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News and Publications
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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