387238a0Nature3876630199705152382390028-0836199710.1038/387238a01476-4679199715 May 1997ukNatureNatureNATUREnatureNature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising conclusions. Nature also provides rapid, authoritative, insightful and arresting news and interpretation of topical and coming trends affecting science, scientists and the wider public./nature/journal/v387/n6630issueJournal homeArchiveCurrent issueAdvance online publicationPrivacy policySubscribeNature Publishing GroupSupplementsCurrent issue387238a0Cancer drugs better than taxol?
AU  - Cowden, Cameron J.University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.The clinical and commercial success I of taxolBristol-Myers Squibb has registered Taxol as a trademark and wishes the scientific community to use the name paclitaxel.


 (1, Fig. 1) in cancer chemo-I therapy has stimulated a worldwide search for compounds with a similar mode of action but superior properties - particularly activity against drug-resistant tumours. The epothilones are a new class of natural cytotoxic compounds produced by a cultured strain of the myxobacterium Sorangium cellulosuniy which are attracting increasing attention and excitement from chemists, biologists and clinicians1'2. They work in the same way as taxol to stop cancer cells from proliferating3, and based on initial in vitro studies, they may be better drugs, in that they are active against some taxol-resistant cancer-cell lines. In the past six months, no fewer than five total syntheses of epothilone A (2) have been reported (from the groups of Dan -ishefsky, Nicolaou and Schinzer)4. To add to these exciting results, Nicolaou et al (page 268 of this issue5) report the synthesis of both epothilones A (2) and B (3), as well as an epothilone analogue 4 with greater tubulin-assembly activity than either of the naturally occurring epothilones or taxol.


The microtubule cytoskeleton plays an important part in cell mitosis, which relies on polymerization and depolymerization of the protein tubulin. Many established anti-cancer agents such as the vinca alkaloids and colchicine work by inhibiting microtubule assembly; taxol is unusual in that it pro-


motes the formation of stable bundles of microtubules, killing the cell by inhibiting microtubule disassembly. Despite having little structural similarity, the epothilones as well as discodermolide6'7 (5 in the figure), work in the same way as taxol. In fact, the epothilones and discodermolide competitively inhibit the binding of taxol to tubulin polymers, probably indicating overlap between their respective binding sites.


Of these compounds, the epothilones are structurally the simplest, and hence amenable to the synthesis of analogues. With a range of analogues, relationships between structure and activity can be found. The structures of the epothilones (2 and 3) include a 16-membered macrocyclic lac-tone, and differ only in the presence of a hydrogen or methyl group at C12. They both have seven chiral centres with a range of functionality, including a thiazole-contain-ing side chain and an epoxide. Although the epothilones can already be made by fermentation, chemical synthesis will allow access to a wide range of structural analogues.


Figure 1 Some naturally occurring and synthetic cytotoxic agents that bind to microtubules.


Figure 2 Olefin metathesis: a key step in the solid-phase synthesis of epothilone A, which in the process cleaves the linking chain to the resin bead (P = [pound]-BuMe2Si; Cy = cyclohexyl).


The new total synthesis5 of epothilone A is notable in that the initial steps are undertaken on a substrate attached to a resin (Fig. 2). Such solid-phase chemistry is now common practice for the production of combinatorial libraries, primarily in pharmaceutical companies, but is novel in the area of complex natural product synthesis as seen here. The key step is the C12-C13 bond-forming reaction of compound 6 orchestrated by the ruthenium catalyst 7 (ref. 8), which simultaneously generates the 16-membered macrocycle 8 and cleaves the polymer support. Although this process has been widely used in polymer synthesis, its potential in the construction of complex ring systems is only now being realized. Its application to the epothilone system has also been demonstrated independently by Danishefsky and Schinzer4.


The accompanying synthesis5 of epothilone B (3 in Fig. 1) is more traditional, in that a C15-O bond formation (a macrolactoniza-tion) is employed to form the large ring. In contrast, in the first reported synthesis9 of epothilone B, Danishefsky and co-workers used an unusual intramolecular aldol reaction at C2-C3 to close the macrocycle. Both these syntheses proceed via alkene 4 with a selective epoxidation as the final step.


Now that the synthesis of both epothi-lones has been achieved, chemists and biologists can begin to find out what features of the compounds are essential for their activity. Already, compound 4 has been found to be more active than either taxol or the epothilones in a tubulin-assembly assay, indicating that the epoxide may not be essential for microtubule stabilization5'9. A library of further epothilone analogues can now be produced by varying the existing synthetic routes4'5'9, and those analogues with strong antiproliferative properties can go on to clinical evaluation. Unlike the early stages in the development of taxol3, which was originally extracted from the bark of the Pacific yew, work should not be hindered by the availability of these compounds. It is to be hoped that a promising epothilone analogue will retain its activity in vivo.


The unfinished epothilone story is yet another illustration of the wealth of biological activity associated with natural products, and the ingenuity of synthetic chemists in constructing complex molecules. As for whether the epothilones turn out to be better than taxol at fighting cancer, it is far too early to say.


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