The Skaggs Institute
for Chemical Biology

Scientific Report 2008

Chemical Synthesis and Chemical Biology

K.C. Nicolaou, A. Agua, R. Aversa, W. Brenzovich, J. Chen, S. Dalby, D. Edmonds, S. Ellery, A. Estrada, B. Fraga, M. Frederick, M. Freestone, C. Gelin, J. Goodwin-Tindall, V. Gondi, M. Hesse, P. Huang, Z. Huang, V. Jeso, J. Jin, M. Kar, A. Krasovskiy, A. Lemire, R. Levin, A. Li, H. Li, Y. Lim, T. Lister, U. Majumder, C. Mathison, A. Morgan, A. Nold, A. Ortiz, N. Patil, B. Pratt, R. Reingruber, F. Rivas, A. Sanchez Ruiz, D. Sarlah, D. Shaw, A. Stepan, A. Talbot, Y. Tang, V. Trépanier, G. Tria, T. Umezawa, J. Wang, T. Wu, W. Zhan, H. Zhang

During the past year, we made considerable progress in a number of areas, including the total synthesis and biological investigation of neurotoxins, antitumor agents, and antibiotics (Fig. 1). In an effort to resolve a controversy over the structure of maitotoxin, the largest and most potent marine neurotoxin, we synthesized the GHIJK and GHIJKMNO domains of the molecule and provided spectroscopic support for the originally assigned structure of this biomolecule. We also provided synthetic azaspiracids, another group of marine neurotoxins, to biologists who investigated the neurotoxic properties and mechanism of action of the molecules. During the same period, we completed the total synthesis of several members of the artochamin family of natural products, which have cytotoxic properties. We also developed an asymmetric synthesis of the uncialamycins and determined their DNA-cleaving properties and extremely high cytotoxic effects against tumor cells and drug-resistant bacteria. Our research in infectious diseases yielded a series of biyouyanagin analogs, some of which had anti-HIV/AIDS properties. In addition, we developed asymmetric total syntheses of platensimycin and platencin, 2 naturally occurring antibiotics that exert their activities against drug-resistant bacteria through a novel mechanism involving inhibition of fatty acid biosynthesis. Carbaplatensimycin, a carbon analog of platensimycin, was also synthesized and tested. In yet another area, we developed chemistry suitable for the eventual total synthesis of sporolide B, a metabolite of a powerful enediyne antitumor antibiotic. Strides have also been made toward the total synthesis of nocathiacin III and lomaiviticin B, 2 potent antitumor antibiotics.

Fig. 1.Selected target molecules.

Overall, our research programs continue to sharpen the tools of chemical synthesis and provide biologically active molecules, some natural and some designed, for chemical biology studies. By advancing the art of chemical synthesis, and through the preparation of biological tools and potential drug candidates, we strengthen the foundation of the drug discovery and development process.

Publications

Nicolaou, K.C., Chen, J.S., Edmonds, D.J., Estrada, A.A. Recent advances in the total synthesis and biology of naturally occurring antibiotics. Angew. Chem. Int. Ed., in press.

Nicolaou, K.C., Chen, J.S., Zhang, H., Montero, A. Asymmetric synthesis and biological properties of uncialamycin and 26-epi-unicialamycin. Angew. Chem. Int. Ed. 47:185, 2008.

Nicolaou, K.C., Cole, K.P., Frederick, M.O., Aversa, R.J., Denton, R.M. Chemical synthesis of the GHIJK ring system and further experimental support for the originally assigned structure of maitotoxin. Angew. Chem. Int. Ed. 46:8875, 2007.

Nicolaou, K.C., Dethe, D.H., Chen, D.Y.-K. Total syntheses of amythiamicins A, B, and C. Chem. Commun. (Camb.) Issue 23:2632, 2008.

Nicolaou, K.C., Dethe, D.H., Leung, G.Y.C., Zou, B., Chen, D.Y.-K. Total synthesis of thiopeptide antibiotics GE2270A, GE2270T, and GE2270C. Chem. Asian J. 3:413, 2008.

Nicolaou, K.C., Frederick, M.O., Aversa, R.J. The continuing saga of the marine polyether biotoxins. Angew. Chem. Int. Ed. 47:7182, 2008.

