News and Publications

Synthetic Organic and Bioorganic Chemistry

K.C. Nicolaou, C. Agrios, T. Bando, P. Baran, S. Barluenga, F. Bernal, C. Boddy, H.-S. Choi, M. Finlay, K.-C. Fong, J. Gunzner, N. Haddad, A. Hassner, Y. He, D. Hepworth, S. Hosokawa, R. Huber, R. Hughes, N. Jain, R. Jautelat, S. Kim, Y. Kim, N. King, A. Koumbis, H. Li, J. Li, T. Li, H. Mitchell, F. Murphy, K. Namoto, S. Natarajan, S. Ninkovic, T. Ohshima, J. Pastor, J. Pfefferkorn, J. Ramanjulu, R. Rodriguez, F. Roschangar, F. Rubsam, G. Shi, M. Solomon, M. Takayanagi, J. Trujillo, F. van Delft, D. Vourloumis, N. Wanatabe, H. Wei, D. Weinstein, N. Winssinger, J. Xu, G. Yang, Z. Yang, W.-H. Yoon

Our group is involved in the development of new synthetic technologies and strategies and in the total synthesis of natural products and designed molecules (Fig. 1). Major programs under way include the synthesis of target molecules such as brevetoxins, oligosaccharides, enediyne anticancer agents, DNA-interacting molecules, cholesterol-lowering compounds, taxoids, antibiotics, and anti-AIDS and other bioactive molecules. Investigation of the chemical, biological, and medical profiles of such compounds is also a major focus within the group, as is solid-phase synthesis and combinatorial chemistry.

Overall, our programs are based on sophisticated synthetic organic chemistry and are directed toward the construction of novel molecular architectures of natural or designed origins. Emphasis is placed on both biomedical relevance and the advancement of organic synthesis as a science for its own sake.

The marine neurotoxins brevetoxin A, ciguatoxin, and maitotoxin are active principles of the catastrophic "red tide" blooms, whose increasing frequency poses a major menace to marine life, the environment, and humans. Substantial efforts are under way in our laboratories for the chemical synthesis and elucidation of the mechanism of action of these compounds as a first step toward understanding and controlling these phenomena.

Cancer continues to be a major killer, second only to heart disease. New chemotherapeutic agents are in demand, particularly to combat drug-resistant types of cancer. Our efforts in this area include programs for the total synthesis of taxoids, enediynes, and epothilones A and B. Particularly exciting is the last group of compounds because of their effectiveness against cells lines resistant to paclitaxel (Taxol).

Heart disease in humans has been convincingly linked to serum levels of cholesterol, and cholesterol-lowering drugs are therefore of great value for maintaining normal health. We have made substantial progress toward the synthesis of such agents, including the naturally occurring zaragozic acid A, CP-225,917, and CP-263,114.

Antibiotic resistance is a serious threat to human health, and new antibiotics are urgently needed. Vancomycin, teicoplanin, and everninomicin are such compounds for which chemical synthesis is progressing in our laboratories.

In addition to these target-oriented programs, we are also pursuing the discovery and development of new synthetic methods, including new reactions, solid-phase synthesis, and combinatorial chemistry. These research programs are expected to have an important impact on biology and medicine.

PUBLICATIONS

Bifulco, G., Galeone, A., Nicolaou, K.C., Chazin, W.J., Gomez-Paloma, L. Solution structure of the complex between the head-to-tail dimer of calicheamicin /gamma/₁^I oligosaccharide and a DNA duplex containing d(ACCT) and d(TCCT) high affinity binding systems. J. Am. Chem. Soc., in press.

Enders, D., Baus, U., Müller, P., Nicolaou, K.C., Jandeleit, B. Asymmetric synthesis of 3-substituted 4-oxyesters using the SAMP-/RAMP-hydrazone method. Molecules Online 2:1, 1998.

LaMarr, W.A., Yu, L., Nicoloau, K.C., Dedon, P.C. Supercoiling affects the accessibility of glutathione to DNA-bound molecules: Positive supercoiling inhibits calicheamicin-induced DNA damage. Proc. Natl. Acad. Sci. U.S.A. 95:102, 1998.

