Abstract
Epothilones A and B, two compounds that have been recently isolated1 from myxobacterium Sorangium cellulosum strain 90, have generated intense interest2–16 among chemists, biologists and clinicians owing to the structural complexity, unusual mechanism of interaction with micro tubules and anticancer potential of these molecules. Like taxol* (refs 17, 18), they exhibit cytotoxicity against tumour cells by inducing microtubule assembly and stabilization3,4, even in taxol-resistant cell lines. Following the structural elucidation of these molecules by X-ray crystallography in 19961, several syntheses of epothilones A (refs 12–16) and B (ref. 19) have been reported, indicative of the potential importance of these molecules in the cancer field. Here we report the first solid-phase synthesis of epothilone A, the total synthesis of epothilone B, and the generation of a small epothilone library. The solid-phase synthesis applied here to epothilone A could open up new possibilities in natural-product synthesis and, together with solution-phase synthesis of other epothilones, paves the way for the generation of large combinatorial libraries of these important molecules for biological screening.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Höfle, G. et al. Epothilone A and B—novel 16-membered macrolides with cytotoxic activity: isolation, crystal structure, and conformation in solution. Angew. Chem. Int. Edn. Engl. 35, 1567–1569 (1996).
Grever, M. R., Schepartz, S. A. & Chabner, B. A. The national cancer institute: cancer drug discovery and development program. Semin. Oncol. 19, 622–638 (1992).
Bollag, D. M. et al. Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action. Cancer Res. 55, 2325–2333 (1995).
Kowalski, R. J., Giannakakou, P. & Hamel, E. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J. Biol. Chem. 272, 2534–2541 (1997).
Nicolaou, K. C., He, Y., Vourloumis, D., Vallberg, H. & Yang, Z. An approach to epothilones based on olefin metathesis. Angew. Chem. Int. Edn. Engl. 35, 2399–2401 (1996).
Meng, D., Sorensen, E. J., Bertinato, P. & Danishefsky, S. J. Studies toward a synthesis of epothilone A: use of hydropyran templates for the management of acyclic stereochemical relationships. J. Org. Chem. 61, 7998–7999 (1996).
Bertinato, P., Sorensen, E. J., Meng, D. & Danishefsky, S. J. Studies toward a synthesis of epothilone A: stereocontrolled assembly of the acyl region and models for macrocyclization. J. Org. Chem. 61, 8000–8001 (1996).
Schinzer, D., Limberg, A. & Böhm, O. M. Studies toward the total synthesis of epothilones: asymmetric synthesis of the key fragments. Chem. Eur. J. 2, 1477–1482 (1996).
Mulzer, J. & Mantoulidis, A. Synthesis of the C(1)-C(9) segment of the cytotoxic macrolides epothilon A and B. Tetrahedr. Lett. 37, 9179–9182 (1996).
Claus, E., Pahl, A., Jones, P. G., Meyer, H. M. & Kalesse, M. Synthesis of the C1-C9 segment of epothilons. Tetrahedr. Lett. 38, 1359–1362 (1997).
Gabriel, T. & Wessjohann, L. The Chromium-Reformatsky reaction: asymmetric synthesis of the aldol fragment of the cytotoxic epothilons from 3-(2-bromoacyl)-2-oxazolidinones. Tetrahedr. Lett. 38, 1363–1366 (1997).
Balog, A. et al. Total synthesis of (-)-epothilone A. Angew. Chem. Int. Edn Engl. 35, 2801–2803 (1996).
Yang, Z., He, Y., Vourloumis, D., Vallberg, H. & Nicolaou, K. C. Total synthesis of epothilone A: the olefin metathesis approach. Angew. Chem. Int. Edn. Engl. 36, 166–168 (1997).
Nicolaou, K. C., Sarabia, F., Ninkovic, S. & Yang, Z. Total synthesis of epothilone A: the macro-lactonization approach. Angew. Chem. Int. Edn. Engl. 36, 525–527 (1997).
