Brazilian methods of organic synthesis for producing biologically active reagents – that can be used, for example, in medications and agrochemicals – gained prominence with the publication of an article in an international magazine. The chemical reagents, based on selenium and tellurium, were developed by a researcher at the Chemistry Institute of the University of São Paulo (USP) and have been included in the product catalog of the largest fine chemicals company in the world, the American company Aldrich. Agreement has also been reached between the company and the IQ-USP to sell various of these reagents internationally.
The article, Add a Little Tellurium to Your Synthetic Plans!, by the researcher João Valdir Comasseto and his doctoral student Rafael E. Barrientos-Astirraga, was published in the company’s quarterly magazine, Aldrichimica Acta (vol. 33, no. 2, 2000), which has a circulation of 130,000 copies distribution among companies in the field and scientists the world over. It is the first time in more than 40 years of existence that the magazine has published an article on a piece of Brazilian work.
For Comasseto, this shows that the institute’s work, internationally recognized with hundreds of references in scientific publications, has aroused commercial interest. And, he emphasizes that this also results from the laboratory’s technical conditions, which, thanks to constant investment, is as well equipped as any of the world’s great universities. In the project he is running (Organic Synthesis of Selenium and Tellurium Reagents), and which prompted the article, for example, FAPESP is investing R$ 326,000 and US$ 353,000.
Comasseto has been working for more than 20 years on methods of organic synthesis to develop reagents or “building blocks” used to construct bioactive molecules (medications, agrochemicals, fragrances). Synthesized reagents act as pre-fabricated blocks in architecture; they can be assembled to construct the “building” which are complex molecular structures with biological properties.
The method in question uses blocks with selenium or tellurium atoms (see table). One special reaction, the hydrotelluration of acetylenes, produces blocks called vinylic tellurites. These compounds, as they are stable in water and in the air, have the advantage of being able to be stored and transported, and, therefore, can be sold.
One example is macrolactin A, produced naturally by marine bacteria in minute quantities. This substance awaked interest around the world because it showed potent anti-viral activity, inhibiting the replication of the Herpes simplex(Herpes) and HIV (Aids) viruses. It was synthesized in collaboration with researchers at the University of Michigan, in the United States.
Another bioactive molecule that the laboratory synthesizes is cicutoxin, identified in 1999 by Japanese scientists as a component of the poison hemlock (with which Socrates committed suicide). Because it has proved cytotoxic (having a toxic effect on cells), in can be used to fight cancer. The same reagent as that used in synthesizing macrolactin A serves to synthesize cicutoxin. Various other bioactive substances are being obtained in the IQ laboratory using these building blocks, called vinylic tellurides, which can have different structures.
The laboratory can supply these reagents to the manufacturing sector or to other university centers through Aldrich, points out Comasseto. He emphasizes that the importance of the work lies precisely in the development of general synthesizing methods that can be used by research groups around the world, including pharmaceutical companies, to synthesize bioactive compounds.
The article in Aldrichimica Acta led to many e-mails being sent to Comasseto: researchers in the United States, Europe, and Japan make comments and show interest in working in the field. “This interest in our work by laboratories shows that Brazil is already exporting ideas in an extremely important field, namely fine chemicals”. Moreover, the country was host this year to the most important international event in the field, the 8th International Conference on Selenium and Tellurium Chemistry, held in Águas de São Pedro (SP).
Through facts such as these, Comasseto believes the time has come to overturn the myth that Brazil always copies what is being done elsewhere, “In fact, nowadays, it is they who are keeping an eye on our laboratories”. And the institute’s policy is precisely to promote constant interchange with research centers the world over. Since 1986, the laboratory has been promoting meetings between chemists here and abroad for a week of talks and debates with Brazilian students. The Brazilian Meeting on Organic Synthesis (BMOS), for example, is already established as an international event and 300 people on average take part every year. “Generally these meetings culminate in a series of joint works, and, frequently our students spend at least a year studying in countries like the United States, Canada and Britain”, he says.
Besides the relationships with centers abroad, the institute adds its work with the local community to its academic function. Created in 1986, the IQ-USP’s Analytical Center provides services to universities and the manufacturing industry. Since 1997, it has undertaken an average of 10,000 analyses a year. The IQ also takes part in a training program for Micro and Small Businesses in São Paulo, under an agreement with Sebrae and Fiesp.