Nicolaou, K.C., Frederick, M.O., Burtoloso, A.C.B., Denton, R.M., Rivas, F., Cole, K.P., Aversa, R.J., Gibe, R., Umezawa, T., Suzuki, T. Chemical synthesis of the GHIJKLMNO ring system of maitotoxin. J. Am. Chem. Soc. 130:7466, 2008.

Nicolaou, K.C., Krasovskiy, A., Trépanier, V.É., Chen, D.Y.-K. An expedient strategy for the synthesis of tryptamines and other heterocycles. Angew. Chem. Int. Ed. 47:4217, 2008.

Nicolaou, K.C., Leung, G.Y.C., Dethe, D.H., Guduru, R., Sun, Y.-P. Lim, C.S., Chen, D.Y.-K. Chemical synthesis and biological evaluation of palmerolide A analogues. J. Am. Chem. Soc. 130:10019, 2008.

Nicolaou, K.C., Li, A. Total syntheses and structural revisions of α- and β-diversonolic esters and total syntheses of diversonol and blennolide C. Angew. Chem. Int. Ed. 47:6579, 2008.

Nicolaou, K.C., Lister, T., Denton, R.M., Gelin, C.F. Total synthesis of artochamins F, H, I, and J through cascade reactions. Tetrahedron 64:4736, 2008.

Nicolaou, K.C., Ortiz, A., Denton, R.M. Metathesis reactions in the synthesis of complex molecules. Chem. Today 25:70, 2007.

Nicolaou, K.C., Pappo, D., Tsang, K.Y., Gibe, R., Chen, D.Y.-K. A chiral pool based synthesis of platensimycin. Angew. Chem. Int. Ed. 47:944, 2008.

Nicolaou, K.C., Stepan, A.F., Lister, T., Montero, A., Tria, G.S., Turner, C.I., Tang, Y., Wang, J., Denton, R.M., Edmonds, D.J. Design, synthesis, and biological evaluation of platensimycin analogues with varying degrees of molecular complexity. J. Am. Chem. Soc. 130:13110, 2008.

Nicolaou, K.C., Sun, Y.-P., Guduru, R., Banerji, B., Chen, D.Y.-K. Total synthesis of the originally proposed and revised structures of palmerolide A and isomers thereof. J. Am. Chem. Soc. 130:3633, 2008.

Nicolaou, K.C., Sun, Y.-P., Peng, X.-S., Polet, D., Chen, D.Y.-K. Total synthesis of (+)-cortistatin. Angew. Chem. Int. Ed. 47:7310, 2008.

Nicolaou, K.C., Toh, Q.-Y., Chen, D.Y.-K. An expedient asymmetric synthesis of platencin. J. Am. Chem. Soc. 130:11292, 2008.

Nicolaou, K.C., Tria, G.S., Edmonds, D.J. Total synthesis of platencin. Angew. Chem. Int. Ed. 47:1780, 2008.

Nicolaou, K.C., Wang, J., Tang, Y. Synthesis of the sporolide ring framework through a cascade sequence involving an intramolecular [4+2] cycloaddition reaction of an o-quinone. Angew. Chem. Int. Ed. 47:1432, 2008.

Nicolaou, K.C., Wu, T.R., Sarlan, D., Shaw, D.M., Rowcliffe, E., Burton, D.R. Total synthesis, revised structure, and biological evaluation of biyouyanagin A and analogues thereof. J. Am. Chem. Soc. 130:11114, 2008.

Vale, C., Gómez-Limia, B., Nicolaou, K.C., Frederick, M.O., Vieytes, M.R., Botana, L.M. The c-Jun-N-terminal kinase is involved in the neurotoxic effect of azaspiracid-1. Cell. Physiol. Biochem. 20:957, 2007.

Vale, C., Wandscheer, C., Nicolaou, K.C., Frederick, M.O., Alfonso, C., Vieytes, M.R., Botana, L.M. Cytotoxic effect of azaspiracid-2 and azaspiracid-2-methyl ester in cultured neurons: involvement of the c-Jun N-terminal kinase. J. Neurosci. Res. 86:2952, 2008.

Vilariño, N., Nicolaou, K.C., Frederick, M.O., Cagide, E., Alfonso, C., Alonso, E., Vieytes, M.R., Botana, L.M. Azaspiracid substituent at C1 is relevant to in vitro toxicity. Chem. Res. Toxicol. 21:1823, 2008.