Schinzer, D., Limberg, A., Bauer, A., Böhm, O. M. & Cordes, M. Total synthesis of ( – )-epothilone A. Angew. Chem. Int. Edn Engl. 36, 523–524 (1997).
Meng, D. et al. Remote effects in macrolide formation through ring-forming olefin metathesis: an application to the synthesis of fully active epothilone congeners. J. Am. Chem. Soc. 119, 2733–2734 (1997).
Horwitz, S. B., Fant, J. & Schiff, P. B. Promotion of microtubule assembly in vitro by taxol. Nature 277, 665–667 (1979).
Nicolaou, K. C., Dai, W.-M. & Guy, R. K. The chemistry and biology of Taxol. Angew. Chem. Int. Edn. Engl. 33, 15–44 (1994).
Su, D.-S. et al. Total synthesis of ( – )-epothilone B: an extension of the Suzuki coupling method and insights into structure-activity relationships of the epothilones. Angew. Chem. Int. Edn. Engl. 36, 757–759 (1997).
Grubbs, R. H., Miller, S. J. & Fu, G. C. Ring-closing metathesis and related processes in organic synthesis. Acc. Chem. Res. 28, 446–452 (1995).
Miller, S. J., Blackwell, H. E. & Grubbs, R. H. Application of ring-closing metathesis to the synthesis of rigidified amino acids and peptides. J. Am. Chem. Soc. 118, 9606–9614 (1996).
Xu, Z., Johannes, C. W., Salman, S. S. & Hoveyda, A. H. Enantioselective total synthesis of antifungal agent Sch 38516. J. Am. Chem. Soc. 118, 10926–10927 (1996).
van Maarseveen, J. H. et al. Solid phase ring-closing metathesis: cyclization/cleavage approach towards a seven membered cycloolefin. Tetrahedr. Lett. 37, 8249–8252 (1996).
Miller, J. F., Termin, A. & Piscopio, A. D. Ester enolate Claisen-ring closing metathesis route to functionalized carbocycles and heterocycles. Presented at 213th Am. Chem. Soc. Natl Meeting, San Francisco. 13–17 April (1997).
Schuster, M., Pemerstorfer, J. & Blechert, S. Ruthenium-catalyzed metathesis of polymer-bound olefins. Angew. Chem. Int. Edn. Engl. 35, 1979–1980 (1996).
Bernard, M. & Ford, W. T. Wittig reagents bound to cross-linked polystyrenes. J. Org. Chem. 48, 326–332 (1983).
Yang, D., Wong, M.-K. & Yip, Y.-C. Epoxidation of olefins using methyl(trifluoromethyl)dioxirane generated in situ. J. Org. Chem. 60, 3887–3889 (1995).
Lin, C. M. et al. A convenient tubulin-based quantitative assay for paclitaxel (Taxol) derivatives more effective in inducing assembly than the parent compound. Cancer Chetnother. Pharmacol. 38, 136–140 (1996).
Giannakakou, P. et al. Paclitaxel resistant human ovarian cancer cells have mutant β-tubulins that exhibit impaired paclitaxel driven polymeriazation. J. Biol. Chem. (in the press).
Rogan, A. M. et al. Reversal of adriamycin resistance by verapamil in human ovarian cancer. Science 244, 994–996 (1984).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nicolaou, K., Winssinger, N., Pastor, J. et al. Synthesis of epothilones A and B in solid and solution phase. Nature 387, 268–272 (1997). https://doi.org/10.1038/387268a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/387268a0
This article is cited by
-
Solid potential
Nature Chemistry (2021)
-
Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis
Nature Chemistry (2021)
-
A Bayesian machine learning approach for drug target identification using diverse data types
Nature Communications (2019)
-
Phase I clinical, pharmacokinetic, and pharmacodynamic study of KOS-862 (Epothilone D) in patients with advanced solid tumors and lymphoma
Investigational New Drugs (2012)
-
A phase 1 study of KOS-862 (Epothilone D) co-administered with carboplatin (Paraplatin®) in patients with advanced solid tumors
Investigational New Drugs (2012)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
