The Skaggs Institute
for Chemical Biology

Scientific Report 2006

Chemical Synthesis and Chemical Biology

K.C. Nicolaou, X. Alvarez-Mico, I. Andrews, S. Arseniyadis, R. Averso, W. Brenzovich, P. Bulger, A. Burtoloso, J. Chen, K. Cole, A. Converso, A. Corbu, J. Crawford, P. Dagneau, R. Denton, A. Estrada, D. Edmonds, S. Ellery, C. Fang, R. Faraoni, T. Francis, M. Frederick, M. Freestone, R. Gibe, R. Harbach, D. Harris, S. Harrison, V. Jeso, A. Johnson, T. Koftis, A. Lanver, K. Lee, S. Lee, A. Lemire, A. Lenzen, A. Li, H. Li, Y. Lim, T. Ling, T. Lister, D. Lizos, E. Loizidou, N. Mainolfi, S. Mandal, C. Mathison, R. Milburn, R. Mogul, A. Morgan, A. Nold, A. Noncovich, R. Noronha, A. Ortiz, C. Papageorgiou, D. Pappo, L. Pasunoori, K. Pendri, G. Petrovic, J. Piper, D. Polet, A. Polk, G. Pontremoli, B. Pratt, D. Sarlah, P. Sasmal, C. Schindler, D. Shaw, X. Sun, T. Suzuki, W. Tang, Y. Tang, G. Tria, C. Turner, T. Umezawa, J. Wang, H. Xu

During the past year, we made considerable progress toward the synthesis and investigation of several biologically active molecules (Fig. 1). In 2 communications, we described the total synthesis of the newly discovered antibiotic abyssomicin C and its novel atropisomer, atrop-abyssomicin C, both of which have strong antibacterial properties. In a separate communication, we reported our progress toward synthesis of the potent antitumor antibiotics lomaiviticins A and B. We also developed and reported new technologies for preparing important building blocks for chemical and pharmaceutical research. In addition we completed new syntheses of the marine neurotoxins azaspiracid-1, azaspiracid-2, and azaspiracid-3 and published the results. Furthermore, we achieved the total syntheses of a number of antitumor agents from the cytoskyrin family and the first total synthesis of the marine-derived antitumor antibiotics marinomycins A and B. Considerable progress has been made toward the total syntheses of hyperforin and vannusal A. Finally, we designed, synthesized, and evaluated a number of epothilones with antitumor properties.

Fig. 1. Selected target molecules.

Chemical synthesis and chemical biology are among the most active frontiers in chemistry today. Indeed, these disciplines provide unique opportunities for discovery and invention of new science and technology and a vigorous platform for training young chemists and biologists. Often guided by architecturally intriguing and biologically active natural products, investigations in these areas lead to new knowledge that strengthens the foundation on which drug discovery and development rely. The stories of many miracle drugs of our times are associated with chemical synthesis and its creative power, which play pivotal roles either in the discovery or the manufacture of the drugs, and often in both. Advances in the field, therefore, enhance the ability of researchers to discover and develop new medicines for humans. It is within these areas, chemical synthesis and chemical biology, that we endeavor to discover new science, useful biological tools, and potential new drug candidates.

Publications

Alfonso, A., Vieytes, M.R., Ofuji, K., Satake, M., Nicolaou, K.C., Frederick, M.O., Botana, L.M. Azaspiracids modulate intracellular pH levels in human lymphocytes. Biochem. Biophys. Res. Commun. 346:1091, 2006.

Hamel, E., Day, B.W., Miller, J.H., Jung, M.K., Northcote, P.T., Ghosh, A.K., Curran, D.P., Cushman, M., Nicolaou, K.C., Paterson, I., Sorensen, E.J. Synergistic effects of peloruside A and laulimalide with taxoid site drugs, but not with each other, on tubulin assembly. Mol. Pharmacol. 70:1555, 2006.

Ito, E., Frederick, M.O., Koftis, T.V., Tang, W., Petrovic, G., Ling, T., Nicolaou, K.C. Structure toxicity relationships of synthetic azaspiracid-1 and analogs in mice. Harmful Algae 5:586, 2006.

Nicolaou, K.C., Brenzovich, W.E., Bulger, P.G., Francis, T.M. Total synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures: initial forays. Org. Biomol. Chem. 4:2119, 2006.

Nicolaou, K.C., Bulger, P.G., Brenzovich, W.E. Total synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures: revised strategy and final stages. Org. Biomol. Chem. 4:2158, 2006.

