 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. compared to the semisynthesis method, pcf eliminates the need for many hazardous chemicals and saves a considerable amount of energy. in 1993, paclitaxel was discovered as a natural product in a newly described endophytic fungus living in the yew tree. it has since been reported in a number of other endophytic fungi, including nodulisporium sylviforme, 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., pestalotiopsis versicolor, and taxomyces andreanae. however, there has been contradictory evidence for its production by endophytes, with other studies finding independent production is unlikely. biosynthesis biosynthesis of taxol taxol is a tetracyclic diterpene, and the biosynthesis of diterpenes starts with an fpp molecule being elongated by the addition of an ipp molecule in order to form geranylgeranyl diphosphate (ggpp). the biosynthesis of taxol contains nineteen steps. these 19 steps can be considered in several steps, with the first step being the formation of the taxane skeleton, which then undergoes a series of oxygenations. following the oxygenations, two acetylations and a benzoylation occur on the intermediate. the oxygenation of the taxane core is believed to occur on c5 and c10, c2 and c9, c13 followed by c7, and a c1 hydroxylation later on in the pathway. later in the pathway, an oxidation at c9 forms a ketone functional group and an oxetane, forming the intermediate baccatin iii. the final steps of the pathway include the formation of a c13-side chain which is attached to baccatin iii. the biosynthesis of taxol is illustrated in more detail in the figure, with steps 1-7 all occurring in the enzyme taxadiene synthase (ts on the figure). taxol's biosynthesis begins with e,e,e-ggpp losing pyrophosphate via an sn1 mechanism (step 1 in the figure). the double-bond attacks the cation via electrophilic addition, yielding a tertiary cation and creating the first ring closure (step 2). another electrophilic attack occurs, further cyclizing the structure by creating the first 6-membered ring and creating another tertiary cation (step 3). an intramolecular proton transfer occurs, attacking the verticillyl cation (step 4) and creating a double bond, yielding a tertiary cation. an electrophilic cyclization occurs in step 5, and an intramolecular proton transfer attacks the taxenyl cation (step 6). this forms the fused ring structure intermediate known as taxadiene. taxadiene then undergoes a series of 10 oxidations via nadph, forming the intermediate taxadiene-5α-acetoxy-10β-ol (multiple steps later in the figure). a series of hydroxylations and esterficiations occur, forming the intermediate 10-deacetyl-baccatin iii, which undergoes a further series of esterifications and a side-chain hydroxylation. this finally yields the product taxol. total synthesis