Brazilian biodiversity could drive synthesis of bioactive molecules

An international seminar at FAPESP discussed Brazil's potential for synthesis of molecules isolated from natural sources.

By Diego Freire  |  Agência FAPESP – The largest open-air laboratory in the world allows researchers in the field of organic chemistry to assess the potential molecular variety available from Brazil’s biodiversity for the synthesis of bioactive molecules isolated from natural sources. That potential and the latest advances in the investigation of organic synthesis were discussed by scientists at an international seminar entitled “Recent Advances on the Synthesis of Bioactive Natural Metabolites” and held at FAPESP on November 12.

“Brazil’s fantastic biodiversity represents the most fascinating and perfect library of chemical structures there is. It’s the result of the huge diversity of organisms that biosynthesize substances with unusual structures. Nature doesn’t produce this chemical arsenal to cure cancer or diabetes. It does so to maintain vital processes and for cell regulation, adaptation and defense, all of which it has developed throughout the evolution of life. But the molecular structures of natural products can be imitated, copied and even improved by humans, for use in their own benefit,” said Vanderlan da Silva Bolzani, a Full Professor at the Araraquara Chemistry Institute of São Paulo State University (UNESP) and a member of the steering committee of FAPESP’s Research Program on Biodiversity Characterization, Conservation, Restoration and Sustainable Use (BIOTA).

Bolzani opened the seminar by recalling that this year’s Nobel Prize in Physiology or Medicine was awarded to Chinese pharmaceutical chemist Tu Youyou, whose research on natural products and traditional medicine led to the isolation of artemisinin, the main antimalarial drug, from Artemisia annua, or sweet wormwood, and to Irish-born parasitologist William Campbell and Japanese microbiologist Satoshi Omura, whose work with a soil bacterium called Streptomyces avermitilis led to the isolation of avermectin, the basis for a new class of drugs that treat infections caused by parasitic roundworms, such as river blindness (onchocerciasis). All three are specialists in research on neglected diseases.

“Artemisinin and its derivatives are still the most effective medications for treating malaria today,” Bolzani said. “These examples point to the importance of natural products to drug discovery. I believe the award will serve as an incentive to the new generations of researchers who are prospecting for new molecular models from natural sources. Brazil has a critical mass of synthetic researchers with the expertise to build complex substances, although there are still too few for optimal leverage of our rich biodiversity.”

For Roberto Gomes de Souza Berlinck, a Full Professor at the University of São Paulo’s São Carlos Chemistry Institute (IQSC-USP) and also a member of BIOTA’s steering committee, development of this knowledge area is strategic for Brazil.

“We have to develop the organic synthesis field in Brazil in different ways, exploring new strategies for the synthesis of organic molecules or molecules of biological interest for various purposes, such as agrochemicals, biological modulators and new drugs,” said Berlinck, who chaired the seminar.

Advances

Luiz Carlos Dias, a Full Professor at the University of Campinas’s Chemistry Institute (IQ-UNICAMP) and a researcher at the Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), one of the Research, Innovation and Dissemination Centers (RIDCs) supported by FAPESP, addressed the seminar on advances in the chemical synthesis of a range of molecules isolated from natural sources and the methods used in the process.

“Each of these molecules has outstanding bioactive potential as an anti-inflammatory, antitumor or antibiotic agent. They’re isolated in very small amounts. To obtain a sufficiently large amount of a natural product for activity testing, we would have to sacrifice more of the source – hence our work in the lab, where we produce larger amounts of these molecules. That’s the importance of organic synthesis,” Dias said.

Laboratory-synthesized molecules are identical to those isolated from natural sources, but they are produced in amounts appropriate to their use in biological studies. “We would need many kilos of plant leaves or marine sponges, for example, to isolate a few milligrams. That’s unacceptable from an environmental standpoint,” Dias said.

Among the molecules synthesized by Dias and his team is goniotrionin, isolated from the leaves of Goniothalamus giganteus, a tall tree belonging to the family Annonaceae and found in tropical parts of the Asia-Pacific region.

“This molecule’s antitumor activity for breast cancer is more powerful than several antitumor agents used in trials, but it’s highly complex from the structural standpoint, so we tried to simplify it in order to obtain more affordable molecules more quickly and move on to activity testing,” Dias said.

In addition to total synthesis of bioactive natural products, Dias is working with the Drugs for Neglected Diseases Initiative (DNDi) and the Medicines for Malaria Venture (MMV). These are consortia or networks coordinated by international not-for-profit research and development organizations that fund the most expensive stages of new drug development – the discovery of molecules, preclinical trials and toxicity testing, all of which are typically performed by researchers in universities and research institutions in Brazil and other countries around the world.

In addition to identifying molecules with significant potential against Trypanosoma cruzi, the parasite that causes Chagas disease, Brazilian researchers in these networks have synthesized two especially promising antimalarial substances, one of which is active against eight drug-resistant strains of the parasite (read more at http://agencia.fapesp.br/21221).

In addition to Dias, the speakers at the seminar who presented research results in organic synthesis and related areas included Carlos Roque Correia, also from IQ-UNICAMP, Luiz Fernando da Silva Junior and Antonio Carlos Bender Burtoloso from the University of São Paulo’s Chemical Institute (IQ-USP), James Morken from Boston College’s Merkert Chemistry Center in the United States, and Daniel Romo from Baylor University, in Waco, Texas, also in the US.

More information at www.fapesp.br/eventos/metabolites.