Nicolaou, K.C., Bräse, S., Pastor, J., Sarabia, F.R., Rodriguez, R.M. Total synthesis of naturally occurring substances. In: Proceedings of the 26 Reunión Bienal de la Real Sociedad Española de Química. Servicio de Publicaciones de la Universidad de Cadiz, Seville, Spain, in press.

Nicolaou, K.C., Chu, X.-J., Ramanjulu, J.M., Natarajan, S., Bräse, S., Rübsam, F., Boddy, C.N.C. New synthetic technology for the construction of vancomycin-type biaryl ring systems. Angew. Chem. Int. Ed. Engl. 36:1539, 1997.

Nicolaou, K.C., Finlay, M.R.V., Ninkovic, S., King, N.P., He, Y., Li, T., Sarabia, F., Vourloumis, D. Synthesis and biological properties of C12,13-cyclopropyl-epothilone A and related epothilones. Chem. Biol. 5:365, 1998.

Nicolaou, K.C., Finlay, M.R.V., Ninkovic, S., Sarabia, F. Total synthesis of 26-hydroxy-epothilone B and related analogs via a macrolactonization based strategy. Tetrahedron 54:7172, 1998.

Nicolaou, K.C., Gunzner, J.L. Organic synthesis: From art to science to enabling technology for biology and medicine. In: Challenges and Visions: Chemistry Research--2000 and Beyond. American Chemical Society, Washington, DC, in press.

Nicolaou, K.C., Guy, R.K., Gunzner, J.L. Intelligent drug discovery from nature. Pharm. Soc. Jpn. 33:1339, 1997.

Nicolaou, K.C., He, Y., Roschangar, F., King, N.P., Vourloumis, D., Li, T. Total synthesis of epothilone E and side-chain epothilone analogs via the Stille coupling reaction. Angew. Chem. Int. Ed. 37:84, 1998.

Nicolaou, K.C., Hepworth D. Concise and efficient total syntheses of alkannin and shikonin. Angew. Chem. Int. Ed. 37:839, 1998.

Nicolaou, K.C., Kim, S., Pfefferkorn, J., Xu, J.-Y., Ohshima, T., Hosokawa, S., Vourloumis, D., Li, T. Synthesis and biology of sarcodictyins. Angew. Chem. Int. Ed. 37:1418, 1998.

Nicolaou, K.C., King, N.P., He, Y. Ring-closing metathesis in the synthesis of epothilones and polyether natural products. In: Olefin Metathesis. Fürstner, A. (Vol. Ed.). Topics in Organometallic Chemistry. Springer-Verlag, New York, in press.

Nicolaou, K.C., Mitchell, H.J., van Delft, F.L., Rübsam, F., Rodriguez, R.M. Expeditious routes to evernitrose and vacosamine and synthesis of model vancomycin aryl glycoside. Angew. Chem. Int. Ed., in press.

Nicolaou, K.C., Ninkovic, S., Finlay, M.R.V., Sarabia, F. Total synthesis of 26-hydroxyepothilone B and related analogs. Chem. Commun. 2343, 1997.

Nicolaou, K.C., Pastor, J., Winssinger, N. Solid-phase synthesis of macrocycles by intramolecular ketophosphonate-reaction: Synthesis of a (dl)-muscone library. J. Am. Chem. Soc. 120:5132, 1998.

Nicolaou, K.C., Postema, M.H.D., Miller, N.D. Recent advances in the synthesis of cyclic polymer marine natural products. In: Carbohydrate Mimics. Chapleur, Y. (Ed.). Wiley-VCH, New York, 1998, p. 1.

Nicolaou, K.C., Postema, M.H.D., Miller, N.D., Yang, G. A novel approach to the CP-225,917 and CP-263,114 core. Angew. Chem. Int. Ed. Engl. 36:2819, 1997.

Nicolaou, K.C., Ramanjulu, J.M., Natarajan, S., Bräse, S., Li, H., Boddy, C.N.C., Rübsam, F. A Suzuki-coupling macrolactamization approach to the AB-COD bicyclic system of vancomycin. Chem. Commun. 1899, 1997.