Nicolaou, K.C., Chen, D.Y.-K., Li, Y., Uesaka, N., Petrovic, G., Koftis, T.V., Bernal, F., Frederick, M.O., Govindasamy, M., Ling, T., Pihko, P.M., Tang, W., Vyskocil, S. Total synthesis and structural elucidation of azaspiracid-1: synthesis-based analysis of originally proposed structures and indication of their non-identity to the natural product. J. Am. Chem. Soc. 128:2258, 2006.

Nicolaou, K.C., Denton, R.M., Lenzen, A., Li, A., Edmonds, D.J., Milburn, R.R., Harrison, S.T. Stereocontrolled synthesis of model core systems of lomaiviticins A and B. Angew. Chem. Int. Ed. 45:2076, 2006.

Nicolaou, K.C., Edmonds, D.J., Bulger, P.G. Cascade reactions in total synthesis. Angew. Chem. Int. Ed. 45:7134, 2006.

Nicolaou, K.C., Estrada, A.A., Lee, S.H., Freestone, G.C. Synthesis of highly substituted N-hydroxyindoles through 1,5-addition of carbon nucleophiles to unsaturated nitrones. Angew. Chem. Int. Ed. 45:5364, 2006.

Nicolaou, K.C., Frederick, M.O., Loizidou, E.Z., Petrovic, G., Cole, K.P., Koftis, T.V., Yamada, Y.M.A. Second-generation total synthesis of azaspiracids-1, -2, and -3. Chem. Asian J. 1:245, 2006.

Nicolaou, K.C., Frederick, M.O., Petrovic, G., Cole, K.P., Loizidou, E. Total synthesis and confirmation of the revised structures of azaspiracid-2 and azaspiracid-3. Angew. Chem. Int. Ed. 45:2609, 2006.

Nicolaou, K.C., Harrison, S.T. Total synthesis of abyssomicin C and atrop-abyssomicin C. Angew. Chem. Int. Ed. 45:3256, 2006.

Nicolaou, K.C., Kim, D.W., Schlawe, D., Lizos, D.E., de Noronha, R.G., Longbottom, D.A. Total synthesis of halipeptins A and D and analogues. Angew. Chem. Int. Ed. 44:4925, 2005.

Nicolaou, K.C., Koftis, T.V., Vyskocil, S., Petrovic, G., Tang, W., Frederick, M.O., Chen, D.Y.-K., Li, Y., Ling, T., Yamada, Y.M.A. Total synthesis and structural elucidation of azaspiracid-1: final assignment and total synthesis of the correct structure of azaspiracid-1. J. Am. Chem. Soc. 128:2859, 2006.

Nicolaou, K.C., Lim, Y.H., Papageorgiou, C.D., Piper, J.L. Total synthesis of (+)-rugulosin and (+)-2,2′-epi-cytoskyrin A through cascade reactions. Angew. Chem. Int. Ed. 44:7917, 2005.

Nicolaou, K.C., Lizos, D.E., Kim, D.W., Schlawe, D., de Noronha, R.G., Longbottom, D.A., Rodriquez, M., Bucci, M., Cirino, G. Total synthesis and biological evaluation of halipeptins A and D and analogues. J. Am. Chem. Soc. 128:4460, 2006.

Nicolaou, K.C., Nold, A.L., Milburn, R.R., Schindler, C.S. Total synthesis of marinomycins A-C. Angew. Chem. Int. Ed. 45:6527, 2006.

Nicolaou, K.C., Pihko, P.M., Bernal, F., Frederick, M.O., Qian, W., Uesaka, N., Diedrichs, N., Hinrichs, J., Koftis, T.V., Loizidou, E., Petrovic, G., Rodriquez, M., Sarlah, D., Zou, N. Total synthesis and structural elucidation of azaspiracid-1: construction of key building blocks for originally proposed structure. J. Am. Chem. Soc. 128:2244, 2006.

Nicolaou, K.C., Pratt, B.A., Arseniyadis, S., Wartmann, M., O’Brate, A., Giannakakou, P. Molecular design and chemical synthesis of a highly potent epothilone. Chemmedchem 1:41, 2006.

Nicolaou, K.C., Xu, H. Total synthesis of floresolide B and δ^6,7-Z-floresolide B. Chem. Commun. (Camb.) 600, 2006, Issue 6.

Nicolaou, K.C., Zak, M., Rahimipour, S., Estrada, A.A., Lee, S.H., O’Brate, A., Giannakakou, P., Ghadiri, M.R. Discovery of a biologically active thiostrepton fragment. J. Am. Chem. Soc. 127:15042, 2005.