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The Skaggs Institute for Chemical Biology
Scientific Report 1999-2000


Chemical Synthesis and Chemical Biology


K.C. Nicolaou, P. Baran, S. Barluenga, O. Baudoin, F. Bernal, A. Bigot, C. Boddy, B. Bollbuck, G.-Q. Cao, S. Cho, H.-S. Choi, N. Diedrichs, K.-C. Fong, K. Fylaktakidou, J. Gruber, D. Gray, A. Hassner, Y. He, R. Hughes, N. Jain, K. Jíláli, J.-K. Jung, A. Kakolyrí, R. Kranich, A. Koumbis, H. Li, J. Li, T. Li, Y. Li, A. McClory, H. Mitchell, F. Murphy, K. Namoto, M. Orfanopoulos, M. Pereíra, J. Pfefferkorn, A. Pihko, P. Pihko, A. Ritzen, A. Roecker, R. Rodríguez, B. Safina, R. Scarpelli, M. Shoji, K. Simonsen, C. Smethurst, S. Snyder, H. Suzuki, J. Tae, T. Ulven, G. Vassilikogiannakis, J. Vega, H. Wei, B. Werschkun, B. Weyershausen, K. Wilcoxen, N. Winssinger, J. Xu, W.-H. Yoon, Y.-L. Zhong, N. Zou

Today, total synthesis of natural products is associated with prudent and tasteful selection of challenging and preferably biologically important target molecules, the discovery and invention of new synthetic strategies and technologies, and explorations in chemical biology through molecular design and mechanistic studies. Future strides in the field most likely will be aided by advances in the isolation and characterization of naturally occurring novel molecular targets, the availability of new reagents and synthetic methods, and information and automation technologies. Such strides are destined to bring the power of organic synthesis closer to, or even beyond, the boundaries of naturally occurring materials, boundaries that currently, and despite our many advantages, still look so far away.

Today, the power of chemical synthesis is expressed in the endeavors of medicinal and combinatorial chemists who are attempting to confront the human genome with small-molecule libraries in efforts to identify ligands that may become new medicines for humanity. Indeed, most ethical drugs of our times are small organic molecules. Whether derived from naturally occurring materials or man-made, these molecules exert their pharmacologic actions by binding and modulating the function of disease-related biological targets (e.g., genes, proteins). Such molecules include the celebrated drugs aspirin, penicillin, paclitaxel (Taxol), and vancomycin.

The discovery, total synthesis, and chemical biology of several naturally occurring molecules and the contributions of chemical synthesis and combinatorial chemistry to drug discovery and development are the guiding principles of our research efforts supported by the Skaggs Institute.

During the past year or so, we made progress in the areas of anticancer agents, antibiotics effective against drug-resistant bacteria, and combinatorial compound libraries from which a number of biologically active molecules emerged. More specifically, we synthesized and tested a series of epothilone analogs, including the potent pyridine-substituted epothilones, some of which are more powerful antitumor agents than the natural substances. We also synthesized vancomycin, an antibiotic used in hospitals as a last line of defense. We used the developed chemistry to construct a series of highly potent antibiotics effective against vancomycin-resistant bacteria and are further refining the structures of the molecules. Furthermore, we completed the total synthesis of the complex oligosaccharide antibiotic everninomicin (Ziracin) and began a new program based on combinatorial chemistry to discover other types of new antibacterial agents (Fig. 1).

In addition to these programs, we determined the absolute configuration of the CP molecules (potential anticancer and cholesterol-lowering compounds) and completed our studies on the total synthesis of brevetoxin A and trichodimerol. Trichodimerol inhibits the production of tumor necrosis factor and is a lead compound for the development of potential therapies for septic shock. Particularly exciting were our new synthetic technologies for the synthesis of novel molecular diversity from which new leads for drug discovery may arise. Our results in this area include the identification of novel antiviral agents, enzyme inhibitors, and antibacterial and antitumor agents.

Publications

Giannakakou, P., Gussio, R., Nogales, E., Downing, K.H., Zaharevitz, D., Bollbuck, B., Poy, G., Sackett, D., Nicolaou, K.C., Fojo, T. A common pharmacophore for epothilones and taxanes: Molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proc. Natl. Acad. Sci. U. S. A. 97:2904, 2000.

Li, R., Xiao, X.-Y., Nicolaou, K.C. High-output solid phase synthesis of discrete compounds using directed split-and-pool strategy. In: High Throughput Organic Synthesis. Sucholeiki, I. (Ed.). Marcel Dekker, New York, in press.