Nicolaou, K.C., Rodriguez, R.M., Mitchell, H.J., van Delft, F.L. Stereocontrolled synthesis of the everninomicin A₁B(A)C ring framework. Angew. Chem. Int. Ed., in press.

Nicolaou, K.C., Roschangar, F., Vourloumis, D. Chemical biology of epothilones. Angew. Chem. Int. Ed., in press.

Nicolaou, K.C., Sarabia, F., Finlay, M.R.V., Ninkovic, S., King, N.P., Vourloumis, D., He, Y. Total synthesis of oxazole- and cyclopropane-containing epothilone B analogs by the macrolactonization approach. Chem. Eur. J. 3:1971, 1997.

Nicolaou, K.C., Sarabia, F., Ninkovic, S., Finlay, M.R.V., Boddy, C.N.C. Probing the ring size of epothilones: Total synthesis of [14]-, [15]-, [17]-, and [18]-epothilones A. Angew. Chem. Int. Ed. 37:81, 1998.

Nicolaou, K.C., Trujillo, J.I., Jandeleit, B., Chibale, K., Rosenfeld, M., Goodman, S.L., Diefenbach, B., Cheresh, D.A. Design, synthesis and biological evaluation of nonpeptide integrin antagonists. Biol. Med. Chem., in press.

Nicolaou, K.C., Vallberg, H., King, N.P., Roschangar, F., He, Y., Vourloumis, D. Total synthesis of oxazole- and cyclopropane-containing epothilone A analogs by the olefin metathesis approach. Chem. Eur. J. 3:1957, 1997.

Nicolaou, K.C., van Delft, F., Ohshima, T., Vourloumis, D., Xu, J., Hosokawa, S., Pfefferkorn, J., Kim, S., Li, T. Total synthesis of eluetherobin. Angew. Chem. Int. Ed. Engl. 36:2520, 1997.

Nicolaou, K.C., van Delft, F.L., Conley, S.R., Mitchell, H.J., Jin, Z., Rodriguez, R.M. New synthetic technology for the stereocontrolled construction of 1,1-disaccharides and 1,1:1,2-trisaccharides: Synthesis of the FG ring system of everninomicin 13,384-1. J. Am. Chem. Soc. 119:9057, 1997.

Nicolaou, K.C., Vourloumis, D., Li, T., Pastor, J., Winssinger, N., He, Y., Ninkovic, S., Sarabia, F., Vallberg, H., Roschangar, F., King, N.P., Finlay, M.R.V., Giannakakou, P., Verdier-Pinard, P., Hamel, E. Designed epothilones: Solid phase synthesis on microtubes, tubulin assembly properties and cytotoxic action against Taxol-resistant tumor cells. Angew. Chem. Int. Ed. Engl. 36:2097, 1997.

Nicolaou, K.C., Watanabe, N., Li, J., Pastor, J., Winssinger, N. Practical solid phase synthesis of oligosaccharides: Construction of a dodecasaccharide. Angew. Chem. Int. Ed. 37:1559, 1998.

Nicolaou, K.C., Winssinger, N., Pastor, J., Murphy, F. Solid phase synthesis of macrocyclic systems via a cyclorelease mechanism: Application of the Stille coupling to a solid phase synthesis of (S)-zearalenone J. Am. Chem. Soc., in press.

Nicolaou, K.C., Xu, J.-Y., Kim, S., Ohshima, T., Hosokawa, S., Pfefferkorn, J. Synthesis of the tricyclic core of eleutherobin and sarcodictyins and total synthesis of sarcodictyin A. J. Am. Chem. Soc. 119:11353, 1997.

Nicolaou, K.C., Yang, Z., Shi, G.-Q., Gunzner, J.L., Agrios, K.A., Gärtner, P. Total synthesis of brevetoxin A. Nature 392:264, 1998.

Nicolaou, K.C., Yue, E.W. New roads to molecular complexity. In: The New Chemistry. Cambridge University Press, New York, in press.

Papageorgiou, V.P., Assimopoulou, A.N., Couladouros, E.A., Hepworth, D., Nicolaou, K.C. Chemistry and biology of alkannin, shikonin and related naphthazarin natural products. Angew. Chem. Int. Ed., in press.