Will Epothilone Write An Epitaph for Cancer?

Will Epothilone Write An Epitaph for Cancer?

by John Emsley

WHAT'S HOT IN CHEMISTRY...

Rank	Paper	Citations This Period May-June 98	Rank Last Period Mar-Apr 98
1	A.P. Scott, L. Radom, "Harmonic vibrational frequencies: an evaluation of Hartree-Fock, Mřller-Plesset, quadratic configuration interaction, density functional theory, and semiempirical scale factors," J. Phys. Chem., 100(41):16502-13, 10 October 1996. [Australian. Natl. U., Canberra] *VL579	20	4
2	A. Thess, et al., "Crystalline ropes of metallic carbon nanotubes," Science, 273(5274):483-7, 26 July 1996. [Rice U., Houston, TX; U. Pennsylvania, Philadelphia; Inst. Charles Sadron, Strasbourg, France; Michigan St. U., E. Lansing] *UY983	17	3
3	P. Schwab, R.H. Grubbs, J.W. Ziller, "Synthesis and applications of RuCl₂(=CHR')(PR₃)₂: the influence of the alkylidene moiety on metathesis activity," J. Amer. Chem. Soc., 118(1):100-10, 10 January 1996. [Caltech, Pasadena; U. Calif., Irvine] *TQ161	15	7
4	M. Wilm, M. Mann, "Analytical properties of the nanoelectrospray ion source," Analyt. Chem., 68(1):1-8, 1 January 1996. [European Molec. Bio. Lab., Heidelberg, Germany] *TN244	11	5
5	J.-S Wang, K. Matyjaszewski, "Controlled/"living" radical polymerization. Halogen atom transfer radical polymerization promoted by a Cu(I)/Cu(II) redox process," Macromolecules, 28(23):7901-10, 6 November 1995. [Carnegie Mellon U., Pittsburgh, PA] *TD889	11	†
6	Z. Yang, et al., "Total synthesis of epothilone A: the olefin metathesis approach," Angew. Chem., 36(1-2):166-8, February 1997. [Scripps Res. Inst., La Jolla, CA; U. Calif., San Diego] *WH998	11	†
7	D. Meng, et al., "Remote effects in macrolide formation through ring-forming olefin metathesis: an application to the synthesis of fully active epothilone congeners," J. Amer. Chem. Soc., 119(11):2733-4, 19 March 1997. [Sloan-Kettering Inst. Med. Res., New York, NY; Albert Einstein Col. Med., Bronx, NY] *WN855	9	†
8	A.W. Aylor, et al., "An infrared study of NO decomposition over Cu-ZSM-5," J. Catalysis, 157(2):592-602, December 1995. Lawrence Berkeley Natl. Lab; Berkeley, CA; U. Calif, Berkeley, CA] *TK598	7	†
9	D.A. Estrin, et al., "Small clusters of water molecules using density functional theory," J. Phys. Chem., 100(21):8701-11, 23 May 1996. [Ctr. Ricerca, Svil. Stud. Super., Cagliari, Italy; U. Strasbourg, France] *UM677	7	†
10	D. Schinzer, et al., "Total synthesis of ( – )-epothilone A," Angew. Chem., 36(5):523-4, April 1997. [Tech. U. Braunschweig, Germany] *WV556	7	†

SOURCE: ISI's Hot Papers Database. Read the full legend.

The current Hot Ten contains three papers on the same subject: #6, 7, and 10 report the synthesis of epothilone, the forerunner of a new class of anticancer drugs, and ones that can deal with drug-resistant cell lines for breast and colon cancers. Could this compound, or one of its derivatives, possibly repeat the success of the taxol anticancer treatments now in use? Gerhard Höfle of the National Biotechnology Research Institute in Braunschweig, Germany, first extracted epothilones A and B from the myxobacteria Sorangium cellulosum in the late 1980s, and in vitro tests showed A was up to 50 times more potent than taxol-and it acted faster. Two years ago he published its chemical structure in Angewandte Chemie (35[13-14]:1567-9, 1996), and this spurred organic chemists to design ways of making it in the laboratory. In just over a year, three groups had achieved this remkable goal, hence papers #6, 7, and 10.

Paper #6 comes from K.C. Nicolaou's group at the Scripps Research Institute in La Jolla, California, and the work was funded by the Skaggs Institute of Chemical Biology and the U.S. National Institutes of Health. The paper reports the total synthesis of epothilone A, using an elegant, multistep process which requires the assembly of three key building blocks. These are brought together to form the 16-membered ring that is at the heart of this molecule. The ring contains a double bond between carbons 12 and 13; forming this bond is fraught with difficulty. The adding of an oxygen atom, across this double bond, completed the total synthesis of epothilone A. Last year Nicolaou also published papers on the synthesis of epothilones A and B in the solid and solution phase in Nature (387[6630]:268-72, 1997), and on other variants of this molecule in Angewandte Chemie, (36[19]:2079-2103, 1997).

Meantime a group based at the Sloan-Kettering Institute for Cancer Research and the Albert Einstein College of Medicine, in New York, working with Samuel Danishefsky of Columbia University, had also effected an independent synthesis of epothilone A, by an equally elegant method, and this is reported in paper #7. Related papers on the subject from these researchers are to be found in Angewandte Chemie, (35[23-24]:2801-3, 1996; and 36[7]:757-9, 1997-the latter also reporting on epothilone B).

The syntheses of epothilone A in papers #6, 7, and 10 use the same kind of chemical reaction to make the 16-membered ring with its double bond. This is known as olefin metathesis, and it requires the formation of a precursor chain, the ends of which come together to complete the circle. Each end has a double bond, and these react to form the ring double bond.

Danishefsky's team use a slightly different method to construct the precursor chain to that used by Nicolaou, but what he noted was that the epoxy oxygen of epothilone A is not essential for its biological activity. Its forerunner, the so-called desoxy-epothilone molecule, has the same properties when tested in vitro. Danishefsky's paper describes ways in which other derivatives of epothilone can be made, and though these are structurally different from the parent molecule he says they also possess full biological functions.

Finally, paper #10, which comes from Dieter Schinzer's group at the Technical University of Braunschweig, Germany. Schinzer's synthesis route is like that of Nicolaou's, combining three components to make the precursor, and using a protocol he had described earlier (see Chem. Eur. J., 2:1477-82, 1996) which involves an elegant stereo-selective aldol reaction between two of them. He completes the total synthesis using dimethyl dioxirane to add the epoxy oxygen.

Compared to taxol-based drugs, epothilone ones offer three advantages: they are easier to make, as papers #6, 7, and 10 show; they are likely to be more soluble in water, whereas taxol is notoriously insoluble; and they look as if they will be effective against cancer cells that resist conventional chemotherapy treatments.

Dr. John Emsley is Science Writer in Residence at the
Department of Chemistry, University of Cambridge, U.K.