Toxins of the Red Tide: Cures in the Making?

Toxins of the Red Tide: Cures in the Making?

by John Emsley

WHAT'S HOT IN CHEMISTRY...

Rank	Paper	Citations This Period Jan-Feb 99	Rank Last Period Nov-Dec 98
1	A.T. Brünger, et al., "Crystallography & NMR System: a new software suite for macromolecular structure determination," Acta Cryst. D, 54:905-21, 1 September 1998. [10 institutions worldwide] *120JA	23	†
2	G.N. Murshudov, A.A. Vagin, E.J. Dodson, "Refinement of macromolecular structures by the maximum-likelihood method," Acta Cryst. D, 53:240-55, 1 May 1997. [U. York, England; Free U. Brussels, Belgium] *XB256	17	1
3	L.A. Curtiss, et al., "Assessment of Gaussian-2 and density functional theories for the computation of enthalpies of formation," J. Chem. Phys., 106(3):1063-79, 15 January 1997. [Argonne Natl. Lab., IL; Bell Labs, Lucent Technol., Murray Hill, NJ; Northwestern U., Evanston, IL] *WD070	10	5
4	J.D. Gale, "GULP: a computer program for the symmetry-adapted simulation of solids," J. Chem. Soc. – Faraday Trans., 93(4):629-37, 12 February 1997. [Imperial Coll., London, U.K.] *WK271	10	†
5	K.S. Nicolaou, et al., "The olefin metathesis approach to epothilone A and its analogues," J. Amer. Chem. Soc., 119(34):7960-73, 27 August 1997. [Skaggs Inst., La Jolla, CA; Scripps Res. Inst., La Jolla; U. Calif., San Diego] *XT922	10	†
6	J.S. Clark, J.G. Kettle, "Synthesis of brevetoxin sub-units by sequential ring-closing metathesis and hydroboration," Tetrahedron Lett., 38(1):123-6, 6 January 1997. [U. Nottingham, U.K.] *VZ489	8	†
7	B. Betzemeier, P. Knochel, "Palladium-catalyzed cross-coupling of organozinc bromides with aryl iodides in perfluorinated solvents," Angewandte Chemie, 36(23):2623-4, December 1997. [U. Marburg, Germany] *YP033	8	†
8	T. Morimoto, et al., "Ru₃(CO)₁₂-catalyzed cyclocarbonylation of 1,6-enynes to bicyclo[3.3.0]octenones," J. Org. Chem., 62(11):3762-5, 30 May 1997. [Osaka U., Japan] *XC120	8	†
9	J.S. Clark, J.G. Kettle, "Enantioselective synthesis of medium-ring sub-units of brevetoxin A by ring-closing metathesis," Tetrahedron Lett., 38(1):127-30, 6 January 1997. [U. Nottingham, U.K.] *VZ489	7	†
10	A.C. Scheiner, J. Baker, J. W. Andzelm, "Molecular energies and properties from density functional theory: Exploring basis set dependence of Kohn-Sham equation using several density functionals," J. Comput. Chem., 18(6):775-95, 30 April 1997. [Molecular Simulations, Inc., San Diego, CA] *WR036	7	†

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

ed tides are caused by a blooming of the dinoflagellate Gymnodinium breveDavis. They have been known since Biblical times, and also known for their ability to kill fish. The toxins they release cause health problems in parts of the world where seafood contaminated with them may be eaten, but even so they may hold the key to curing human illness. Highly toxic molecules are seen as possible anticancer and antifungal agents–hence the interest in them.

Gymnodinium breve Davis and the related organism Gambierdiscus toxicus produce several deadly molecules including the brevetoxins, ciguatoxins and the gambieric acids. Brevetoxin A will kill zebra fish at concentrations of only 3 parts per billion, and a lethal dose of ciguatoxin for a mouse can be just a few billionths of a gram. They kill by disrupting the channels that allow sodium ions to pass through nerve cell walls.

Gambieric acid A is one of the most potent antifungal agents known but has resisted all attempts to synthesize it in the laboratory. However, both brevetoxins A and B have been synthesized by K. C. Nicolaou and his group at the Scripps Research Institute in California, although it required many steps to achieve this (see, for example, Angewandte Chemie Int. Ed. Engl. 35:589-607, 1996).

His work is testimony to the chemists' skill, but commercial exploitation will require simpler methods. In the current Hot Ten–at positions #6 and #9–are two papers by Stephen Clark and Jason Kettle of the University of Nottingham, England, showing how this might be done. The papers report an efficient way of making the linked cyclic ethers that are the key features of the brevetoxin structures. (K.C. Nicolaou also has a paper in the current Hot Ten list at #5, on the synthesis of epothilone.)

Brevetoxins A and B consist of ladder-like arrays of joined rings–10 and 11 such rings, respectively. These rings are ethers–that is, they incorporate an oxygen atom, compounding the difficulty of making them. Clark's team have devised new ring-closing metathesis reactions for doing this, which he sees as the reason his papers are being so highly cited. Indeed ring-closing metathesis is one of the most important ring constructing reactions to have emerged in the last 30 years.

Clark's method represents what he terms a "second generation" strategy for the synthesis for the brevetoxins. His work reduces the number of steps needed to make sub-units. "Our goal is to synthesise compounds like ciguatoxins and gambieric acids in fewer than 30 steps," he tells Science Watch. "The ring-closing metathesis reaction is already finding use in industry and there are reports of applications to solid phase and combinatorial chemistry. It is likely to have a huge impact in industry in future."

Clark has published two further papers on the synthesis of these compounds, in Tetrahedron Letters (39: 8321,1998) and Chemical Communications ( 29:2629, 1998). The former refers to the preparation of units found in brevetoxins and ciguatoxins by ring closing metathesis, and the latter to a new catalytic ring closure reaction involving alkynes.

What fascinates him about this area of research? "The brevetoxins are the ultimate challenge in terms of medium-ring synthesis, containing as they do rings of 7-, 8- and 9-atoms that are difficult to construct in high yields. and they are complicated by the large number of stereogenic centers they contain," says Clark. "I wanted to tackle the most difficult targets so that we could really test our chemistry under challenging circumstances. I also wanted to choose targets that would force us to develop new strategies and reactions and to use existing chemistry in very creative ways." In this respect he appears to have succeeded.

Clark is now exploring new coupling strategies to form larger multi-ring arrays. He is also exploring syntheses in which the growing chain of rings builds outward in two directions simultaneously and has just been able to do this for the first time, constructing two seven-membered rings onto a six-membered ring–and in high yield.

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