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Almost Impossible Challenge

Almost Impossible Challenge


Some people like a good challenge and some don’t. Some people like the challenge of climbing Mount Everest, while others would prefer to stay home. Such people might point out that there are some challenges which are best ignored. There could well be challenges which are just too difficult or time consuming to undertake. For example, in August a team from Cambridge University reported that it took them twenty two years to produce a synthetic version of azadirachtin, a product which India’s neem tree (Azadirachta indica) effortlessly produces in large quantities.

There are a number of reasons why synthetic chemistry is sometimes hard pressed to reproduce natural products. The synthesis of azadirachtin required 64 steps. Much of the time was spent figuring out what the next step should be, one presumes, and how to bring about the appropriate transformation in what they already had. Some chemists criticized the English team for pursuing this project for so long. Many chemists today recognize that it is impossible, or nearly so, to duplicate some natural products. It seems strange however that scientists who so confidently claim that they will create life in a test tube within the next few years, nevertheless cannot duplicate some of the products of living cells. There is an obvious disconnect here. Can it be that technological man lacks many of the skills programmed into numerous organisms such as microbes or even like the neem tree?

The problem which the English chemists faced was that they lack many of the skills and the tools which living cells use to produce natural products. For a start, living cells are particular about what compounds they produce. All organic compounds are carbon based, that is the molecules are built around a core of carbon. The possible number and arrangement of additions to this core are infinite as far as the synthetic chemist is concerned. Computers can design compounds which differ endlessly in small details. Living cells however are far more particular. They produce only a few products (thousands compared to infinity) and many of these are much more unusual in their design that the computer generated products. Computers after all are not ingenious or original, but it seems that living cells (or at least the designer of living cells) is/are highly original. Thus even the huge libraries of synthetic compounds available to chemists, may not reflect the “rich chemical diversity of the much smaller numbers of natural products.” (Christopher M. Dobson. Nature Dec. 16, 2004 p. 826)

Obviously chemists start out at a disadvantage when they undertake to duplicate in the laboratory a synthesis which is naturally carried out by a living organism. The disadvantages to the chemists are compounded by the fact that natural products tend to be much larger and more complicated than compounds designed in the laboratory. Natural products tend to have centres in their structure that allow for twisting so that the molecule can assume alternate shapes. This is not true of synthetic molecules. Also the arrangement of elements in natural products often produces elaborate, not easily described shapes (compared to the basic geometry in a chemist’s designed products.) In addition, somehow and unexpectedly, the large natural products have greater solubility in water than synthetic designs.

Just as the end results of living processes in the cell are fancier than synthetic products, so too, the processes for producing natural products are much more sophisticated than in the laboratory. Most cells, for a start, package information controlling the manufacture of assembly line machinery (in the form of certain proteins) next to information which ensures that the appropriate raw products are produced at the appropriate time and in suitable amounts (like an ideal factory). So the assembly line receives what it needs when it needs it. One interesting thing is that the raw products in cells are simple organic molecules in common use in the cell. Lastly a third cluster of information brings about unusual modifications or tailoring, to intermediate and final steps. It is the unusual modifications to the final product which make the compound biologically active (able to carry out its designated task).

The living cell has the ability to build into a molecule the capacity to change quickly into a desired active form. For example, some products called enediynes have been isolated from certain microbes. These compounds include some of the most potent toxins known. For example, the concentration required to kill 50% of victims is so low that it works out to about one molecule per cell! One of these products, calicheamicin, has an unusual triple sulphur (-S-S-S-) bond. Another one, dynemicin has a modified benzene like ring. These components of the molecules, allow for a rapid cascade of change when conditions in the cell are appropriate. This sequence of events results in molecules which are able to aggressively oxidize things like DNA. The genetic information breaks up and the cell dies. Such chemical changes to a stored, seemingly innocent compound, show the finesse of organisms in producing fancy molecules. The process may require 20-40 steps to complete, including final processing, but 50 or more steps are not uncommon. Such lengthy manufacturing processes with unusual intermediate steps, indicate that these manufacturing procedures are not the result of randomly accumulating know how. The cells use assembly lines which are dedicated to the final product. The chemical steps in between are relevant to the cell only in that they represent stepping stones to the final product. There is no biological process, such as evolution, which could preserve a partly developed manufacturing process. What would be the point of conserving a product that does nothing? These metabolic pathways are clearly designed.

Chemists are not anywhere nearly as sophisticated as living cells in their approach to artificially synthesizing natural products. Whereas organisms carry out late-stage modifications to the reactivity of these molecules, chemists try to build the reactive groups into the component parts which they then piece together. Thus they are forced to start with bigger, more elaborate initial components. Chemists thus need a much larger collection of possible component parts than the cell does. Nevertheless, because the characteristics of some natural products are determined by the complex final three dimensional arrangement of parts, arrangements which cannot easily be produced by piecemeal processes, the synthetic chemist is at a distinct disadvantage. This is why some products appear nearly impossible to produce in the lab, and this is why azadirachtin took 22 years to produce.

The question then arises as to why this compound was so interesting to the synthetic chemists. In fact Azadirachtin, and other compounds from the neem tree, have many interesting properties. For 2000 or more years, people in India have exploited almost all parts of the neem tree. To people living in the shade of its ample canopy, this tree represents the cornucopia tree, the free tree, the blessed tree, or the village pharmacy tree. Indeed the Latin name for the tree, Azadirachta indica, comes from the Persian name Azad-Darakth, meaning “the free tree”. Claims for the usefulness of products from the tree include uses as a pesticide (against 200 important insect pests), as a fungicide, as treatments for malaria, leprosy, diabetes, ulcers, skin disorders and constipation! Moreover its wood is said to be resistant to termite damage.

Azadirachtin is a potent compound with a distant chemical resemblance to steroids. This compound is found in all parts of the neem tree, but is most concentrated in the seed. At least 70 other unusual compounds are also produced by the neem tree. Until 2007, none had been artificially synthesized. Now, of course, azadirachtin has been synthesized in a program so long running and so expensive that no one would want to do it again.

In all of this, few people perhaps reflect on how amazing the neem tree really is. Related to mahogany, this attractive evergreen tree, produces chemical compounds that illustrate how poor our chemical expertise is compared to the synthesizing capabilities of this plant. Indeed the wonders of nature can only to serve to increase our awe at the amazing creation from which we all benefit.

Margaret Helder
December 2007

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