paclitaxel, with rings labeled and accepted numbering scheme shown. by 1992, at least thirty academic research teams globally were working to achieve a total synthesis of this natural product, with the synthesis proceeding from simple natural products and other readily available starting materials. this total synthesis effort was motivated primarily by the desire to generate new chemical understanding, rather than with an expectation of the practical commercial production of paclitaxel. the first laboratories to complete the total synthesis from much less complex starting materials were the research groups of robert a. holton, who had the first article to be accepted for publication, and of k. c. nicolaou who had the first article to appear in print (by a week, on 7 february 1994). though the holton submission preceded the nicolaou by a month (21 december 1993 versus 24 january 1994), the near coincidence of the publications arising from each of these massive, multiyear efforts—11–18 authors appearing on each of the february 1994 publications—has led the ending of the race to be termed a "tie" or a "photo finish", though each group has argued that their synthetic strategy and tactics were superior. as of 2006, five additional research groups had reported successful total syntheses of paclitaxel: wender et al. in 1997, and kuwajima et al. and mukaiyama et al. in 1998 with further linear syntheses, and danishefsky et al. in 1996 and takahashi et al. in 2006 with further convergent syntheses. as of that date, all strategies had aimed to prepare a 10-deacetylbaccatin-type core containing the abcd ring system, followed generally by last stage addition of the "tail" to the 13-hydroxyl group. while the "political climate surrounding and in the early 1990s ... helped bolster link between total synthesis and the supply problem," and though total synthesis activities were a requisite to explore the structure-activity relationships of paclitaxel via generation of analogs for testing, the total synthesis efforts were never seen "as a serious commercial route" to provide significant quantities of the natural product for medical testing or therapeutic use. history the discovery of paclitaxel began in 1962 as a result of a nci-funded screening program. a number of years later it was isolated from the bark of the pacific yew, taxus brevifolia, hence its name "taxol". the discovery was made by monroe e. wall and mansukh c. wani at the research triangle institute, research triangle park, north carolina, in 1971. these scientists isolated the natural product from the bark of the pacific yew tree, determined its structure and named it "taxol", and arranged for its first biological testing. the compound was then developed commercially by bms, who had the generic name assigned as "paclitaxel". plant screening program in 1955, the nci in the united states set up the cancer chemotherapy national service center (ccnsc) to act as a public screening center for anticancer activity in compounds submitted by external institutions and companies. although the majority of compounds screened were of synthetic origin, one chemist, jonathan hartwell, who was employed there from 1958 onwards, had experience with natural product derived compounds, and began a plant screening operation. after some years of informal arrangements, in july 1960, the nci commissioned the united states department of agriculture (usda) botanists to collect samples from about 1,000 plant species per year. on 21 august 1962, one of those botanists, arthur s. barclay, collected bark from a single pacific yew tree in a forest north of the town of packwood, washington, as part of a four-month trip to collect material from over 200 different species. the material was then processed by a number of specialist ccnsc subcontractors, and one of the tree's samples was found to be cytotoxic in a cellular assay on 22 may 1964. accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by monroe e. wall in research triangle park, north carolina, began work on fresh taxus samples, isolating the active ingredient in september 1966 and announcing their findings at an april 1967 american chemical society meeting in miami beach. they named the pure compound taxol in june 1967. wall and his colleague wani published their results, including the chemical structure, in 1971. the nci continued to commission work to collect more taxus bark and to isolate increasing quantities of taxol. by 1969, 28 kg (62 lb) of crude extract had been isolated from almost 1,200 kg (2,600 lb) of bark, although this ultimately yielded only 10 g (0.35 oz) of pure material, but for several years, no use was made of the compound by the nci. in 1975, it was shown to be active in another in vitro system; two years later, a new department head reviewed the data and finally recommended taxol be moved on to the next stage in the discovery process. this required increasing quantities of purified taxol, up to 600 g (21 oz), and in 1977 a further request for 7,000 lb (3,200 kg) of bark was made. in 1978, two nci researchers published a report showing taxol was mildly effective in leukaemic mice. in november 1978, taxol was shown to be effective in xenograft studies. meanwhile, taxol began to be well known in the cell biology, as well as the cancer community, with a publication in early 1979 by susan b. horwitz, a molecular pharmacologist at albert einstein college of medicine, showing taxol had a previously unknown mechanism of action involving the stabilization of microtubules. together with formulation problems, this increased interest from researchers meant that, by 1980, the nci envisaged needing to collect 20,000 lb (9,100 kg) of bark. animal toxicology studies were complete by june 1982, and in november nci applied for the ind necessary to begin clinical trials in humans. early clinical trials, supply and the transfer to bms phase i clinical trials began in april 1984, and the decision to start phase ii trials was made a year later. these larger trials needed more bark and collection of a further 12,000 pounds was commissioned, which enabled some phase ii trials to begin by the end