Nicolaou, K.C., Baran, P.S., Zhong, Y.-L., Choi, H.-S., Fong, K.C., He, Y., Yoon, W.H. New synthetic technology for the synthesis of hindered α-diazoketones via acyl mesylates. Org. Lett. 1:883, 1999.

Nicolaou, K.C., Baran, P.S., Zhong, Y.-L., Vega, J.A. New synthetic technologies for combinatorial chemistry and molecular diversity: Novel IBX-mediated processes for the synthesis of amino sugars and libraries thereof. Angew. Chem. Int. Ed., in press.

Nicolaou, K.C., Boddy, C.N.C., Bräse, S., Winssinger, N. The chemistry, biology and medicine of the glycopeptide antibiotics. Angew. Chem. Int. Ed. 38:2096, 1999.

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. 5:2602, 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. 1:63, 1999.

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. 519, 1999.

Nicolaou, K.C., Hepworth, D., King, N.P., Finlay, M.R.V. Chemistry, biology and medicine of selected tubulin polymerizing agents. Pure Appl. Chem. 71:989, 1999.

Nicolaou, K.C., Hepworth, D., King, N.P., Finlay, M.R.V., Scarpelli, R., Pereíra, M.M.A., Bollbuck, B., Bigot, A., Werschkun, B. Total synthesis of 16-desmethylepothilone B, epothilone B10, epothilone F, and related side-chain modified epothilone B analogues. Chem. Eur. J., in press.

Nicolaou, K.C., Jautelat, R., Vassilikogiannakis, G., Baran, P.S., Simonsen, K. Studies towards trichodimerol: Novel cascade reactions and polycyclic frameworks. Chem. Eur. J. 5:3651, 1999.

Nicolaou, K.C., Jung, J.-K., Yoon, W.H., He, Y., Zhong, Y.-L., Baran, P.S. The absolute configuration and asymmetric total synthesis of the CP molecules (CP-263,114 and CP-225,917, phomoidrides B and A). Angew. Chem. Int. Ed., in press.

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. 7:665, 1999.

Nicolaou, K.C., Koumbis, A.E., Snyder, S.A., Simonsen, K.B. Novel reactions initiated by titanocene methylidenes: Deoxygenation of sulfoxides, N-oxides, and selenoxides. Angew. Chem. Int. Ed., in press.

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. 5:2622, 1999.

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. 5:2584, 1999.

Nicolaou, K.C., Li, Y., Weyerhausen, B., Wei, H. Synthesis of the macrocyclic core of apoptolidin. Chem. Commun. 307, 2000.

Nicolaou, K.C., Mitchell, H.J., Fylaktakidou, K.C., Suzuki, H., Rodríguez, R. 1,2-Seleno migrations in carbohydrate chemistry: Solution and solid-phase synthesis of 2-deoxy glycosides, orthoesters, and allyl orthoesters. Angew. Chem. Int. Ed. 39:1089, 2000.

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. 5:2648, 1999.

Nicolaou, K.C., Mitchell, H.J., Rodríguez, R.M., Fylaktakidou, K.C., Suzuki, H. Total synthesis of everninomicin 13,384-1, 3: Synthesis of the DE fragment and completion of the total synthesis. Angew. Chem. Int. Ed. 38:3345, 1999.

Nicolaou, K.C., Mitchell H.J., Suzuki, H., Rodríguez, R.M., Baudoin, O., Fylaktakidou, K.C. Total synthesis of everninomicin 13,384-1, 1: Synthesis of the A1B(A)C fragment. Angew. Chem. Int. Ed. 38:3334, 1999.

Nicolaou, K.C., Murphy, F., Barluenga, S., Ohshima, T., Wei, H., Xu, J., Gray, D.L.F., Baudoin, O. Total synthesis of the immunosuppressant sanglifehrin A. J. Am. Chem. Soc., in press.

Nicolaou, K.C., Ohshima, T., Murphy, F., Barluenga, S., Xu, J. Synthesis of the macrocyclic core of sanglifehrin A. Chem. Commun. 809, 1999.

Nicolaou, K.C., Pfefferkorn, J., Xu, J., Winssinger, N., Ohshima, T., Kim, S., Hosokawa, S., Vourloumis, D., van Delft, F., Li, T. Total synthesis and chemical biology of the sarcodictyins. Chem. Pharm. Bull. 47:1199, 1999.

Nicolaou, K.C., Pfefferkorn, J.A., Cao, G.-Q. Selenium-based solid phase synthesis of benzopyrans, I: Applications to combinatorial synthesis of natural products. Angew. Chem. Int. Ed. 39:734, 2000.

Nicolaou, K.C., Pfefferkorn, J.A., Cao, G.-Q. Selenium-based solid phase synthesis of benzopyrans, II: Applications to combinatorial synthesis of medicinally relevant small organic molecules. Angew. Chem. Int. Ed. 39:739, 2000.

