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The Skaggs Institute For Chemical Biology
Scientific Report 1997-1998


Chemical Synthesis and Chemical Biology


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 focuses on research in chemistry, biology, and medicine. Specifically, we are involved in the chemical synthesis and chemical biology of naturally occurring and designed substances. Nature has been amply generous to us as synthetic chemists, biologists, and clinicians by providing us with wondrous molecules that have interesting biological activities and that often can cure disease and provide challenges and opportunities in research. Aspirin, penicillin, and paclitaxel (Taxol) are natural products well known for their biological effects on the human body and for their beneficial value in treating pain, infectious disease, and cancer, respectively. As chemists, we can synthesize such natural compounds and redesign their molecular structures to produce new substances with improved pharmacologic properties.

Such naturally occurring target molecules provide unique opportunities for us to make discoveries and inventions in new synthetic technology and synthetic strategies, total synthesis, chemical biology, and medicine. Currently, targets in our group include the anticancer agents epothilones A and B, eleutherobin, and sarcodictyins A and B; the antibiotics vancomycin, teicoplanin, and everninomicin; the cholesterol-lowering agents CP-225,917 and CP-263,114; a number of angiogenesis inhibitors and potential gene therapy agents; the TNF production inhibitor BMS-182123; and a number of marine neurotoxins associated with the "red tide" phenomenon (Fig. 1).

Particularly exciting is our program in cancer chemotherapy involving the molecular design, chemical synthesis, and biological screening of new classes of compounds called epothilones, sarcodictyins, and eleutherobins. Aided by principles of organic chemistry and computer modeling, we design new molecules, synthesize the molecules in the laboratory, and then test them against cancer cells in a search for potential anticancer agents that may be superior to the known anticancer agents such as paclitaxel. Progress in this and other fronts during the past year has been both exciting and highly rewarding.

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 1I oligosaccharide and a DNA duplex containing d(ACCT) and d(TCCT) high affinity binding systems. J. Am. Chem. Soc. 120:7183, 1998.

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

LaMarr, W.A., Yu, L., Nicolaou, 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. Barkin, P. (Vol. Ed.). Oxford University Press, New York, 1998, p. 66.

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. 37:1871, 1998.

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. 37:1874, 1998.

Nicolaou, K.C., Roschangar, F., Vourloumis, D. Chemical biology of epothilones. Angew. Chem. Int. Ed. 37:2014, 1998.

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. 6:1185, 1998.

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 eleutherobin. 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 Angew. Chem. Int. Ed. 37:2534, 1998.

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.

 

 







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