Comasseto began developing methods for synthesizing tellurium compounds in the 80s, leading to various vinylic tellurites. Nowadays, he devotes himself also to introducing a new line of work into the IQ, which, among other objectives, aims to lower the large volume of toxic by-products generated in the chemical reactions.
“It is estimated that for a kilogram of medication synthesized, a hundred kilos of pollutants are produced”, he states. That is why one of chemistry’s great challenges is to replace highly polluting traditional methods with “clean” methods using less solvent; replacing organic solvents with water, using smaller quantities of reagents that are biodegradable.
The researcher suggests developing methods of organic synthesis based on enzymes produced by microorganisms, following a natural principle, “Cane or grape sugar, for example, undergo a fermentation process caused by microorganisms, to be turned into ethanol. We can imitate this natural method in the laboratory to synthesize other substances without producing pollutants. By doing this, we intend to teach new generations of chemists to work ecologically so as to eliminate pollutants from the production process”.
The ill smelling
Discovered in 1782 by the Austrian mineralogist Franz Joseph Muller von Reichstein, tellurium (Te) was only recognized and named 16 years later by the German Martin Heinrich Klaproth (1743-1817). In 1817, the Swede Jöns Jakob Berzelius (1779-1848) discovered an element with similar properties: selenium (Se). Semi-metals in the sulfur group, both are rare elements, found chiefly as byproducts of copper mining.
The curious thing about the history of these elements is that for a long time they were rejected because of the bad smell. This also helped encourage mistaken notions of the effect that both would have on the human organism (only later would it be discovered that some of their compounds can be practically odorless). For several decades, they were considered highly toxic and with no biochemical use, so that their use was practically confined to the materials industry.
Thus, as selenium is a good conductor of electricity in the presence of light, it has been used for along time in photoelectric cells (converting light into electricity), was used in the image transmitting experiments that led to the creation of television, also took part in photocopying, glass coloring and the restoration of monuments and arched roofs covered by green tarnish produced by impurities in the iron.
Tellurium is used in the manufacture of transformers and thermoelectric apparatuses, the production of anti-explosive additives for gasoline, vulcanization, and glass coloring.
The chemistry of selenium and tellurium has been a tradition at USP’s Chemistry Institute since it was founded in 1933. The institute’s founder, Heinrich Rheinboldt (1891- 1955), introduced it because it was a little known field at that time. In the 30s and 40s, when few laboratories spent time on these elements, USP’s IQ established itself as the first center of international excellence in chemistry in Brazil. It centralized the development of the chemistry of selenium and tellurium.
It was only in the 60s that two elements aroused the interest of international laboratories, encouraged by the big copper mining companies, which accumulated mountains of selenium and tellurium at their mines. The setting up of the International Association for the Development of Selenium and Tellurium Chemistry, sponsored by the mining companies, helped, over the next twenty years, establish the organic chemistry of selenium as one of the most active fields in organic synthesis.
So, contrary to what one might think, it was discovered that selenium compounds are essential micronutrients: their deficiency leads to muscular and cardiac dysfunctions; it is essential for the proper functioning of the immunological system; and it protects the cellular membranes against oxidative changes associated with cancer and premature aging.
More recent studies have shown that ingesting selenium in above the minimum recommended quantities – 0.1 milligrams per gram of food consumed – lowers the incidence of rectal colon, lung, and prostate cancer. And, it has been discovered that it plays an essential part in fertility; its absence in the diet of rats caused lesions to the spermatozoids, while high doses of selenium considerably increased their activity. Nowadays, there are various food supplements based on selenium and scientists are trying to discover the richest natural sources of this element.
The ill smelling element has effectively been rehabilitated. As to its relation tellurium, its successful career seems to be only at the threshold, according to Comasseto, “In the case of tellurium, this type of study is less well-advanced, but there is some evidence to suggest that it may help in controlling cholesterol levels”.
João Valdir Comasseto, 50 years old, has been a professor at the USP’s Chemistry Institute since 1992. He graduated in chemistry (1972) from the Federal University of Santa Maria (RS). He did his master’s degree in Organic Chemistry and his doctorate in Selenium Chemistry at UPS’ IQ (1973-1977) and post-doctorate (1980) At the University of Cologne (Germany) and was appointed a member of the teaching staff (1984) of USP.
Selenium and Tellurium Reagents in Organic Synthesis (nº 00/01011-6); Modality Projeto Temático; Coordinator João Vladir Comasseto; Investment: R$ 326,896.69 plus US$ 353,142.25