The Skaggs Institute
for Chemical Biology

Scientific Report 2007

Chemical Synthesis and Chemical Biology

K.C. Nicolaou, X. Alvarez-Mico, R. Aversa, W. Brenzovich, P. Bulger, A. Burtoloso, J. Chen, K. Cole, J. Crawford, P. Dagneau, S. Dalby, R. Denton, D. Edmonds, S. Ellery, A. Estrada, M. Frederick, M. Freestone, C. Gelin, S. Harrison, P. Huang, V. Jeso, A. Johnson, A. Kislukhin, A. Lanver, G. Lee, K. Lee, A. Lemire, A. Li, H. Li, Y. Lim, T. Lister, N. Mainolfi, C. Mathison, A. Morgan, A. Nold, A. Ortiz, K. Otrubova, K. Pendri, D. Polet, G. Pontremoli, B. Pratt, F. Rivas, A. Sanchez Ruiz, D. Sarlah, D. Shaw, A. Stepan, A. Talbot, Y. Tang, V. Trepanier, G. Tria, C. Turner, T. Umezawa, J. Wang, K. Worrell, T. Wu, H. Zhang

During the last year, we made considerable progress toward the synthesis and evaluation of several biologically active molecules (Fig. 1). In a communication in Angewandte Chemie, we described the structural elucidation of uncialamycin, a scarce naturally occurring substance with extremely potent antibacterial and antitumor properties. In a separate communication in the same journal, we reported the total synthesis and structural revision of biyouyanagin, a natural product with anti-HIV activity. In the Journal of the American Chemical Society, we reported the total synthesis of kinamycin C and its relatives, naturally occurring compounds with antitumor properties. And in an article in the same journal, we described the full details of our work on the abyssomycins, a group of newly discovered antibiotics. In addition, we completed the total synthesis of platensimycin and adamantaplatensimycin, a family of new antibiotics with exceptional activity against drug-resistant bacteria, and reported the results in Angewandte Chemie. We have also started synthetic studies to confirm the assigned structure of maitotoxin, the largest and most toxic secondary metabolite ever isolated. In addition, we reported new synthetic technologies for the construction of biologically and pharmaceutically relevant compounds in an article in Tetrahedron.

Fig. 1. Selected target molecules.

In summary, our investigations in chemical synthesis and chemical biology are continuing. Our aims are to strengthen the foundation for drug discovery and development. Indeed, one of our inventions in the epothilone area has recently been licensed for development as an anticancer agent by a biotechnology company.

Publications

Altmann, K.-H., Pfeiffer, B., Arseniyadis, S., Pratt, B.A., Nicolaou, K.C. The chemistry and biology of epothilones: the wheel keeps turning. Chemmedchem 2:396, 2007.

Nicolaou, K.C., Edmonds, D.J., Li, A., Tria, G.S. Asymmetric syntheses of platensimycin. Angew. Chem. Int. Ed. 46:3942, 2007.

Nicolaou, K.C., Estrada, A.A., Freestone, G.C., Lee, S.H., Alvarez, X.M. New synthetic technology for the construction of N-hydroxyindoles and synthesis of nocathiacin I model systems. Tetrahedron 63:6088, 2007.

Nicolaou, K.C., Frederick, M.O. On the structure of maitotoxin. Angew. Chem. Int. Ed. 46:5278, 2007.

Nicolaou, K.C., Guduru, R., Sun, Y.-P., Banerji, B., Chen, D.Y.-K. Total synthesis of the originally proposed and revised structures of palmerolide A. Angew. Chem. Int. Ed. 46:5896 2007.

Nicolaou, K.C., Harrison, S.T. Total synthesis of abyssomicin C, atrop-abyssomicin C, and abyssomicin D: implications for natural origins of atrop-abyssomicin C. J. Am. Chem. Soc. 129:429, 2007.

Nicolaou, K.C., Li, H., Nold, A.L., Pappo, D., Lenzen, A. Total synthesis of kinamycins C, F, and J. J. Am. Chem. Soc. 129:10356, 2007.

Nicolaou, K.C., Lim, Y.H., Piper, J.L., Papageorgiou, C.D. Total synthesis of 2,2′-epi-cytoskyrin A, rugulosin, and the alleged structure of rugulin. J. Am. Chem. Soc. 129:4001, 2007.

Nicolaou, K.C., Lister, T., Denton, R.M., Gelin, C.F. Cascade reactions involving [2+2] thermal cycloadditions: total synthesis of artochamins F, H, I, and J, Angew. Chem. Int. Ed. 46:7501, 2007.

Nicolaou, K.C., Lister, T., Denton, R.M., Montero, A., Edmonds, D.J. Adamantaplatensimycin: a bioactive analogue of platensimycin. Angew. Chem. Int. Ed. 46:4712, 2007.

Nicolaou, K.C., Majumder, U., Roche, S.P., Chen, D.Y.-K. Construction of the left-domain of haplophytine. Angew. Chem. Int. Ed. 46:4715, 2007.

Nicolaou, K.C., Nold, A.L., Milburn, R.R., Schindler, C.S., Cole, K.P., Yamaguchi, J. Total synthesis of marinomycins A-C and of their monomeric counterparts monomarinomycin A and iso-monomarinomycin A. J. Am. Chem. Soc. 129:1760, 2007.

Nicolaou, K.C., Sarlah, D., Shaw, D.M. Total synthesis and revised structure of biyouyanagin A. Angew. Chem. Int. Ed. 46:4708, 2007.

Nicolaou, K.C., Tang, Y., Wang, J. Formal synthesis of (±)-platensimycin. Chem. Commun. (Camb.) 1922, 2007, Issue 19.

Nicolaou, K.C., Tang, Y., Wang, J., Stepan, A.F., Li, A., Montero A. Total synthesis and antibacterial properties of carboplatensimycin. J. Am. Chem. Soc. 129:14850, 2007.

Nicolaou, K.C., Zhang, H., Chen, J.S., Crawford, J., Pasunoori, L. Total synthesis and stereochemistry of uncialamycin. Angew. Chem. Int. Ed. 46:4704, 2007.

Nicolaou, K.C., Zou, B., Dethe, D.H., Li, D.B., Chen, D.Y.-K. Total synthesis of antibiotics GE2270A and GE2270T. Angew. Chem. Int. Ed. 45:7786, 2006.

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., Nicolaou, K.C., Frederick, M.O., Gómez-Limia, B., Alfonso, A., Vieytes, M.R., Botana, L.M. Effects of azaspiracid-1, a potent cytotoxic agent, in primary neuronal cultures: a structure-activity relationship study. J. Med. Chem. 50:356, 2007.

Vilariño, N., Nicolaou, K.C., Frederick, M.O., Cagide, E., Ares, I.M., Louzao, M.C., Vieytes, M.R., Botana, L.M. Cell growth inhibition and actin cytoskeleton disorganization induced by azaspiracid-1: structure-activity studies. Chem. Res. Toxicol. 19:1459, 2006.

Vilariño, N., Nicolaou, K.C., Frederick, M.O., Vieytes, M.R., Botana L.M. Irreversible cytoskeletal disarrangement is independent of caspase activation during in vitro azaspiracid toxicity in human neuroblastoma cells. Biochem. Pharmacol. 74:327, 2007.