SCIENCE/TECHNOLOGY
Anticipated New Synthesis Of Taxol May Generate Beneficial Analogs • Improved route begins with glucose, involves construction of taxane skeleton, and likely will result in novel analogs Michael Freemantle, C&EN London
B
ritish organic chemist Paul Jenkins is optimistic that his group at Leicester University will soon be able to synthesize analogs of the anticancer compound taxol from glucose. Speaking last month at a meeting at Trinity College in Dublin, Ireland, he said that his research group "aims not only to develop an improved and efficient synthesis of taxol but also to generate unique taxol-like compounds that will show improved antitumor activity." Jenkins' group has already synthesized model taxoid structures by two different routes. Taxoid compounds, which include taxol, all have the taxane skeleton—a carbocyclic structure with three rings known as A, B, and C. Jenkins' synthetic pathways use a C-ring precursor and involve an intramolecular Diels-Alder strategy to construct the taxane structure. Jenkins, a senior lecturer in organic chemistry, hopes that his group's new route starting from glucose will generate novel taxane compounds, although, as he points out, the original aim of this approach was simply to synthesize taxol. The taxol molecule is chiral and has an oxetane ring, known as the D ring, together with various functional groups attached to the taxane skeleton. Scientists conclude that the secret of taxol's anticancer activity almost certainly lies in these functional groups. He and others working on taxol chemistry believe that analogs of the compound with other functional groups may well prove more beneficial as anticancer drugs than taxol itself. The Leicester researchers used a pro34
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tected glucose methyl ketone as a starting material for their synthesis. 'The compound is readily obtained from glucose and has a necklace of asymmetric centers," Jenkins notes. "Our route p r e serves the chirality of the glucose ring right through to the taxol molecule." The initial part of the group's strategy was to convert the sugar ring to the carbocyclic C ring of the taxol structure. In 1991, the researchers subjected the glucose derivative to annulation to produce a tricyclic enone. This was the first reported application of this annulation reaction to the synthesis of annulated sugars, according to Jenkins. Jenkins announced at the Dublin meeting that his group had recently taken the glucose-to-taxol synthesis an important stage further by constructing a taxoid C ring attached to a diene. "We now plan to construct dienophiles and then use the intramolecular DielsAlder reaction to produce the A and B rings of the taxoid structure," he says. The natural product taxol is clinically effective for the treatment of refractory human ovarian and breast cancer. It has been hailed as one of the most significant advances in cancer therapy. The taxol molecule promotes anticancer ac-
tivity by enhancing polymerization of tubulin and stabilization of microtubules. It is thus able to inhibit cell division. The drug was licensed in the U.S. by the Food & Drug Administration for the treatment of ovarian cancer in December 1992 and for the treatment of breast cancer earlier this year. In July 1993, Sweden became the first European country to approve its use, and then in October the European Union's Committee for Proprietary Medicinal Products recommended the licensing of taxol within the EU. Ingrid Hook, senior lecturer in pharmacognosy at Trinity College's school of pharmacy, tells C&EN, 'Taxol is only presently recommended for the treatment of those cases of ovarian and breast cancers that have failed to respond to other forms of treatment." She adds, though, that "taxol is currently being evaluated for the treatment of other cancers." Bristol-Myers Squibb produces the drug by extraction from the bark of the Pacific yew tree Taxus brevifolia. This type of yew is found in old-growth forests of the North American Pacific
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Jenkins (left): goal is taxol analogs with improved anticancer activity; Potier: semisynthesis from precursor