of 1986. but by then it was recognized that the demand for taxol might be substantial and that more than 60,000 pounds of bark might be needed as a minimum. this unprecedentedly large amount brought ecological concerns about the impact on yew populations into focus for the first time, as local politicians and foresters expressed unease at the program. the first public report from a phase ii trial in may 1988 showed promising effects in melanoma and refractory ovarian cancer. at this point, gordon cragg of the nci's natural product branch calculated the synthesis of enough taxol to treat all the ovarian cancer and melanoma cases in the us would require the destruction of 360,000 trees annually. for the first time, serious consideration was given to the problem of supply. because of the practical and, in particular, the financial scale of the program needed, the nci decided to seek association with a pharmaceutical company, and in august 1989, it published a cooperative research and development agreement (crada) offering its current stock and supply from current bark stocks, and proprietary access to the data so far collected, to a company willing to commit to providing the funds to collect further raw material, isolate taxol, and fund a large proportion of clinical trials. in the words of goodman and welsh, authors of a substantial scholarly book on taxol, "the nci was thinking, not of collaboration, ... but of a hand-over of taxol (and its problems)". although the offer was widely advertised, only four companies responded to the crada, including the american firm bristol-myers squibb (bms), which was selected as the partner in december 1989. the choice of bms later became controversial and was the subject of congressional hearings in 1991 and 1992. while it seems clear the nci had little choice but to seek a commercial partner, there was also controversy about the terms of the deal, eventually leading to a report by the general accounting office in 2003, which concluded the nih had failed to ensure value for money. in related cradas with the usda and department of the interior, bristol-myers squibb was given exclusive first refusal on all federal supplies of taxus brevifolia. this exclusive contract lead to some criticism for giving bms a "cancer monopoly". eighteen months after the crada, bms filed a new drug application (nda), which was given fda approval at the very end of 1992. although there was no patent on the compound, the provisions of the waxman-hatch act gave bristol-myers squibb five years exclusive marketing rights. in 1990, bms applied to trademark the name taxol as taxol(r). this was controversially approved in 1992. at the same time, paclitaxel replaced taxol as the generic (inn) name of the compound. critics, including the journal nature, argued the name taxol had been used for more than two decades and in more than 600 scientific articles and suggested the trademark should not have been awarded and the bms should renounce its rights to it. bms argued changing the name would cause confusion among oncologists and possibly endanger the health of patients. bms has continued to defend its rights to the name in the courts. bms has also been criticized for misrepresentation by goodman and walsh, who quote from a company report saying "it was not until 1971 that ... testing ... enabled the isolation of paclitaxel, initially described as 'compound 17". this quote is, strictly speaking, accurate: the objection seems to be that this misleadingly neglects to explain that it was the scientist doing the isolation who named the compound taxol and it was not referred to in any other way for more than twenty years. annual sales peaked in 2000, reaching us$1.6 billion; paclitaxel is now available in generic form. society and culture as of 2006, the cost to the nhs per patient in early breast cancer, assuming four cycles of treatment, was about £4,000 (approx. $6,000). research caffeine has been speculated to inhibit paclitaxel-induced apoptosis in colorectal cancer cells. aside from its direct clinical use, paclitaxel is used extensively in biological and biomedical research as a microtubule stabilizer. in general, in vitro assays involving microtubules, such as motility assays, rely on paclitaxel to maintain microtubule integrity in the absence of the various nucleating factors and other stabilizing elements found in the cell. for example, it is used for in vitro tests of drugs that aim to alter the behavior of microtubule motor proteins, or for studies of mutant motor proteins. moreover, paclitaxel has been used in vitro to inhibit insulin fibrillation; in a molar ratio of 10:1 (insulin:paclitaxel), it hindered insulin fibrillation near 70%. iso-thermal titration calorimetry (itc) findings indicated a spontaneous tendency of paclitaxel to interact with insulin through hydrogen bonds and van der waal's forces. also, the inhibitory role of paclitaxel is attributed to its impact on the colloidal stability of protein solution, as it was observed that paclitaxel inhibited lysozyme fibrillation by inducing the formation of "off-pathway" oligomeric intermediates and increasing the colloidal stability subsequently. paclitaxel is sometimes used for in vivo studies as well; it can be fed to test organisms, such as fruit flies, or injected into individual cells, to inhibit microtubule disassembly or to increase the number of microtubules in the cell. paclitaxel induces remyelination in a demyelinating mouse in vivo and inhibits hpad2 in vitro though its methyl ester side chain. angiotech pharmaceuticals inc. began phase ii clinical trials in 1999 as a multiple sclerosis treatment but in 2002, reported that the results showed no statistical significance. in 2016 in vitro multi-drug resistant mouse tumor cells were treated with paclitaxel encased in exosomes. doses 98% less than common dosing had the same effect. also, dye-marked exosomes were able to mark tumor cells, potentially aiding in diagnosis. additional images space-filling model of paclitaxel rotating paclitaxel molecule model crystal structure of paclitaxel total charge surface of taxol. minimum energy conformation.