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The Skaggs Institute for Chemical Biology
Scientific Report 1998-1999


Chemical Synthesis and Chemical Biology


K.C. Nicolaou, K.A. Agrios, T. Bando, P. Baran, S. Barluenga, O. Baudoin, F. Bernal, A. Bigot, C. Boddy, B. Bollbuck, G.-Q. Cao, S. Cho, H.-S. Choi, E. Couladouros, M. Finlay, K.-C. Fong, D. Gray, J. Gunzner, A. Hassner, Y. He, D. Hepworth, R. Hughes, N. Jain, R. Jautelat, S. Kim, N. King, A. Koumbis, H. Li, J. Li, T. Li, Y. Li, H. Mitchell, F. Murphy, K. Namoto, S. Natarajan, T. Ohshima, J. Pfefferkorn, J. Ramanjulu, R. Rodriguez, R. Scarpelli, K. Simonsen, M. Shoji, C. Smethurst, M. Solomon, M. Takayanagi, J. Trujillo, H. Suzuki, G. Vassilikogiannakis, D. Vourloumis, H. Wei, D. Weinstein, B. Werschkun, B. Weyershausen, N. Winssinger, M. Woodrow, J. Xu, Z. Yang, W.-H. Yoon, Y.-L. Zhong

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 everninomycin; 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 over the last year has been both exciting and highly rewarding.

Publications

Hamel, E., Sackett, D.L., Nicolaou, K.C., Vourloumis, D. The coral-derived natural products eleutherobin and sarcodictyins A and B: Effects on the assembly of purified tubulin with and without microtubule-associated proteins and binding at the polymer taxoid site. Biochemistry 28:5490, 1999.

Lode, H.N., Reisfeld, R.A., Handgretinger, R., Nicolaou, K.C., Gaedicke, G., Wrasidlo, W. Targeted therapy with a novel enediyne antibiotic calicheamicin τI1 effectively suppresses growth and dissemination of liver metastases in a syngeneic model of murine neuroblastoma. Cancer Res. 58:2925, 1998.

Narayana, N., Diller, T.C., Koide, K., Bunnage, M.E., Nicolaou, K.C., Brunton, L.L., Xuong, N.-H., Ten Eyck, L.F., Taylor, S.S. Crystal structure of the potent natural product inhibitor balanol in complex with the catalytic subunit of cAMP-dependent protein kinase. Biochemistry 38:2367, 1999.

Nicolaou, K.C., Baran, P.S., Jaudelat, R., He, Y., Fong, K.C., Choi, H.-S., Yong, W.H., Zhong, Y.-L. Novel chemistry route to the fused maleic anhydride moiety of CP molecules. Angew. Chem. Int. Ed. 38:549, 1999.

Nicolaou, K.C., Boddy, C.N.C., Bräse, S., Winssinger, N. The chemistry, biology and medicine of the glycopeptide antibiotics. Angew. Chem. Int. Ed., in press.

Nicolaou, K.C., Boddy, C.N.C., Li, H., Koumbis, A.E., Hughes, R., Natarajan, S., Jain, N.F., Ramanjulu, J.M., Bräse, S. Total synthesis of vancomycin, 2: Retrosynthetic analysis, synthesis of amino acid building blocks and strategy evaluations. Chem. Eur. J., in press.

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., Bunnage, M.E., McGarry, D.G., Shi, S., Somers, P.K., Wallace, P.A., Chu, X.-J., Agrios, K.A., Gunzner, J.L., Yang, Z. Total synthesis of brevetoxin A, 1: First-generation strategy and construction of BCD ring system. Chem. Eur. J. 5:599, 1999.

Nicolaou, K.C., Gunzner, J.L., Shi, G.-Q., Agrios, K.A., Gärtner, P., Yang, Z. Total synthesis of brevetoxin A, 4: Final stages and completion. Chem. Eur. J. 5:646, 1999.

Nicolaou, K.C., He, Y., Fong, K.C., Yoon, W.H., Choi, S., Zhong, Y.L., Baran,P.S., Zhong, L. Novel strategies to construct the γ-hydroxy lactone moiety of the CP molecules: Synthesis of the CP-225,917 core skeleton. Org. Lett., in press.

Nicolaou, K.C., Hepworth, D., Finlay, M.R.V., King, N.P., Werschkun, B., Bigot, A. Synthesis of 16-desmethylepothilone B: New methodology for the rapid, highly selective and convergent construction of epothilone B and related analogues. Chem. Commun., in press.

Nicolaou, K.C., Hepworth, D., King, N.P., Finlay, M.R.V. Chemistry, biology and medicine of selected tubulin polymerizing agents. Pure Appl. Chem., in press.

Nicolaou, K.C., Jain, N.F., Natarajan, S., Hughes, R., Solomon, M.E., Li, H., Ramanjulu, J.M., Takayanagi, M., Koumbis, A.E., Bando, T. Total synthesis of vancomycin aglycon, 2: Synthesis of amino acids 1-3 and construction of the AB-COD-DOE ring skeleton. Angew. Chem. Int. Ed. 37:2714 1998.