Northwest, the habitat of the endangered spotted owl. The bark of about three trees is needed to treat one patient. Unfortunately, these yews grow very slowly— about 8 inches per year—and so the trees can only be a limited source of taxol. The need to meet the growing demand for the drug without harvesting the Pacific yew tree has stimulated intense research activity to produce the compound by alternative processes. These include total or partial synthesis, leaf extractions, tissue culture, and cultivation. The first total syntheses of taxol were published independently by teams led by chemistry professors Robert A. Holton of Florida State University, Tallahassee, and K. C. Nicolaou of Scripps Research Institute, La Jolla, Calif., and the University of California, San Diego, in February (C&EN, Feb. 21, page 32). Holton adopted a linear approach to taxol synthesis starting from the inexpensive commodity chemical camphor. Nicolaou used a convergent route starting from the A and C rings. Other chemists are also working on the synthesis of taxol and particularly of analogs that may be more effective as anticancer drugs. For example, chemistry professor Paul A. Wender of Stanford University has synthesized a range of taxol analogs from pinene with the "right-handedness" of taxol. Wender predicted in 1989 that simpler analogs could be as effective as taxol. He tells C&EN that "deoxy analogs are now showing activity comparable with, and in some cases better than, lead clinical candidates such as taxol/' Wender's work includes a five-step synthesis of the tricyclic taxane core. He now aims to add functionalities to this core to produce taxol analogs and elucidate the molecular mode of action of taxol. "This is the holy grail in the field/' says Wender. "If we knew how taxol is doing what it is doing, we might be able to design simpler compounds that are superior in terms of their medicinal performance." Jenkins agrees. "The first synthesis of an important drug is rarely the best synthesis," he says. "Different synthetic routes can sometimes produce not only practical routes to the drug but also to unique and important analogs. The various routes for the total synthesis of taxol and its analogs are not commercial propositions at present. However, they are great monuments to the achievements of organic synthesis."
Jenkins' approach starts with glucose derivative Annulation OCHo
The Dublin meeting, which was organized by the Fine Chemicals & Medicinals Group of the Royal Society of Chemistry, concerned drugs from natural products and attracted nearly 200 scientists from around the world. Several other contributors, as well as Jenkins, focused on recent developments in taxol chemistry. Pierre Potier, director of the Institut de Chimie des Substances Naturelles of the Centre National de la Recherche Scientifique (CNRS), in Gif-sur-Yvette, France, spoke about the semisynthesis of the anticancer compound Taxotere, a patented taxol analog that has a textbutoxycarbonyl group instead of the benzoyl group on the taxol side chain and a hydroxyl group instead of the acetoxyl group on the taxol B ring (C&EN, Sept. 2,1991, page 13). Taxotere is synthesized from the precursor 10-deacetylbaccatin EI, which is isolated from the needles of the European yew tree Taxus baccata. Because the tree continues growing after the branches providing the needles have been harvested, this type of yew tree provides a renewable source of the precursor. According to Jean-Louis Fabre, project leader for Taxotere at drug producer Rhone-Poulenc Rorer, Phase III clinical trials (large-scale efficacy studies) of the drug are currently under way. He says that industrial-scale production of Taxotere has begun. Taxotere is currently not marketed in any country, although regulatory approvals by the relevant health authorities are pending. On May 25, Rhone-
Poulenc Rorer filed a new drug application in Japan with the Ministry of Health & Welfare's new drugs division. A worldwide filing for registration in key tumor types such as breast and lung cancer is expected to be made later this year. Taxotere is considered to have certain advantages over taxol. First, it is easier to administer to cancer patients because it is more soluble in water. It has a shorter infusion time, requires no in-line filter, and can be used with standard plastic equipment. Taxotere also appears to be more potent than taxol against a variety of murine solid tumors. A recent Phase II study reported the highest antitumor activity ever for patients with advanced breast cancer. Taxol can also be synthesized from 10-deacetylbaccatin III. Bristol-Myers Squibb now plans to manufacture taxol from this precursor as soon as it receives approval from FDA. The company intends to phase out production of taxol extracted from Pacific yew tree bark by the end of this year. Trinity's Hook and research student Jacintha Griffin have been able to extract significant amounts of taxol from the needles and stems of the Irish yew (Taxus baccata var. fastigiata). They ob-
tained a percentage yield comparable with that obtained from the Pacific yew. Their work was outlined in a poster presented at the Dublin meeting. A team including Hook and Potier has recently received European funding for a project to investigate growing the Irish yew commercially. • AUGUST 1, 1994 C&EN
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