Nicolaou, K.C., Pfefferkorn, J.A., Cao, G.-Q., Kim, S., Kessabi, J. A facile method for the solution and solid-phase synthesis of substituted [3.3.1] bicycles. Org. Lett. 1:807, 1999.

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. 121:4724, 1999.

Nicolaou, K.C., Rodríguez, R.M., Fylaktakidou, K.C., Suzuki, H., Mitchell, H.J. Total synthesis of everninomicin 13,384-1, 2: Synthesis of the FGHA2 fragment. Angew. Chem. Int. Ed. 38:3340, 1999.

Nicolaou, K.C., Roecker, A.J., Pfefferkorn, J.A., Cao, G.-Q. A novel strategy for the solid-phase synthesis of substituted indolines. J. Am. Chem. Soc. 122:2966, 2000.

Nicolaou, K.C., Scarpelli, R., Bollbuck, B., Werschkun, B., Pereíra, M.M.A., Wartmann, M., Altmann, K.-H., Zaharevitz, D., Gussio, R., Giannakakou, P. Chemical synthesis and biological properties of pyridine epothilones. Chem. Biol. 7:593, 2000.

Nicolaou, K.C., Snyder, S., Bigot, A., Pfefferkorn, J. Solution and solid-phase synthesis of functionalized 3-arylbenzofurans by a novel cyclofragmentation-release pathway. Angew. Chem. Int. Ed. 39:1093, 2000.

Nicolaou, K.C., Vassilikogiannakis, G., Simonsen, K.B., Baran, P.S., Zhong, Y.-L., Vidali, V.P., Pitsinos, E.N., Couladouros, E.A. Biomimetic explorations toward the bisorbicillinoids: Total synthesis of bisorbicillinol, bisorbibutenolide, and trichodimerol. Angew. Chem. Int. Ed. 38:3555, 1999.

Nicolaou, K.C., Vassilikogiannakis, G., Simonsen, K.B., Baran, P.S., Zhong, Y.-L., Vidali, V.P., Pitsinos, E.N., Couladouros, E.A. Biomimetic total synthesis of bisorbicillinol, bisorbitutenolide, trichodimerol, and designed analogues of the bisorbicillinoids. J. Am. Chem. Soc. 122:3071, 2000.

Nicolaou, K.C., Vourloumis, D., Winssinger, N., Baran, P.S. Art and science of total synthesis at the dawn of the twenty-first century. Angew. Chem. Int. Ed. 39:44, 2000.

Nicolaou, K.C., Winssinger, N., Hughes, R., Smethurst, C., Cho, S.Y. New selenium-based safety catch-linkers: Solid-phase semisynthesis of vancomycin. Angew. Chem. Int. Ed. 39:1084, 2000.

Nicolaou, K.C., Xu, J., Murphy, F., Barluenga, S., Baudoin, O., Wei, X., Gray, D., Ohshima, T. Total synthesis of sanglifehrin A. Angew. Chem. Int. Ed. 38:2447, 1999.

Nicolaou, K.C., Yue, E.W. New roads to molecular complexity. In: The New Chemistry. Cambridge University Press, Port Chester, NY, in press.

Nicolaou, K.C., Zhong, Y.-L., Baran, P.S. New synthetic technology for the rapid construction of novel heterocycles, 1: The reaction of Dess-Martin periodinane with anilides and related compounds. Angew. Chem. Int. Ed. 39:622, 2000.

Nicolaou, K.C., Zhong, Y.-L., Baran, P.S. New synthetic technology for the rapid construction of novel heterocycles, 2: The reaction of IBX with anilides and related compounds. Angew. Chem. Int. Ed. 39:625, 2000.

Setyawan, J., Koide, K., Diller, T.C., Taylor, S.S., Nicolaou, K.C., Brunton, L.L. Inhibition of protein kinases by balanol: Specificity within the serine/threonine protein kinase subfamily. Mol. Pharmacol. 56:370, 1999.

Xiao, X.-Y., Li, R., Zhuang, H., Ewing, B., Karunaratne, K., Lillig, J., Brown, R., Nicolaou, K.C. Solid-phase combinatorial synthesis using MicroKan reactors, Rf tagging, and directed sorting. Biotechnol. Bioeng. 71:44, 2000.

Xiao, X.-Y., Nicolaou, K.C. High throughput combinatorial synthesis of discrete compounds in multimilligram quantity: Non-chemical encoding and directed sorting. In: Combinatorial Chemistry: A Practical Approach. Fenniri, H. (Ed.). Oxford University Press, New York, 2000, p. 432.

 

 







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