Nicolaou, K.C., King, N.P., Finlay, M.R.V., He, Y., Roschangar, F., Vourloumis, D., Vallberg, H., Sarabia, F., Ninkovic, S., Hepworth, D. Total synthesis of epothilone E and related side chain modified analogs via a Stille coupling based strategy. Bioorg. Med. Chem., in press.

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, 1998, p. 73.

Nicolaou, K.C., Koumbis, A.E., Takayanagi, M., Natarajan, S., Jain, N.F., Bando, T., Li, H., Hughes, R. Total synthesis of vancomycin, 3: Synthesis of the aglycon. Chem. Eur. J., in press.

Nicolaou, K.C., Li, H., Boddy, C.N.C., Ramanjulu, J.M., Yue, T.Y., Natarajan, S., Chu, X.-J., Bräse, S., Rübsam, R. Total synthesis of vancomycin, 1: Design and development of methodology. Chem. Eur. J., in press.

Nicolaou, K.C., Mitchell, H.J., Jain, N.F., Hughes, R., Winssinger, N., Natarajan, S., Koumbis, A.E. Total synthesis of vancomycin, 4: Attachment of the sugar moieties and completion of the synthesis. Chem. Eur. J., in press.

Nicolaou, K.C., Mitchell, H.J., Jain, N.F., Winssinger, N., Hughes, R., Bando, T. Total synthesis of vancomycin. Angew. Chem. Int. Ed. 38:240, 1999.

Nicolaou, K.C., Natarajan, S., Li, H., Jain, N.F., Hughes, R., Solomon, M.E., Ramanjulu, J.M., Boddy, C.N.C., Takayanagi, M. Total synthesis of vancomycin aglycon, 1: Synthesis of amino acids 4-7 and construction of the AB-COD ring skeleton. Angew. Chem. Int. Ed. 37:2708, 1998.

Nicolaou, K.C., Ohshima, T., Hosokawa, S., van Delft, F., Vourloumis, D., Xu, J., Pfefferkorn, J., Kim, S. Total synthesis of eleutherobin and eleuthosides A and B. J. Am. Chem. Soc. 120:8674, 1998.

Nicolaou, K.C., Ohshima, T., Murphy, F., Barluenga, S., Xu, J. Synthesis of the macrocyclic core of sanglifehrin A. Chem. Commun., in press.

Nicolaou, K.C., Pastor, J., Barluenga, S., Winssinger, N. Polymer supported selenium reagents for organic synthesis. Chem. Commun. 1947, 1998.

Nicolaou, K.C., Pfefferkorn, J.A., Kim, S., Wei, H.X. Synthesis of the fully functionalized bicyclic core of garsubellin A. J. Am. Chem. Soc., in press.

Nicolaou, K.C., Shi, G.-Q., Gunzner, J.L, Gärtner, P., Wallace, P.A., Ouellette, M.A., Shi, S., Bunnage, M.E., Agrios, K.A., Veale, C.A., Hwang, C.-K., Hutchinson, J., Prasad, C.V.C., Ogilvie, W.W., Yang, Z. Total synthesis of brevetoxin A, 3: Construction of GHIJ and BCDE ring systems. Chem. Eur. J. 5:628, 1999.

Nicolaou, K.C., Shi, G.-Q., Namoto, K., Bernal, F. Synthesis of N-heterocycles via lactam-derived ketene aminal phosphates: Asymmetric synthesis of cyclic amino acids. Chem. Commun. 1757, 1998.

Nicolaou, K.C., Takayanagi, M., Jain, N.F., Natarajan, S., Koumbis, A.E., Bando, T., Ramanjulu, J.M. Total synthesis of vancomycin aglycon, 3: Final stages. Angew. Chem. Int. Ed. 37:2717, 1998.

Nicolaou, K.C., Wallace, P.A., Shi, S., Ouellette, M.A., Bunnage, M.E., Gunzner, J.L, Agrios, K.A., Shi, G.-Q., Yang, Z. Total synthesis of brevetoxin A, 2: Second generation strategy and construction of EFGH model system. Chem. Eur. J. 5:618, 1999.

Nicolaou, K.C., Winssinger, N., Vourloumis, D., Ohshima, T., Kim, S., Pfefferkorn, J., Xu, J.Y., Li, T. Solid and solution phase synthesis and biological evaluation of combinatorial sarcodictyin libraries. J. Am. Chem. Soc. 120:10814, 1998.

Nicolaou, K.C., Xu, J., Kim, S., Pfefferkorn, J., Ohshima, T., Vourloumis, D., Hosokawa, S. Total synthesis of sarcodictyins A and B. J. Am. Chem. Soc. 120:8661, 1998.

Nicolaou, K.C., Yue, E.W. New roads to molecular complexity. In: The New Chemistry. Cambridge University Press, Cambridge, England, 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. 38:270, 1999.

Weinstein, D.A., Nicolaou, K.C. Synthesis of namenamicin A-C disaccharide: Towards the total synthesis of namenamicin. J. Chem. Soc. Perkin Trans. 1 545, 1999.

 

 







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